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WO2016065177A1 - Procede de traitement de la depression et d'autres troubles lies au stress - Google Patents

Procede de traitement de la depression et d'autres troubles lies au stress Download PDF

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Publication number
WO2016065177A1
WO2016065177A1 PCT/US2015/056967 US2015056967W WO2016065177A1 WO 2016065177 A1 WO2016065177 A1 WO 2016065177A1 US 2015056967 W US2015056967 W US 2015056967W WO 2016065177 A1 WO2016065177 A1 WO 2016065177A1
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WIPO (PCT)
Prior art keywords
disorder
crf
crfr1
nbi
antagonist
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PCT/US2015/056967
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English (en)
Inventor
Alexis R. HOWERTON
Tracy L. Bale
Alison ROLAND
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University of Pennsylvania Penn
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University of Pennsylvania Penn
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

Definitions

  • Corticotropin-releasing factor represents an important link between stress and mood regulation.
  • CRFr1 small molecule antagonists toward this end.
  • none of the CRFr1 antagonists brought to clinical trial over the past decade have successfully completed a Phase III trial (Koob, et al., Neuropsychopharmacology 2012, 37:308–309).
  • the present invention includes a method of treating a disorder in a male subject, comprising administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist, or a salt or solvate thereof, wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF) and the disorder is selected from the group consisting of an anxiety-related disorder, a mood disorder, a post-traumatic stress disorder, immune suppression, drug or alcohol withdrawal symptoms, a sleep disorder induced by stress, fibromyalgia, dysthemia, a bipolar disorder, cyclothymia, fatigue syndrome, stress-induced irritable bowel syndrome, and stress-induced headache.
  • CRF corticotropin-releasing factor
  • the disorder is selected from the group consisting of an anxiety-related disorder, a mood disorder, a bipolar disorder, and a post-traumatic stress disorder.
  • the anxiety-related disorder is selected from the group consisting of an anxiety state, a generalized anxiety disorder, a social anxiety disorder, an anxiety with co-morbid depressive illness, a panic disorder, an obsessive-compulsive disorder, a phobic disorder, a post-traumatic stress disorder, and an atypical anxiety disorder.
  • the mood disorder is depression selected from the group consisting of major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression.
  • the CRFr1 antagonist is selected from the group consisting of LY2371712, NBI-35965, NBI-30775, Antalarmin, CP-316,311, CRA 5626, CP- 154,526, Emicerfont, ONO-2333Ms, Pexacerfont, SSR125543, NBI-34101 , DMP-696, DMP-904, DMP-695, SC-241, BMS-561388, R121919, NBI-30545, CP-376,396, NBI- 27914, NBI-34101, PF-572778, GSK561579, and GSK586529.
  • the present invention includes a method of treating a disorder in a male subject, comprising administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist, or a salt or solvate thereof, and a second therapeutic agent, or a salt or solvate thereof, wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF) and the second therapeutic agent is selected from the group consisting of sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, trazodone, desvenlafaxine , duloxetine, venlafaxine, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, nefazodone, trazodone, isocarboxazid, phenelzine, selegiline, trany
  • the male subject is a male human.
  • the CRFr1 antagonist is simultaneously administered with the second therapeutic agent.
  • the CRFr1 antagonist is administered 1-6 hours before the administration of the second therapeutic agent.
  • the CRFr1 antagonist is administered 1 -6 hours after the administration of the second therapeutic agent.
  • FIG. 1 illustrates the effects of small molecule antagonist NBI 35965 and or corticotropin-releasing factor (CRF) on dorsal raphe infusion of the corticotropin-releasing factor receptor-1 (CRFr1 ).
  • Panel A illustrates the time course of corticosterone response to a 15-min restraint (indicated by shaded region) in males.
  • Panel B illustrates the area under the curve analysis demonstrating a significant reduction of corticosterone output by NBI 35965 in males.
  • Panel C illustrates the time course of corticosterone response to a 15-min restraint (indicated by shaded region) in females.
  • Panel D illustrates the area under the curve analysis demonstrating not a significant reduction of corticosterone output by NBI 35965 in females.
  • Panel E illustrates corticosterone response to infusion of 50 ng CRF in males.
  • Panel F illustrates the area under the curve analysis demonstrating that CRF enhancement of corticosterone release was specific to males.
  • Panel G illustrates the corticosterone response to infusion of 50 ng CRF in females.
  • FIG. 2 illustrates the finding that males and females show divergent behavioral responses to CRFr1 antagonism or CRF infusion into the dorsal raphe.
  • Panel A illustrates the effects of CRFr-1 antagonist NBI 35965 on total immobile time.
  • Panel B illustrates latency to first bout of immobility in the tail suspension test (TST). Males showed a greater latency to immobility.
  • Panel C illustrates the finding that CRFr1 antagonism had no effect in the light-dark box (LD) on measures of total time spent in the light compartment.
  • Panel D illustrates the finding that CRFr1 antagonists had no effect in latency to first exit from the light compartment.
  • Panel E illustrates the finding that the 50-ng CRF infusion reduced immobile time.
  • Panel F illustrates the finding that the 50-ng CRF infusion increased latency to immobility in males in the TST.
  • Panel G illustrates the finding that the 50-ng CRF infusion increased total light time in males in the LD.
  • Panel H illustrates the finding that the 50-ng CRF infusion increased latency to exit the light in males in the LD.
  • FIG. 3 illustrates the finding that a 50-ng corticotropin-releasing factor (CRF) infusion elicited differential patterns of neuronal activation in males and females across dorsal raphe (DR) subregions.
  • Panels A and B illustrate the finding that cFos induction 90 min after CRF infusion is enhanced in males shown by representative dorsomedial (dmDR) sections.
  • Panels C and D illustrate the finding that cFos induction 90 min after CRF infusion is reduced in females shown by representative dorsomedial (dmDR) sections.
  • Panel E illustrates the finding that Fos-positive cell counts from DR subregions demonstrate increased counts in males but reduced counts in females, particularly in dmDR and rostral lateral wing (rLW) and caudal lateral wing (cLW) subregions. Values represent the difference in mean number of Fos-positive cells in sections from mice administered CRF or artificial cerebrospinal fluid (ASCF). Data represent the difference in averages from 7–9 mice/group. *p ⁇ 0.05.
  • FIG. 4 illustrates the finding that CRFr1 is expressed on different cell populations
  • Panel B illustrates regional but no sex differences in number of green fluorescent protein immunoreactive (GFP-ir) cells throughout subregions of the DR.
  • Panel C illustrates brain atlas diagrams depict the region viewed in the
  • Panels C illustrates brain atlas diagrams depicting the region viewed in the representative images of the dmDR.
  • Panels E and G illustrate representative, split channel confocal images from the rLW.
  • Panels I and K illustrate representative, split channel confocal images from the dmDR.
  • Panels F and G illustrate sections dual-labeled with anti-parvalbumin (PV) to identify the phenotype of GFP cells in the DR.
  • Panels J and K illustrate sections dual-labeled with anti-TPH to identify the phenotype of GFP cells in the DR.
  • Arrows denote location of GFP-ir cells enlarged to illustrate co-localization (single arrow, GFP only; double arrow, co-localized).
  • Panel M illustrates probability that a given GFP-ir cell colocalizes with PV.
  • Panel N illustrates probability that a given GFP-ir cell colocalizes with TPH.
  • Females presented with an overall reduction in the probability that a given GFP-ir cell colocalizes with PV and reduced likelihood that GFP-ir cells within the rDR colocalize with TPH.
  • Data are presented as an average probability ⁇ SEM. *p ⁇ 0.05 in comparison with male.
  • FIG. 5 illustrates the finding that males and females exhibit differences in baseline characteristics as well as divergent responses to bath applied corticotropin-releasing factor (CRF).
  • Panel A illustrates representative inhibitory postsynaptic current trace.
  • Panel B illustrates scaled inhibitory postsynaptic currents averaged from a single male.
  • Panel C illustrates scaled inhibitory postsynaptic currents averaged from a single female.
  • Insets B’ and C’ illustrate sex difference in effect of CRF on rise time.
  • Panel D illustrates the finding that CRF rise time increases in males but decreases in females.
  • Panel E illustrates the finding that CRF half-width increases in males but decreases in females.
  • Panel F illustrates the finding that CRF decay time increases in males but decreases in females.
  • the present invention relates to the unexpected discovery of gender or sex differences in behavioral and physiological effects of a CRFr1 antagonist and CRF in the DR.
  • the invention includes a method of treating a disorder in a male subject, comprising administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist or a salt or solvate thereof, wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF).
  • a CRFr1 antagonist or a salt or solvate thereof wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF).
  • the invention includes a method of treating a disorder in a male subject, comprising administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist or a salt or solvate thereof, together with a second therapeutic agent or a salt or solvate thereof.
  • the articles“a” and“an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • “an element” means one element or more than one element.
  • the term“about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, or ⁇ 0.l% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • the term“CNS” refers to central nervous system.
  • the instructional material may be part of a kit useful for effecting alleviating or treating the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit may, for example, be affixed to a container that contains the compounds and/or compositions of the invention or be shipped together with a container that contains the compounds and/or compositions.
  • the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound and/or composition
  • the instructional material is for use of a kit; instructions for use of the compound and/or composition; or instructions for use of a formulation of the compound and/or composition.
  • the term“patient” or“individual” or“subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, individual or subject is human.
  • the terms“pharmaceutically effective amount” and“effective amount” and“therapeutically effective amount” refer interchangeably to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine
  • the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term“pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid;
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • the language“pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
  • ethanesulfonic benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric, salicylic, galactaric and galacturonic acid.
  • pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • composition refers to a mixture of at least one compound useful within the invention with a
  • the pharmaceutical composition facilitates
  • administering includes, but not limited to, intravenous, oral, aerosol, inhalational, rectal, vaginal, transdermal, intranasal, buccal, sublingual, parenteral, intrathecal, intragastrical, ophthalmic, pulmonary and topical administration.
  • the term“prevent” or“prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • solvent refers to a complex with one or more solvent molecules, which may comprise water, methanol, ethanol, 1-propanol, 2-propanol, DMSO, DMF, ethyl ether, acetone, and/or MTBE, and the like.
  • the term“substrate” as relating to a drug efflux transporter refers to a compound (such as a small molecule compound, peptide or protein) that is transported across an extra- or intracellular membrane by the drug efflux transporter.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound useful within the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder, a symptom of a disease or disorder or the potential to develop a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, the symptoms of the disease or disorder, or the potential to develop the disease or disorder.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • the term“sertraline” refers to (1S,4S)-4-(3,4-dichlorophenyl)- N-methyl-1 ,2,3,4-tetrahydronaphthalen-1-amine, or a salt or solvate thereof.
  • fluoxetine refers to ( ⁇ )-N-methyl-3-phenyl-3- [( ⁇ , ⁇ , ⁇ -trifluoro-p-tolyl)oxy]propylamine, or a salt or solvate thereof.
  • citalopram refers to (RS)-1-[3-(dimethylamino)- propyl]-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-5-carbonitrile, or a salt or solvate thereof.
  • escitalopram refers to (S)-1-[3-(dimethylamino)- propyl]-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-5-carbonitrile, or a salt or solvate thereof.
  • the term“paroxetine” refers to (3S,4R)-3-[(2H-1,3- benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine, or a salt or solvate thereof.
  • fluvoxamine refers to 2- ⁇ [(E)- ⁇ 5-methoxy-1-[4- (trifluoromethyl)phenyl]pentylidene ⁇ amino]oxy ⁇ ethanamine, or a salt or solvate thereof.
  • trazodone refers to 2- ⁇ 3-[4-(3- chlorophenyl)piperazin-1-yl]propyl ⁇ [1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, or a salt or solvate thereof.
  • the term“desvenlafaxine” refers to 4-[2-dimethylamino-1-(1- hydroxycyclohexyl) ethyl]phenol, or a salt or solvate thereof.
  • duloxetine refers to (+)-(S)-N-methyl-3- (naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine, or a salt or solvate thereof.
  • vendor refers to (RS)-1-[2-dimethylamino-1- (4-methoxyphenyl)-ethyl]cyclohexanol, or a salt or solvate thereof.
  • amitriptyline refers to 3-(10,11-dihydro-5H- dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine, or a salt or solvate thereof.
  • amoxapine refers to 2-chloro-11-(piperazin-1- yl)dibenzo[b,f][1 ,4]oxazepine, or a salt or solvate thereof.
  • clomipramine refers to 3-(3-chloro-10,11-dihydro- 5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine, or a salt or solvate thereof.
  • the term“desipramine” refers to 3-(10,11-dihydro-5H- dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine, or a salt or solvate thereof.
  • doxepin refers to (E/Z)-3-(dibenzo[b,e]oxepin- 11(6H)-ylidene)-N,N-dimethylpropan-1-amine, or a salt or solvate thereof.
  • imipramine refers to 3-(10,11-dihydro-5H- dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1 -amine, or a salt or solvate thereof.
  • the term“nortriptyline” refers to 3-(10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1 -propanamine, or a salt or solvate thereof.
  • protriptyline refers to 3-(5H- dibenzo[a,d][7]annulen-5-yl)-N-methylpropan-1-amine, or a salt or solvate thereof.
  • trimipramine refers to ( ⁇ )-3-(10,11 -dihydro-5H- dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine, or a salt or solvate thereof.
  • maprotiline refers to N-Methyl-9,10- ethanoanthracene-9(10H)-propanamine, or a salt or solvate thereof.
  • nefazodone refers to 1 -(3-[4-(3-chlorophenyl)- piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1H-1 ,2,4-triazol-5(4H)-one, or a salt or solvate thereof.
  • trazodone refers to 2- ⁇ 3-[4-(3- chlorophenyl)piperazin-1-yl]propyl ⁇ [1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, or a salt or solvate thereof.
  • isocarboxazid refers to N′-benzyl-5- methylisoxazole-3-carbohydrazide, or a salt or solvate thereof.
  • phenelzine refers to 2-phenylethylhydrazine, or a salt or solvate thereof.
  • the term“selegiline” refers to (R)-N-methyl-N-(1- phenylpropan-2-yl)prop-1-yn-3-amine, or a salt or solvate thereof.
  • tranylcypromine refers to ( ⁇ )-trans-2- phenylcyclopropan-1-amine or 1 R*,2S*)-2-phenylcyclopropan-1-amine, or a salt or solvate thereof.
  • mirtazapine refers to ( ⁇ )-2-methyl-1,2,3,4,10,14b- hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine, or a salt or solvate thereof.
  • quetiapine refers to 2-(2-(4-dibenzo[b,f][1,4]- thiazepine- 11-yl- 1 -piperazinyl)ethoxy)ethanol, or a salt or solvate thereof.
  • buspirone refers to 8-[4-(4-pyrimidin-2- ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione, or a salt or solvate thereof.
  • bupropion refers to ( ⁇ )-2-(tert-Butylamino)-1-(3- chlorophenyl)propan-1-one, or a salt or solvate thereof.
  • NBI-30775 or“R-121919” refers to 3-[6- (dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin- 7-amine, or a salt or solvate thereof.
  • Alarmin refers to N-butyl-N-ethyl-2,5,6- trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine, or a salt or solvate thereof.
  • the term“ONO-2333Ms” refers to 10-(2-chloro-4- methoxyphenyl)-11 -methyl-N-(pentan-3-yl)-1,8,12-triazatricyclo[7.3.0.0 3,7 ]dodeca-2,7,9,11- tetraen-2-amine, or a salt or solvate thereof.
  • the term“Pexacerfont” refers to 8-(6-methoxy-2- methylpyridin-3-yl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo[1,5-a]-1,3,5-triazin-4- amine, or a salt or solvate thereof.
  • SSR125543 refers to (S)-4-(2-chloro-4-methoxy-5- methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2- ynyl)thiazol-2-amine, or a salt or solvate thereof.
  • the present invention includes a method of treating a disorder in a male subject, comprising administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist, or a salt or solvate thereof, wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF).
  • a CRFr1 antagonist or a salt or solvate thereof, wherein the disorder manifests hypersecretion of corticotropin-releasing factor (CRF).
  • the disorder manifests hypersecretion of CRF.
  • the disorder is selected from the group consisting of anxiety-related disorders, mood disorders, post-traumatic stress disorder, immune suppression, drug or alcohol withdrawal symptoms, sleep disorders induced by stress, fibromyalgia, dysthemia, bipolar disorders, cyclothymia, fatigue syndrome, stress-induced irritable bowel syndrome, and stress-induced headache.
  • the disorder is selected from the group consisting of anxiety-related disorders, mood disorders, bipolar disorders, and post-traumatic stress disorder.
  • the anxiety-related disorder is selected from the group consisting of anxiety states, generalized anxiety disorder, social anxiety disorder, anxiety with co-morbid depressive illness, panic disorder, obsessive-compulsive disorder, phobic disorders, post-traumatic stress disorder, and atypical anxiety disorders.
  • the mood disorder is selected from the group consisting of depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; and cyclothymia.
  • the CRFr1 antagonist for the invention is selected from the group consisting of LY2371712, NBI-35965, NBI-30775 (Neurocrine), Antalarmin, CP-316,311 (Pfizer), CRA 5626, CP-154,526 (Pfizer), Emicerfont (Glaxo), ONO-2333Ms (Ono Pharmaceuticals), Pexacerfont (Bristol-Myers-Squibb), SSR125543 (Sanofi-Aentis), NBI-34101 (Neurocrine), DMP-696, DMP-904, DMP-695, SC-241, BMS-561388, R121919, NBI-30545, CP-376,396, NBI-27914, NBI-34101, PF-572778, GSK561579 and GSK586529.
  • the present invention includes a method of treating a disorder in a male subject.
  • the method comprises administering to the male subject a pharmaceutically effective amount of a CRFr1 antagonist or a salt or solvate thereof, and a second therapeutic agent or a salt or solvate.
  • the second therapeutic agent is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, tetracyclic antidepressants, dopamine reuptake blocker, 5-HT2 receptor antagonists, 5-HT3 receptor antagonists, monoamine oxidase inhibitors, noradrenergic antagonist, and a mixture thereof.
  • the second therapeutic agent is selected from the group consisting of sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, trazodone, desvenlafaxine , duloxetine, venlafaxine, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, nefazodone, trazodone, isocarboxazid, phenelzine, selegiline, tranylcypromine, mirtazapine, quetiapine, buspirone, bupropion, and a mixture thereof.
  • the CRFr1 antagonist is administered simultaneously with the second therapeutic agent. In another embodiment, the CRFr1 antagonist is formulated with the second therapeutic agent, then the formulated product is administered to a male subject in need thereof. In yet another embodiment, the CRFr1 antagonist is administered 1-6 hours before the administration of the second therapeutic agent. In yet another embodiment, the CRFr1 antagonist is administered 1 -6 hours after the administration of the second therapeutic agent.
  • the invention includes a pharmaceutical composition comprising a CRFr1 antagonist.
  • the pharmaceutical composition further comprises a second therapeutic agent.
  • the male subject treated by the method of the invention is a male human.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the patient either prior to, around the time, or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions useful within the present invention may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • an effective dose range for a therapeutic compound of the invention ranges from about 1 to about 5,000 mg/kg of body weight/day. In other embodiments, an effective dose range for a therapeutic compound of the invention ranges from about 100 to about 1,000 mg/kg of body weight/day. In yet other embodiments, an effective dose range for a therapeutic compound of the invention ranges from about 10 to about 50 mg/kg of body weight/day. In yet other embodiments, an effective dose range for a therapeutic compound of the invention ranges from about 1 to about 50 mg/kg of body weight/day. In yet other embodiments, an effective dose range for a therapeutic compound of the invention ranges from about 1 to about 10 mg/kg of body weight/day.
  • an effective dose range for a therapeutic compound of the invention is about 2.5 mg/kg of body weight/day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of
  • compositions useful within the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound useful within the invention and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • it may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • compositions useful within the invention are administered to the patient in dosages that range from one to five times per day or more.
  • the compositions useful within the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks.
  • the frequency of administration of the various combination compositions useful within the invention will vary from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors.
  • the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physical taking all other factors about the patient into account.
  • Compounds for administration may be in the range of from about 1 ⁇ g to about 10,000 mg, about 20 ⁇ g to about 9,500 mg, about 40 ⁇ g to about 9,000 mg, about 75 ⁇ g to about 8,500 mg, about 150 ⁇ g to about 7,500 mg, about 200 ⁇ g to about 7,000 mg, about 3050 ⁇ g to about 6,000 mg, about 500 ⁇ g to about 5,000 mg, about 750 ⁇ g to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound is from about 1 mg and about 2,500 mg.
  • compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, intranasal drug delivery, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other cognition improving agents.
  • the term“container” includes any receptacle for holding the pharmaceutical composition.
  • the container is the packaging that contains the pharmaceutical composition.
  • the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
  • packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a patient.
  • compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, intranasal drug delivery, or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein. Oral Administration
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or
  • the tablets may be coated using suitable methods and coating materials such as OPADRYTM film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRYTM OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorb
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a“granulation.”
  • solvent-using“wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents.
  • the low melting solids when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.
  • the liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together.
  • the resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.
  • Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.
  • U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties.
  • the granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture.
  • certain flow improving additives such as sodium bicarbonate
  • the present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of a disease or disorder.
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • the compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Solutions, suspensions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos.2003/0147952, 2003/0104062, 2003/0104053, 2003/0044466, 2003/0039688, and 2002/0051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos.
  • the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use the method of the invention may be
  • microparticles for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound will depend on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1 ,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the compounds for use in the method of the invention may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, are within the scope of the present application.
  • mice A total of 268 adult male and female littermate mice were used for all experiments. Mice were maintained under a 12-hour light/dark cycle with ad libitum access to food and water. For behavioral experiments and electrophysiological studies, C57Bl/ 6:129S/J F1 hybrid mice were obtained from the Jackson Laboratory (Bar Harbor, Maine) or bred in house. For CRFr1 colocalization studies, mice with fluorescent-labeled CRFr1 containing neurons were generated as previously described (Justice, et al., J Comp Neurol 2008, 511 :479–496). Mice received implantation between ages 7 and 8 weeks, were allowed to recover for at least 1 week, and were behaviorally tested in age-matched cohorts at 8–20 weeks of age.
  • mice were singly housed after cannulation to prevent disturbance of the cannula.
  • slices were obtained from mice at 9–13 weeks of age. Mice were individually housed for 7–12 days before recording, to mimic the housing conditions of behavioral studies. All studies were conducted in accordance with experimental protocols approved by the University of Pennsylvania Institutional Animal Use and Care Committee and, where applicable, by the Institutional Animal Care and Use Committee of the Weizmann Institute of Science. Stereotaxic Surgery and Placement Verification
  • mice were anesthetized with isofluorane and implanted with a 26-gauge guide cannula (Plastics One, Roanoke, Virginia) with a stereotaxic instrument (Kopf, Tujunga, California) positioned 1 mm from the DR with the following coordinates (from brain surface): AP 4.36 mm, ML 1.5 mm, DV 2.0 mm, angled 26 degrees.
  • mice were transcardially perfused, and cannula placement was verified on the basis of the termination point of the injector as estimated from the location of scar tissue in 50- ⁇ m sections through the DR. Mice with incorrect cannula placement were dropped from the statistical analysis. Group sizes reported represent the final group size after subjects with incorrect placements were omitted.
  • mice in the NBI 35965 study were restrained in a 50-mL conical tube with a 5-mm air hole. Corticosterone was measured as described previously (Gerber, et al., Endocrinology 2012, 153:4830–4837). Behavioral Testing
  • mice The tail suspension test (TST) and light-dark box (LD) were performed on separate cohorts of mice 30 min after drug or ACSF infusion. Methods were similar to those described previously (McEuen, et al., J Neurosci 2008, 28:8169–8177; Bale, et al., Nat Genet 2000, 24:410–414).
  • TST tail suspension test
  • LD light-dark box
  • Dual immunofluorescence was performed to detect enhanced green fluorescent protein (GFP) and TPH or parvalbumin in DR sections from paraformaldehyde- fixed male and female CRFr1- GFP mice.
  • the 5-HT output from the DR has modulatory activity on the hypothalamic- pituitary-adrenal (HPA) axis.
  • HPA hypothalamic- pituitary-adrenal
  • corticosterone response to restraint stress was assessed (FIG. 1).
  • the effect of CRF infusion on the HPA axis was tested next.
  • CRFr1-GFP transgenic mouse was used in which GFP is transcribed under the control of the CRFr1 promoter to identify CRFr1 positive neurons in the DR (FIG. 4, Panels B-N). Sections throughout the DR from these mice were dual labeled for either GFP and parvalbumin to identify putative GABAergic neurons expressing CRFr1 or GFP and TPH to identify serotonergic neurons expressing CRFr1.
  • mice Male and female mice received an infusion of the CRFrl small molecule antagonist, NBI 35965, or one of two doses of CRF directly into the DR and were evaluated for changes in physiological and behavioral stress responsiveness.
  • the NBI 35965 in the DR significantly blunted corticosterone levels in response to a restraint stress only in males.
  • the 5-HT system is a known activator of the HPA axis, where selective SSRIs and 5-HT agonists increase corticosterone production during and independent of stress.
  • PVN paraventricular nucleus
  • this reporter mouse provided an excellent tool to identify CRFr1 -positive neurons in the DR. Sex differences was quantified in co-expression of GFP with TPH, a marker of 5-HTergic neurons, or with parvalbumin, a marker of a subset of GABAergic neurons. Parvalbumin was used to mark GABAergic neurons, because 87% of GAD67-ir neurons in the DR co-express parvalbumin. These neurons might display some functional differences compared with the broader population of GABAergic neurons but were selected on the basis of reliable somal immunoreactivity for co- expression analysis with CRFr1.
  • CRF might be activating a population of parvalbumin-negative GABA neurons in the female DR.
  • IPSC half-width in response to CRF exhibited by females also supports this sex difference in the number of GABAergic release sites onto 5-HT neurons.

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Abstract

La présente invention concerne un procédé de traitement d'un trouble chez un sujet mâle, comprenant l'administration au sujet mâle d'une quantité pharmaceutiquement efficace d'un antagoniste du récepteur de type 1 de la corticolibérine (CRFR1), le trouble se manifestant par une hypersécrétion de la corticolibérine (CRF). Le procédé comprenant en outre l'administration au sujet mâle d'une quantité pharmaceutiquement efficace d'un second agent thérapeutique.
PCT/US2015/056967 2014-10-22 2015-10-22 Procede de traitement de la depression et d'autres troubles lies au stress Ceased WO2016065177A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
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CN113518616A (zh) * 2018-12-07 2021-10-19 纽罗克里生物科学有限公司 用于治疗先天性肾上腺皮质增生症的crf1受体拮抗剂、其药物制剂和固体形式
JP2022000473A (ja) * 2018-12-07 2022-01-04 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト、その医薬製剤および固体形態
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JP2023531164A (ja) * 2020-06-10 2023-07-21 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト
US12383536B2 (en) 2019-09-27 2025-08-12 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods of use

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US11311544B2 (en) 2014-01-21 2022-04-26 Neurocrine Biosciences, Inc. Treatment of congenital adrenal hyperplasia
US11730739B2 (en) 2014-01-21 2023-08-22 Neurocrine Biosciences, Inc. Treatment of congenital adrenal hyperplasia
CN113518616A (zh) * 2018-12-07 2021-10-19 纽罗克里生物科学有限公司 用于治疗先天性肾上腺皮质增生症的crf1受体拮抗剂、其药物制剂和固体形式
JP2022000473A (ja) * 2018-12-07 2022-01-04 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト、その医薬製剤および固体形態
JP2022508317A (ja) * 2018-12-07 2022-01-19 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト、その医薬製剤および固体形態
JP7238130B2 (ja) 2018-12-07 2023-03-13 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト、その医薬製剤および固体形態
JP7532328B2 (ja) 2018-12-07 2024-08-13 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト、その医薬製剤および固体形態
US12128033B2 (en) 2018-12-07 2024-10-29 Neurocrine Biosciences, Inc. Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine
US12383536B2 (en) 2019-09-27 2025-08-12 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods of use
JP2023531164A (ja) * 2020-06-10 2023-07-21 ニューロクライン バイオサイエンシーズ，インコーポレイテッド 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト

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