WO2004014854A1 - 3-imino-2-indolones pour traiter la depression et/ou l'anxiete - Google Patents

3-imino-2-indolones pour traiter la depression et/ou l'anxiete Download PDF

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Publication number
WO2004014854A1
WO2004014854A1 PCT/US2003/024867 US0324867W WO2004014854A1 WO 2004014854 A1 WO2004014854 A1 WO 2004014854A1 US 0324867 W US0324867 W US 0324867W WO 2004014854 A1 WO2004014854 A1 WO 2004014854A1
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compound
branched
alkyl
straight chained
aryl
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PCT/US2003/024867
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English (en)
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Michael Konkel
John M. Wetzel
Jamie Talisman
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Synaptic Pharmaceutical Corporation
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Priority to AU2003259689A priority Critical patent/AU2003259689A1/en
Publication of WO2004014854A1 publication Critical patent/WO2004014854A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone

Definitions

  • Depression is the most common of mental disorders and yet is often underdiagnosed and undertreated, inflicting substantial morbidity and psychosocial impairment on its sufferers. Depression is mainly characterized by sadness, flatness, loss of feeling, anhedonia (lack of pleasure) , tearfulness, agitation or retardation, thoughts of guilt and worthlessness; in severe cases, suicide, hallucinations and delusions.
  • Depression can be mainly categorized into bipolar disorders, identifying wide swings of mood; major depressive illness, marked by severe depressive symptoms but without manic swings; and less defined milder forms of bipolar disorder and major depression that fall short of the specific diagnostic criteria, e.g. dysthymic disorder (formerly called depressive neurosis) .
  • the symptomatology and diagnostic criteria for depression are set out in the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition. Although many patients have single episodes of major depressive illness, the condition also can be repetitive, and this recurrent condition is frequently called unipolar depressive illness.
  • the key features of depressive illness are a markedly gloomy mood in which there is a loss of interest in life, and general feelings of hopelessness and worthlessness. Depressive symptoms range in severity from mild mood swings to severe delusions about self-worth, accomplishments, and the future .
  • anxiety disorders relate to various combinations of psychological and physical manifestations of anxiety, not attributable to real danger and occurring either in attacks (panic disorder or PD) or as a persisting state (generalized anxiety disorder or GAD) .
  • Other neurotic features may be present (obsessional or hysterical symptoms) but do not dominate the clinical picture .
  • noradrenaline and dopamine include the success of pharmacological agents in treating depressive disorders.
  • Many of the tricylic antidepressants (TCAs), selective serotonin re-uptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) effective in the treatment of depression increase the availability of the catecholamines (noradrenaline and dopamine) and indolamines (serotonin) in the central nervous system (CNS).
  • TCAs tricylic antidepressants
  • SSRIs selective serotonin re-uptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • the clinical efficacy of these agents has given rise to the catecholamine-indolamine hypothesis of depression. This theory postulates that a certain level of amines and/or receptor sensitivity to catecholamines functions to generate a normal mood.
  • Drugs used to treat depression include MAOIs, atypical antipsychotics, lithium, TCAs, and SSRIs.
  • off-label agents such as antiepileptics are used to treat depression in treatment- resistant patients.
  • Tricyclic antidepressants are about equal to SSRIs in effectiveness against depression, thus providing supporting evidence for the catecholamine-indolamine hypothesis of depression.
  • SSRIs have largely displaced TCAs because of side effects associated with TCAs and the need to monitor EKG and plasma drug concentration.
  • the SSRIs are viewed as an improvement over other antidepressants, they are not without their clinical problems.
  • Adverse effects on sexual function primarily
  • GalR3 receptor protein also localizes to areas of the rat brain associated with mood and emotion.
  • GalR3 receptor plays a role in controlling the activity of catecholamine and indolamine neurons in the CNS .
  • Galanin is known to hyperpolarize neurons, including monoaminergic neurons (Seutin, et al . , 1989) and to have inhibitory effects on 5- HT neurons (Xu, et al . , 1998), and dopamine neurons (Gopalan, et al . , 1993; De Weille, et al . , 1989; Jansson, et al . , 1989; Nordstrom, et al., 1987; Weiss, et al., 1998) .
  • the rat Forced Swim Test is a behavioral test that is used to screen compounds for antidepressant efficacy
  • animals are placed in a cylinder of water, from which there is no escape, for an extended period of time.
  • animals will display a range of behaviors such as immobility, climbing, swimming, and diving, with immobility being predominant after several minutes of immersion in the water. Consequently, many past studies have only measured or scored immobility after the administration of the test agent.
  • this method does not score any other active behaviors that may be produced, by potential antidepressants.
  • a particular class of antidepressant were to have very little effect on immobility, yet produce characteristic behaviors during the FST, these behaviors would not be scored and the conclusion would be that the compound in question does not possess antidepressant action.
  • Rat Social Interaction Test There are a number of paradigms that have been used to determine whether a compound possesses anxiolytic action. A number of these tests involve food or water deprivation, punishment or measurement of consummatory behavior (see File, et al . , 1980; File, 1985; Rodgers, et al . , 1997; and Treit, 1985, for review) . In addition, in these models, prior conditioning reduces the uncertainty or anxiety. In general, these tests lack ethological validity.
  • SIT Social Interaction Test
  • rats previously housed singly are placed in a familiar, dimly lit, test arena with weight-matched, novel partners .
  • the principal anxiogenic stimulus under these conditions is the partner novelty, which involves an unconditioned response to a potential threat.
  • the following behaviors are scored as active social interaction: grooming, sniffing, biting, boxing, wrestling, following, crawling over and crawling under.
  • the social interaction test can detect anxiogenic agents, including the inverse benzodiazepine receptor agonists (File, et al . , 1982; File and Pellow, 1983; File
  • novel tricyclic imines described herein are high affinity antagonists of GalR3, and are useful, by virtue of their ability to antagonize the GalR3 receptor, for the treatment of depression and/or anxiety.
  • the synthesis of tricyclic imines which bind with high affinity to the cloned human GalR3 receptor is disclosed.
  • the GalR3 receptor antagonists described herein which may be further classified as neutral antagonists, inverse agonists or allosteric modulators, provide a novel method to treat depressive disorders and/or anxiety.
  • the invention provides a compound having the structure :
  • each of Yi, Y 2/ Y 3 and Y 4 is independently -H, straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, -F, -CI, -Br, -I, -N0 2 , -CN, -OR 3 , -OCOR 3 , -NCOR 3 , -N(R 3 ) 2 , -CON(R 3 ) 2 , -COOR 3 , aryl, heteroaryl or any two of Yi, Y 2 , Y 3 and Y 4 moieties present on adjacent carbon atoms can constitute a methylenedioxy group;
  • Ri is -H, straight chained or branched C 1 -C7 alkyl, -F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON (R 3 ) 2 , -COOR 3 , C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl, aryl or heteroaryl ;
  • each R 2 is independently -H, straight chained or branched C 1 -C7 alkyl or monofluoroalkyl, -F, -CI, -Br, -I, - N 3/ -CN, -OR3, -CON(R 3 ) 2 , -COOR3, aryl, heteroaryl, C 1 -C7 cycloalkyl or cycloalkenyl or any two R 2 moieries present on adjacent carbon atoms can constitute a methylenedioxy group or a difluoromethylenedioxy group or any two R 2 moieties present on adjacent carbon atoms along with the adjacent carbon atom can constitute an aryl or a heteroaryl ring; wherein each R 3 is independently -H, straight chained or branched C 3. -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 -C 7 cycloalkyl or C5-C7 cycloalkenyl
  • R is -H, -F, -CI or methyl
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • the present invention provides for the use of any of the chemical compounds of the invention for the preparation of a pharmaceutical composition for treating an abnormality.
  • the invention also provides for the use of any of the chemical compounds of the invention for the preparation of a pharmaceutical composition for treating an abnormality, wherein the abnormality is alleviated by decreasing the activity of a human GalR3 receptor.
  • the abnormality is depression.
  • the abnormality is anxiety.
  • the present invention provides for a method of treating a subject suffering from depression which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's depression.
  • the invention also provides a method of treating anxiety in a subject which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's anxiety.
  • the invention provides for a compound having the structure:
  • each of Y lf Y 2 , Y 3 and Y 4 is independently -H, straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, -F, -CI, -Br, -I, -N0 2 , -CN, -OR 3 , OCOR 3 , -NCOR 3 , -N(R 3 ) 2 , -CON(R 3 ) 2 , -COOR 3 , aryl, heteroaryl or ⁇ any two of Yi, Y 2 , Y 3 and Y 4 moieties present on adjacent carbon atoms- can constitute a methylenedioxy group;
  • each Ri is independently -H, straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, - F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR 3 , C 3 -C7 cycloalkyl or C 5 -C 7 cycloalkenyl, aryl or heteroaryl;
  • each R 2 is independently -H, straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl, - F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR3, aryl, heteroaryl, C 1 -C7 cycloalkyl or cycloalkenyl or any two R 2 moieties present on adjacent carbon atoms can constitute, a methylenedioxy group or a difluoromethylenedioxy group or any two R 2 moieties present on adjacent carbon atoms along with the adjacent carbon atom can constitute an aryl or a heteroaryl ring;
  • each R 3 is independently -H, straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl, aryl or heteroaryl;
  • R 4 is -H, -F, -CI or methyl
  • each of Y l r Y 2 , Y 3 and Y 4 is independently --H, -F, -CI, -CF 3 , -OR 3 , straight chained or branched C 1 -C 4 alkyl;
  • each R 2 is independently -H, -F, -CI, -Br, -I, -CN, straight chained or branched C ⁇ -C 4 alkyl or any two R 2 moieties present on adjacent carbon atoms can constitute, a difluoromethylenedioxy group;
  • each R 4 is H.
  • the compound is selected from the group consisting of:
  • the invention also provides a compound having the structure :
  • each of Yi, Y 2 , Y3 and Y 4 is independently -H, straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl, -F, -CI, -Br, -I, -N0 2 , -CN, -0R 3 ,
  • Ri is -H, straight chained or branched C 1 -C 7 alkyl, -F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR 3 , C 3 -C 7 cycloalkyl or C5-C7 cycloalkenyl, aryl or heteroaryl;
  • each R 2 is independently -H, straight chained or branched C 1 -C7 alkyl or monofluoroalkyl, -F, -CI, -Br, -I, - N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR 3 , aryl, heteroaryl, C1-C7 cycloalkyl or cycloalkenyl or any two R 2 moieties present on adjacent carbon atoms can constitute a methylenedioxy group or a difluoromethylenedioxy group or any two R 2 moieties present on adjacent carbon atoms along with the adjacent carbon atom can constitute an aryl or a heteroaryl ring;
  • each R 3 is independently -H, straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 -C 7 cycloalkyl or C5-C7 cycloalkenyl, aryl or heteroaryl;
  • R 4 is -H, -F, -CI or methyl
  • Y 2 , Y 3 and Y 4 is independently -H, -F, -CI, -CF 3 , -OR 3 , straight chained or branched Ci-C 4 alkyl;
  • Ri is -H
  • the compound has the structure
  • the compound is selected from the group consisting of:
  • the invention provides a compound having the structure:
  • the invention provides a compound having the structure:
  • each of Yi, Y 2 and Y 3 is independently -H, straight 'chained or branched C ⁇ -C alkyl, monofluoroalkyl or polyfluoroalkyl, -F, -CI, -Br, -I, -N0 2 , -CN, -0R 3 ,
  • Ri is -H, straight chained or branched C 1 -C 7 alkyl, -F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR3, C3-C7 cycloalkyl or C 5 -C7 cycloalkenyl, aryl or heteroaryl;
  • each R 2 is independently -H, straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, - F, -CI, -Br, -I, -N 3 , -CN, -OR 3 , -CON(R 3 ) 2 , -COOR3, aryl, heteroaryl, C 1 -C7 cycloalkyl or cycloalkenyl or any two R 2 moieties present on adjacent carbon atoms can constitute a methylenedioxy group or a difluoromethylenedioxy group or any two R 2 moieties present on adjacent carbon atoms along with the adjacent carbon atom can constitute an aryl or a heteroaryl ring;
  • each R3 is independently -H, straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 -C 7 cycloalkyl or C 5 -C7 cycloalkenyl, aryl or heteroaryl;
  • R 4 is -H, -F, -Cl or methyl
  • each Y x , Y 2 , Y3 and Y 4 is -H, -F,-CN, C x - C 4 alkyl or polyfluoroalkyl;
  • each R 2 is independently -H, -F, -Cl, -Br, -I, -CN, straight chained or branched C 1 -C 4 alkyl or any two R 2 moieties present on adjacent carbon atoms can constitute, a difluoromethylenedioxy group;
  • each R 4 is H.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of :
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is enantiomerically pure.
  • the compound is diastereomerically pure.
  • the compound is enantiomerically and diastereomerically pure.
  • heteroaryl is used to include five and six membered unsaturated rings that contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2, 1-b] thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2 , 1, 3-benzothiazolyl .
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C alkynyl, C 3 -C7 cycloalkyl, C 3 -C7 monofluorocycloalkyl, - C 3 -C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl.
  • heteroaryl further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
  • aryl is phenyl or naphthyl .
  • the term “aryl” also includes phenyl and naphthyl which may be substituted with one or more of the following: -F, -d, -Br, -I,--N0 2 , -CN, straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, C 3 -C7 cycloalkyl, monofluorocycloalkyl or polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl.
  • cycloalkyl includes C 3 -C 7 cycloalkyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C 1 -C7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C7 alkynyl, C 3 -C7 cycloalkyl, C 3 -C7 monofluorocycloalkyl, C 3 -C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl.
  • cycloalkenyl includes C 5 -C 7 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, - Br, -I, -N0 2 , -CN, straight chained or branched C 1 -C7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C5-C7 cycloalkenyl.
  • the invention provides for each pure stereoisomer of any of 'the compounds described herein.
  • Such stereoisomers may include -enantiomers, dia ' stereomers, or E or Z alkene or imine isomers .
  • the invention also provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures.
  • Stereoisomers can be synthesized in pure form (N ⁇ gradi, M.,
  • the compounds of the present invention are preferably greater than 80% pure, more preferably greater than 90% pure, and most preferably greater than 95% pure.
  • the acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein.
  • the acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the acids include, but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, ' piperazine and guanidine .
  • This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
  • the present invention includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
  • the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, 1985.
  • the present invention further includes metabolites of the compounds of the present invention.
  • Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • the present invention provides for the use of any of the chemical compounds of the invention for the preparation of a pharmaceutical composition for treating an abnormality.
  • the invention also provides for the use of any of the claims
  • the abnormality is depression.
  • the abnormality is anxiety.
  • the abnormality is major depressive disorder.
  • the abnormality is obsessive compulsive disorder.
  • the abnormality is panic disorder, with or without agoraphobia.
  • the abnormality is social anxiety disorder.
  • the abnormality is generalized anxiety disorder.
  • the abnormality is post-traumatic stress disorder.
  • the amount of the compound is from about 0.01 mg to about ⁇ 1000 mg . In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg . In yet another embodiment, the amount of the compound is from about 0.1 mg to about 500 mg . In another embodiment, the amount of the compound is from about 1.0 mg to about 200 mg. In yet another embodiment, the amount of the compound is from about 10 mg to about 100 mg .
  • the carrier is a liquid, and the composition is a solution.
  • the carrier is a solid and the composition is a tablet.
  • the carrier is a gel and the composition is a capsule, suppository or a cream.
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • the compound may be delivered to the subject by means of a spray or inhalant.
  • a solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers) , flavoring agents, lubricants, solubilizers", suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins .
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators .
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil)
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic) , bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • the compound is administered in combination
  • Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • depressive and anxiety disorders are provided for the purpose of facilitating an understanding of the utility of the compounds of this invention.
  • the definitions of depressive and anxiety disorders given below are those listed in American Psychiatric Association, 1994a or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in this reference, as well as other references cited below, all of which are hereby incorporated herein by reference.
  • Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b) .
  • Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes.
  • a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms : change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
  • Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
  • the compounds of this invention will be effective in treating depression in patients who have been diagnosed as having depression based upon the administration of any of the following tests : Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI ) -Severity of Illness. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI- Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
  • HDRS Hamilton Depression Rating Scale
  • CGI Clinical Global Impressions
  • the present invention provides for a method of treating a subject suffering from depression which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's depression.
  • the invention provides a method of treating a subject suffering from major depressive disorder, which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's major depressive disorder.
  • Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating ' these disorders in patients who have been diagnosed as having such disorders.
  • the present invention provides for a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's anxiety.
  • Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a) .
  • the obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
  • the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed as having obsessive compulsive disorder based upon administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS) , CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this invention will be effective in preventing relapse of obsessive compulsive disorder.
  • YBOCS Yale Brown Obsessive Compulsive Scale
  • NIMH GOCS National Institute of Mental Health Global OCD Scale
  • CGI-Severity of Illness scale CGI-Severity of Illness scale. It is further contemplat
  • the invention provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's obsessions and compulsions.
  • Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a) .
  • a panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
  • Panic, disorder may or may not be associated
  • the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be
  • the invention provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's panic disorder.
  • Social anxiety disorder also known as social phobia
  • social phobia is characterized by a marked and persistent fear of one or more social or p.erformance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a) .
  • Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack.
  • the feared situations are avoided or endured with intense anxiety or distress.
  • the avoidance, anxious anticipation, or distress in the feared situation interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias.
  • Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment .
  • the compounds of the invention will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS) , or a CGI- Global Improvement score of 1 (very much improved) , 2 (much improved) or 3 (minimally improved) . It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
  • the invention provides a method of treating social anxiety disorder in a subject which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's social anxiety disorder.
  • Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a) . It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
  • the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed as having this disorder based upon the diagnostic criteria described in DSM-IV. It is further contemplated that the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds of this invention will be effective in preventing relapse of general anxiety disorder.
  • the invention provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's generalized anxiety disorder.
  • Post-traumatic stress disorder (PTSD) , as defined by DSM- III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a) , requires exposure' to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.
  • DSM- III-R/IV American Psychiatric Association, 1987, American Psychiatric Association, 1994a
  • Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.
  • a PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning .
  • the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed as having PTSD based upon the administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS) , the patient-rated Impact of Event Scale (IES) . It is further contemplated that the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
  • CAPS Clinician-Administered PTSD Scale Part 2
  • IES patient-rated Impact of Event Scale
  • the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
  • the invention provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount of any of the compounds of the invention effective to treat the subject's post-traumatic stress disorder.
  • the invention also provides a method of treating a subject suffering from dysthymic disorder, bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
  • the invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of a GalR3 antagonist effective to alleviate the symptoms, wherein the GalR3 antagonist is any of the compounds of the invention.
  • the disorder is depression.
  • the disorder is anxiety.
  • the disorder is major depressive disorder.
  • the disorder is obsessive compulsive disorder.
  • the disorder is panic disorder, with or without agoraphobia.
  • the disorder is social anxiety disorder.
  • the disorder is generalized anxiety disorder.
  • the disorder is post- traumatic stress disorder.
  • the invention provides a method of treating a subject suffering from a disorder mediated by the GalR3 receptor comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the compounds of the invention.
  • the disorder is depression.
  • the disorder is anxiety.
  • the disorder is major depressive disorder.
  • the disorder is obsessive compulsive disorder.
  • the disorder is a disorder mediated by the GalR3 receptor.
  • -disorder is panic disorder, with or without agoraphobia.
  • the disorder is social anxiety disorder. In one embodiment, the disorder is generalized anxiety disorder. In one embodiment, the disorder is post- traumatic stress disorder.
  • This invention provides a method of treating a subject suffering from an abnormality, wherein the abnormality is alleviated by decreasing the activity of a GalR3 receptor which comprises administering to the subject an amount of a compound of the invention which is a GalR3 antagonist effective to treat the subject's abnormality.
  • the abnormality is depression, anxiety, major depressive disorder, obsessive compulsive disorder, panic disorder with or without agoraphobia, social anxiety disorder, generalized anxiety disorder or post-traumatic stress disorder.
  • a "therapeutically effective amount” is an amount of a compound which, when administered to a subject suffering from a disease causes a reduction, remission, or regression of the disease and/ or of symptoms associated with that disease.
  • a "subject” includes any vertebrate, more particularly any mammal, e.g. any human or canine.
  • the amount of the compound is from about 0.01 to about 1000 mg per day. In another embodiment, the amount of the compound is from about 0.1 to about 500 mg per day. In another embodiment, the amount of the compound is from about 1.0 to about 200 mg per day. In yet another embodiment, the amount of the compound is from about 10 to about 100 mg per day.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • binding affinity describes the concentration of a compound required to occupy one-half of the binding sites in a receptor population, as detectable by radioligand binding. Binding affinity concentration can be represented as K x , inhibition constant, or K D , dissociation constant.
  • selectivity of binding affinity refers to the ability of a chemical compound to discriminate one receptor from another. For example, a compound showing selectivity for receptor A versus receptor B will bind receptor A at lower concentrations than those required to bind receptor B .
  • antagonist refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using an appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase, inositol phospholipid hydrolysis, and
  • agonist refers to a compound which binds to, and increases the activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
  • Methods to perform second messenger assays are described in PCT International Publication No. 97/46250 and in PCT International Publication No. 98/15570, the contents of which are hereby incorporated by reference. '
  • the antagonist may act as an inverse agonist or an allosteric modulator, as opposed to a neutral antagonist, and suppress receptor signaling independent of the agonist (Lutz and Kenakin, 1999) .
  • the categories of "antagonist compounds” are therefore seen to include 1) neutral antagonists (which block agonist actions but do not affect constitutive activity); 2) inverse agonists (which block agonist actions as well as constitutive activity by stabilizing an inactive receptor conformation) ; 3) and allosteric modulators (which block agonist actions to a limited extent and which may also block constitutive activity through allosteric regulation) .
  • atypical antipsychotics drugs such- as sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine and tenilapine displayed potent inverse activity whereas typical antipsychotic drugs such as chlorpromazine, thioridazine, spiperone and thiothixene were classified as neutral antagonists (Herrick-Davis et al, 2000) .
  • a GalR3 antagonist useful in the treatment of depression is one which a) selectively binds to the GalR3 receptor, and b) displays antidepressant activity in the rat Forced Swim Test.
  • a GalR3 antagonist useful in the treatment of anxiety is one which a) selectively binds to the GalR3 receptor, and b) displays anxiolytic activity in the rat Social Interaction.
  • a GalR3 antagonist useful in the treatment of depression and anxiety is one which a) selectively binds to the GalR3 receptor, b) displays antidepressant activity in the rat Forced Swim Test, and c) displays anxiolytic activity in the rat Social Interaction Test .
  • the cloned cDNAs encoding both the human and rat GALRl and GALR2 receptors may be used.
  • the cloning and assay methods for the human and rat GALRl receptors may be found in PCT International Publication No. WO 95/22608, the contents of which are hereby incorporated by reference.
  • the cloning and assay methods for the human and rat GALR2 receptors may be found in PCT International Publication No. WO 97/26853, the contents of which are hereby incorporated by reference.
  • the present ' invention provides for a method of determining the binding affinity of a GalR3 antagonist, wherein the GalR3 antagonist is dissolved in a "suitable solvent".
  • a "suitable solvent” means one which permits the measurement of binding affinity of the GalR3 antagonist to the human GalR3 receptor at concentrations less than 1 ⁇ M, preferably less than 100 nM.
  • solvents include, but are not limited to, DMSO, ethanol, N,N-dimethylacetamide, or water.
  • the preferred solvent is 3% DMSO (final concentration in the assay) .
  • the preferred solvent is the solvent which permits the measurement of binding affinity of a GalR3 antagonist at the lowest concentration.
  • the crude mixture was then treated with 1M HCl (3 X 350 mL) , followed by aqueous saturated NaHC ⁇ 3 solution (3 x 350 mL) .
  • the resulting organic faction was concentrated in vacuo and the residue was dissolved in CH 2 CI 2 , dried over MgS04, concentrated in va cuo, and re-suspended in CH 2 C1 2 .
  • the suspension was filtered and the filtrate was concentrated in va cuo .
  • the crude product was recrystallized from a mixture of toluene/hexane (3:1), giving the desired product (7.6 g, 27 mmol) .
  • 6-HYDROXY-1-PHENYL-1H-INDOLE-2 3-DIONE : A mixture of 6- methoxy-l-phenyl-lH ⁇ indole-2, 3-dione (50 mg, 0.20 mmol) and BBr 3 (418 mg, 1.67 mmol) in CH 2 C1 2 (6 mL) was stirred at 0 °C for 1 hour. The crude product was purified by preparative TLC [Eluent: EtOAc/hexane (1:1)], giving the desired product (13 mg, 28%).
  • Example 5 Synthesized by Procedures A, B and C (3,4- dichloroaniline was used in place of 3, 5-difluoroaniline) .
  • Example 7 Synthesized by Procedures D [3- (trifluoromethyl) aniline was used in place of 3,4- dichloroaniline] and E (the product of the first step was used in place of 3- [ (3, 4-dichlorophenyl) imine] -1, 3-dihydro- 2fT-indol-2-one and 3-hydroxyphenylboronic acid was used in place of 4-methoxypyridine-5-boronic acid) .
  • Example 8 Synthesized by Procedures D [3- (trifluoromethyl) aniline was used in place of 3,4- dichloroaniline] and E (the product of the first step was used in place, of 3- [ (3, -dichlorophenyl) imine] -1, 3-dihydro-
  • Example 10 synthesized as followed: Dichloromethane (25 ml) was added to a mixture of copper (II) acetate (250 mg, 1.4 mmol), 3- [ [3- (trifluoromethyl) phenyl] imino] -lff-indol-2- one (200 mg, 0.7 mmol), and 2-methoxy-5-pyridineboronic acid (210 mg, 1.4 mmol), followed by triethylamine (0.39 ml, 2.8 mmol) under ambient atmosphere. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo, suspended in 75 ml ethyl acetate, and filtered through a 1 cm x 3 cm silica plug. The filtrate was concentrated in vacuo and purified by silica gel chromatography using 2:3 ethyl acetate in hexane giving the desired product as a yellow solid (159 mg, 0.4 mmol, 58%) .
  • Examples that could be used in place of tetrahydroquinoline in the exemplary procedures to synthesize compounds of this invention include, but are not limited to, indoline, acridine, carbazole, benzazepine or hexahydrocarbazole .
  • Methods for the synthesis of tetrahydroquinolines, indoline, acridine, carbazole, benzazepine and hexahydrocarbazole may be found in the reference section.
  • an oral composition of a compound of this invention 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of about 580 to 590 mg to fill a size 0 hard gel capsule.
  • the binding properties of the compounds of the present invention may be evaluated at one or more cloned receptors or native, tissue-derived transporters, using protocols described below.
  • COS-7 cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10%
  • Mouse fibroblast LM(tk-) cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin, 100 ⁇ g/mL streptomycin) at 37°C with 5% C0 2 . Stock plates of LM(tk-) cells were trypsinized and split 1:10 every 3-4 days.
  • CHO cells were grown on 150 mm plates in HAM' s F12 medium with (HAM' s F-12 with 10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin, 100 ⁇ g/mL streptomycin) at 37°C with 5% C0 2 .
  • Stock plates of CHO cells were trypsinized and split 1:8 every 3-4 days.
  • LM(tk-) cells were stably transfected with the human GalR3 receptor.
  • Stable Transfection cDNAs for the human and rat GalR3 receptors were transfected with a G-418 resistant gene into the mouse fibroblast LM(tk-) cell line by a calcium phosphate transfection method (Cullen, 1987) .
  • Membranes were harvested from stably transfected LM(tk-) cells . Adherent cells were washed twice in ice-cold
  • Membranes were collected from the supernatant fraction by centrifugation (32,000 x g, 18 min, 4°C) , washed with ice-cold hypotonic buffer, and collected again by centrifugation (32,000 x g, 18 min, 4°C) .
  • the final membrane pellet was resuspended by sonication into a small volume of ice-cold binding buffer ( ⁇ 1 ml for every 5 plates: 10 mM NaCl, 20 mM HEPES, 0.22 mM KH 2 P04, 1.26 mM CaC12, 0.81 mM MgS04, pH 7.4) .
  • Protein concentration was measured by the Bradford method (Bradford, 1976) using Bio-Rad Reagent, with bovine serum albumin as a standard. Membranes were held on ice for up to one hour and used ' fresh, or flash frozen and stored in liquid nitrogen. Membranes were prepared similarly from CHO cells.
  • the methods to obtain the cDNA of the receptors, express said receptors in heterologous systems, and carry out assays to determine binding affinity are described as follows .
  • Galanin Receptors Binding assays ⁇ were performed according to the following published method: human GALR3 (PCT International Publication No. WO 98/15570) .
  • the following in vivo methods are performed to predict the efficacy of ' GalR3 antagonists for the treatment depression (forced swim test) and anxiety (social interaction test) .
  • Rats are housed 5 per cage and maintained on a 12:12-h light-dark cycle. Rats are handled for 1 minutes each day for 4 days prior to behavioral testing.
  • Animals are randomly assigned to receive a single i.p. administration of vehicle (2.5% EtOH / 2.5% Tween-80), imipramine (positive control; 60 mg/kg) , or Test Compound 60 minutes before the start of the 5 minute test period. All injections are given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, NJ) . The volume of injection is 1 ml/kg.
  • the rat's behavior is rated at 5 second intervals during the 5 minute test by a single individual, who is blind to the treatment condition. Scored behaviors are:
  • Immobility- rat remains floating in the water without struggling and is only making those movements necessary to keep its head above water;
  • Climbing - rat is making active movements with its forepaws in and out of the water, usually directed against the walls ;
  • swimming - rat is making active swimming motions, more than necessary ' to merely maintain its head above water, e.g. moving around in the cylinder;
  • the forced swim test data (immobility, swimming, climbing, diving) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test.
  • the data are analyzed using the GprahPad Prism(v2.01) (GraphPad Software, Inc., San Diego, CA) . All data are presented as means + S.E.M. All data are presented as means + S.E.M.
  • mice (Taconic Farms, NY) are used in all experiments. Animals are housed 5 per cage in a controlled environment under a 12:12 hour light: dark cycle. Animals are handled 1 min each day for 4 days prior to the experiment. This procedure included a mock gavage with a 1.5 inch feeding tube .
  • Animals are randomly assigned to receive a single administration of vehicle (5% EtOH/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
  • the procedure for the forced swim test in the mouse is similar to that described above for the rat, with some modifications.
  • the cylinder used for the test is a 1 liter beaker (10.5cm diameter X 15 cm height) fill to 800ml (10cm depth) of 23-25°C water. Only one 5-minute swim test is conducted for each mouse, between 1300 and 1700 hours. Drug treatments are administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes. All test sessions are videotaped using a Sony color video camera and recorder for scoring later.
  • the behavior during minutes 2-5 of the test is played back on a TV monitor and scored by the investigator.
  • the total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) are recorded.
  • the forced swim test data time exhibiting immobility, mobility; seconds
  • the data are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test.
  • the data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA) . All data are presented as means + S.E.M.
  • Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day. The design and procedure for the Social Interaction Test is carried out as previously described by Kennett, et al. (1997) . On the test day, weight matched pairs of rats (+ 5%) , unfamiliar to each other, are given identical treatments and returned to their home cages. Animals are randomly divided into 5 treatment groups, with 5 pairs per group, and are given one of the following i.p. treatments: Test Compound (10, 30 or 100 mg/kg) , vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg) . Dosing is 1 hour prior to testing.
  • Rats are subsequently placed in a white perspex test box or arena (54 x 37 x 26 cm), whose floor is divided up into 24 equal squares, for 15 minutes.
  • An air conditioner is used to generate background noise and to keep the room at approximately 74 °F.
  • All sessions are videotaped using a JVC camcorder (model GR-SZ1, Elmwood Park, NJ) with either TDK (HG ultimate brand) or Sony 30 minute videocassettes . All sessions are conducted between 1300 - 1630 hours.
  • Active social interaction defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch
  • Drug Administration Test Compound is dissolved in 100% DMSO or 5% lactic acid, v/v (Sigma Chemical Co., St. Louis, MO) . Chlordiazepoxide (Sigma Chemical Co., St. Louis, MO) is dissolved in double distilled water. The vehicle consists of 50% DMSO (v/v) or 100% dimethylacetamide (DMA) . All drug solutions are made up 10 minutes prior to injection and the solutions are discarded at the end of the test day. The volume of drug solution administered is 1 ml/kg.
  • the social interaction data time interacting, rearing and squares crossed
  • the data are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Student- Newman-Keuls test.
  • the data are subjected to a test of normality (Shapiro-Wilk test) .
  • the data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, ' MD, 1997). All data are presented as means + S.E.M.

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Abstract

La présente invention concerne: des dérivés d'indolone qui sont des antagonistes sélectifs du récepteur GalR3; une composition pharmaceutique comprenant une quantité efficace d'un point de vue thérapeutique d'un composé de l'invention et un excipient pharmaceutiquement acceptable; une composition pharmaceutique préparée par combinaison d'une quantité efficace d'un point de vue thérapeutique d'un composé de l'invention et d'un excipient pharmaceutiquement acceptable; un procédé pour produire une composition pharmaceutique, comprenant la combinaison d'une quantité efficace d'un point de vue thérapeutique d'un composé de l'invention et d'un excipient pharmaceutiquement acceptable; un procédé pour traiter un individu atteint de dépression et/ou d'anxiété, comprenant l'administration à l'individu d'une quantité d'un composé de l'invention, efficace pour traiter la dépression et/ou l'anxiété dont souffre l'individu; un procédé pour traiter la dépression et/ou l'anxiété chez un individu, comprenant l'administration à l'individu d'une composition comprenant un excipient pharmaceutiquement acceptable et une quantité active d'un point de vue thérapeutique d'un antagoniste du récepteur GalR3.
PCT/US2003/024867 2002-08-07 2003-08-07 3-imino-2-indolones pour traiter la depression et/ou l'anxiete WO2004014854A1 (fr)

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WO2007070362A1 (fr) * 2005-12-09 2007-06-21 Helicon Therapeutics, Inc. Composés d'indolone pouvant être employés pour traiter la déficience cognitive
US7642281B2 (en) 2002-08-07 2010-01-05 Helicon Therapeutics, Inc. Indolone compounds useful to treat cognitive impairment
WO2011067273A1 (fr) * 2009-12-04 2011-06-09 F. Hoffmann-La Roche Ag Dérivés de tétrahydroquinoline indole en tant qu'inhibiteurs de la recapture des monoamines
US8277842B1 (en) 2012-01-20 2012-10-02 Dart Neuroscience (Cayman) Ltd. Enteric-coated HT-2157 compositions and methods of their use

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US6512125B1 (en) * 1994-05-13 2003-01-28 Aventis Pharmaceuticals Inc. Preparation of 1H-indol-1-amines
US6541503B2 (en) * 1997-09-05 2003-04-01 Smithkline Beecham Corporation Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7642281B2 (en) 2002-08-07 2010-01-05 Helicon Therapeutics, Inc. Indolone compounds useful to treat cognitive impairment
WO2007070362A1 (fr) * 2005-12-09 2007-06-21 Helicon Therapeutics, Inc. Composés d'indolone pouvant être employés pour traiter la déficience cognitive
EP2241316A1 (fr) * 2005-12-09 2010-10-20 Helicon Therapeutics, Inc. Composés d'indolone pouvant être employés pour traiter la déficience cognitive
AU2006326665B2 (en) * 2005-12-09 2012-11-15 Dart Neuroscience (Cayman) Ltd Indolone compounds useful to treat cognitive impairment
WO2011067273A1 (fr) * 2009-12-04 2011-06-09 F. Hoffmann-La Roche Ag Dérivés de tétrahydroquinoline indole en tant qu'inhibiteurs de la recapture des monoamines
CN102639524A (zh) * 2009-12-04 2012-08-15 霍夫曼-拉罗奇有限公司 作为单胺再摄取抑制剂的四氢喹啉吲哚衍生物
US8277842B1 (en) 2012-01-20 2012-10-02 Dart Neuroscience (Cayman) Ltd. Enteric-coated HT-2157 compositions and methods of their use

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