WO2008052086A1 - Dérivés de benzodioxane et leurs utilisations - Google Patents

Dérivés de benzodioxane et leurs utilisations Download PDF

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Publication number
WO2008052086A1
WO2008052086A1 PCT/US2007/082450 US2007082450W WO2008052086A1 WO 2008052086 A1 WO2008052086 A1 WO 2008052086A1 US 2007082450 W US2007082450 W US 2007082450W WO 2008052086 A1 WO2008052086 A1 WO 2008052086A1
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disorder
hydrogen
compound
formula
compounds
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PCT/US2007/082450
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English (en)
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Gary Paul Stack
William Demaio
John Chuck Lem Erve
Karthick Vishwanathan
Jianyao Wang
Sarvesh Vashishtha
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Wyeth
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to 5-HT 2C receptor agonists and uses thereof.
  • Schizophrenia affects approximately 5 million people.
  • the most prevalent treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine dopamine (D 2 ) and serotonin (5-HT 2A ) receptor antagonism.
  • D 2 dopamine
  • 5-HT 2A serotonin receptor antagonism
  • these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison, D. B., et. al., Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1-9, 2000).
  • Atypical antipsychotics also bind with high affinity to 5-HT 2 c receptors and function as 5-HT 2 c receptor antagonists or inverse agonists.
  • Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT 2 c antagonism is responsible for the increased weight gain.
  • stimulation of the 5-HT 2 c receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., Human Psychopharmacology 10: 385-391, 1995; Rosenzweig-Lipson, S., et.
  • 5-HT 2 c agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953-955, 1998; Di Matteo, V., et. al., Neuropharmacology 3£: 1195-1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine.
  • 5-HT 2 c agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects.
  • 5-HT 2 c agonists decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra.
  • VTA ventral tegmental area
  • 5-HT 2 c agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
  • the present invention relates to 5-HT 2 c agonists and uses thereof.
  • the compounds of the present invention are useful, for example, to treat schizophrenia and the concomitant mood disorders and cognitive impairments of schizophrenia.
  • compounds of the present invention are less likely to produce the body weight increases associated with current atypical antipsychotics.
  • the compounds of the present invention are also useful for the treatment of obesity and its comorbidities.
  • the present invention provides a compound of formula I:
  • R 1 is hydrogen, Ci-C 4 alkyl, -S(O) 2 OH, or -C(O)R, wherein R is hydrogen or Ci-C 4 alkyl optionally substituted with -OH;
  • A is -N(H)-, -N(OH)- or -O-;
  • R 2 is hydrogen or -OH;
  • each of R 3 and R 4 is independently hydrogen, halogen, methyl, methoxy, or -OH;
  • each of R a and R b is independently hydrogen or -OH, or R a and R b are taken together with the carbon to which they are attached to form a carbonyl moiety, provided that when the adjacent
  • R b is absent; each of R c and R d is independently hydrogen or -OH, or R c and R d are taken together with the carbon to which they are attached to form a carbonyl moiety, provided that when the adjacent
  • R d is absent
  • each R x is independently hydrogen, halogen, -CF 3 , or Ci-C 4 alkyl, provided that both R x groups are not simultaneously hydrogen; each R y is independently hydrogen or -OH; m is one, two or three; and n is one or two; provided that at least one of the following applies: (a) one of R 2 , R 3 , R 4 , R a , R b , R c , R d , and R y is
  • R 1 is -C(O)R;
  • R 1 is -S(O) 2 OH; or
  • at least one pair of R a and R b or R c and R d are taken together with the carbon to which they are attached to form a carbonyl moiety.
  • the invention relates to methods for treating a patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, intellectual deficit associated with Alzheimer's disease, bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders, migraines, sexual dysfunction, substance abuse, addiction to alcohol and various other drugs, including cocaine and nicotine, gastrointestinal disorders, obesity, or a central nervous system deficiency associated with trauma, stroke, or spinal cord injury that includes administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the invention relates to compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable
  • the present invention relates to compounds that are agonists or partial agonists of the
  • alkyl includes, but is not limited to, straight- and branched-chain saturated hydrocarbon groups of 1-6 carbon atoms, e.g. 1-4 carbon atoms, preferably 1-3 carbon atoms, more preferably 1-2 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.
  • halogen or halo, refer to chlorine, bromine, fluorine or iodine.
  • an effective amount refers to the amount of a compound of formula I that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering from.
  • Such conditions include, but are not limited to, schizophrenia, schizoaffective disorder, schizophreniform disorder, L-DOPA-induced psychosis, bipolar disorder, obesity, obsessive compulsive disorder, depression, panic disorder, sleep disorders, eating disorders, and epilepsy.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salt” refers to salts derived from treating a compound of formula I with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, or similarly known acceptable acids.
  • an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glyco
  • the present invention provides the hydrochloride salt of a compound of formula I.
  • pharmaceutically acceptable salt refers to salts derived from treating a compound of formula I with an organic or inorganic base. Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal
  • patient refers to a mammal. In certain embodiments, the term “patient”, as used herein, refers to a human.
  • administer refers to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
  • treat refers to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving the condition.
  • shocker or “suffering” as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.
  • the invention relates to a compound of formula I:
  • R 1 is hydrogen, Ci-C 4 alkyl, -S(O) 2 OH, or -C(O)R, wherein R is hydrogen or Ci-C 4 alkyl optionally substituted with -OH;
  • A is -N(H)-, -N(OH)- or -O-;
  • R 2 is hydrogen or -OH;
  • each of R 3 and R 4 is independently hydrogen, halogen, methyl, methoxy, or -OH;
  • each of R a and R b is independently hydrogen or -OH, or R a and R b are taken together with the carbon to which they are attached to form a carbonyl moiety, provided that when the adjacent
  • R b is absent; each of R c and R d is independently hydrogen or -OH, or R c and R d are taken together with the carbon to which they are attached to form a carbonyl moiety, provided that when the adjacent
  • R d is absent
  • each R x is independently hydrogen, halogen, -CF 3 , or Ci-C 4 alkyl, provided that both R x groups are not simultaneously hydrogen; each R y is independently hydrogen or -OH; m is one, two or three; and n is one or two; provided that at least one of the following applies: (a) one of R 2 , R 3 , R 4 , R a , R b , R c , R d , and R y is
  • R a and R b are each hydrogen or -OH or are taken together to form an oxo moiety
  • R c and R d are each hydrogen or -OH or are taken together to form an oxo moiety.
  • the n group of formula I is 1. [0023] In other embodiments, the n group of formula I is 2. [0024] In certain embodiments, the m group of formula I is 1. [0025] In other embodiments the m group of formula I is 2. [0026] In still other embodiments, the m group of formula I is 3. [0027] As defined generally above, the R 1 group of formula I is R 1 is hydrogen, C 1 -C 4 alkyl,
  • R 1 group of formula I is hydrogen. In other embodiments, the R 1 group of formula I is C 1 -C 4 alkyl. In other embodiments, the R 1 group of formula I is -S(O) 2 OH.
  • the R 1 group of formula I is methyl. According to another aspect, the
  • R 1 group of formula I is -C(O)R wherein R is hydrogen, methyl or hydroxy-substituted butyl.
  • the A group of formula I is -N(H)-, -N(OH)- or -O-. In certain embodiments, the
  • a group of formula I is -N(H). In other embodiments, the A group of formula I is -N(OH)-. In still other embodiments, the A group of formula I is -O-.
  • the R 3 group of formula I is fluoro or chloro. In other embodiments, the R 3 group of formula I is fluoro.
  • the R 2 group of formula I is -OH and the R 4 group is hydrogen. In other embodiments, the R 2 group is hydrogen and the R 4 group of formula I is
  • both of the R 2 and R 4 groups of formula I are -OH.
  • each R x group of formula I is independently halogen, -CF 3 , or methyl. In other embodiments, each R x group of formula I is independently a halogen group.
  • both R x groups of formula I are chloro. In certain embodiments, one
  • R x group is hydrogen and the other R x group is halogen, -CF 3 , or methyl.
  • At least one of the R 2 , R 4 , and R y groups of formula I is -OH.
  • the present invention provides a compound of any of formulae I-a,
  • R a and R b are taken together with the carbon to which they are attached to form a carbonyl moiety.
  • R c and R d are taken together with the carbon to which they are attached to form a carbonyl moiety.
  • the present invention provides a compound of formula I-g or I-h:
  • the present invention provides a compound of formula I' :
  • each of R 1 , R 2 , R 3 , R 4 , R x , R y and m is as defined above and in classes and subclasses described herein.
  • the present invention provides a compound of formula II-a or ll-b:
  • each R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R x , R y and m are as defined above for compounds of formula I and in classes and subclasses as described above and herein.
  • the present invention provides a compound of formula II-a, as depicted above, or a pharmaceutically acceptable salt thereof, wherein each R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R x , R y and m are as defined above for compounds of formula I and in classes and subclasses as described above and herein.
  • the present invention provides a compound of formula II-c or II-d:
  • an enantiomer may, in some embodiments be provided substantially free of the corresponding enantiomer.
  • an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. "Substantially free,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, EX.
  • Atropisomers of the present compounds may exist.
  • the present invention thus encompasses atropisomeric forms of compounds of formula I as defined above, and in classes and subclasses described above and herein.
  • Exemplary compounds of formula I are set forth in Table 1 , below.
  • the present invention also provides compounds of formula III useful as prodrugs of 5-HT 2 c agonists or partial agonists of formula I, as defined herein. These compounds have the general formula III:
  • R a and R b are each hydrogen or are taken together to form an oxo moiety; and R c and R d are each hydrogen or are taken together to form an oxo moiety.
  • Compounds of the present invention are also useful for the study of 5-HT 2C agonists or partial agonists in biological and pathological phenomena and the comparative evaluation of 5-HT 2 c agonists or partial agonists.
  • the present compounds were discovered as a result of metabolic studies of 5-HT 2 c agonists or partial agonists. Without wishing to be bound by theory, it is believed that the present compounds are metabolites of 5-HT 2 c agonists or partial agonists, such as those described in United States patent application serial number 11/409,466, filed April 21, 2006, the entirety of which is hereby incorporated herein by reference. Accordingly, the present compounds are also useful for studying the effects of such 5-HT 2 c agonists or partial agonists in vivo or in vitro.
  • prodrug refers to a derivative of a parent drug molecule that requires transformation within the body in order to release the active drug, and that has improved physical and/or delivery properties over the parent drug molecule.
  • a compound may be transformed by metabolic means (such as by hydrolysis), to a compound of formula I.
  • Prodrugs are designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent drug molecule.
  • the advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage.
  • esters as a prodrug type for drugs containing carboxyl or hydroxyl function is known in the art as described, for example, in "The Organic Chemistry of Drug Design and Drug Interaction” Richard Silverman, published by Academic Press (1992).
  • Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
  • Glucos glucosyl moiety
  • the n group of formula III is 1. [0051] In other embodiments, the n group of formula III is 2. [0052] In certain embodiments, the m group of formula III is 1. [0053] In other embodiments the m group of formula III is 2. [0054] In still other embodiments, the m group of formula III is 3.
  • R 1 group of formula III is hydrogen, -OH, -OGIu, -GIu,
  • the R 1 group of formula III is hydrogen. In other embodiments, the R 1 group of formula III is -OH or -OGIu. In still other embodiments, the R 1 group of formula III is -GIu. In still other embodiments, the R 1 group of formula III is -C(O)GIu. In still other embodiments, the R 1 group of formula III is
  • the R 1 group of formula III is -C(O)R, wherein R is hydrogen or C1-C4 alkyl optionally substituted with -OH.
  • the A group of formula III is -N(H)-, -N(OH)- or -0-. In certain embodiments, the A group of formula III is -N(H). In other embodiments, the A group of formula III is
  • the A group of formula III is -0-.
  • the R group of formula III is fluoro or chloro. In other embodiments, the R 3 group of formula III is fluoro.
  • the R 2 group of formula III is -OH and the R 4 group is hydrogen. In other embodiments, the R 2 group is hydrogen and the R 4 group of formula III is
  • both of the R 2 and R 4 groups of formula III are -OH.
  • the R 2 group of formula III is -OGIu and the R 4 group is hydrogen. In other embodiments, the R 2 group is hydrogen and the R 4 group of formula III is
  • each R x group of formula III is independently hydrogen, halogen, -CF 3 , or methyl. In other embodiments, each R x group of formula III is independently a halogen group. In still other embodiments, both R x groups of formula III are chloro. In certain embodiments, one R x group of formula III is chloro, -CF 3 , or methyl and the other R x group is hydrogen.
  • the present invention provides a compound of formula IV:
  • each R x , m, R 1 , and R 5 are as defined generally above and in classes and subclasses described above and herein.
  • the present invention provides a compound of formula IV-a, IV-b, or IV-C :
  • each R x , m, R 2 , R 4 , and R 5 are as defined generally above and in classes and subclasses described above and herein.
  • the present invention provides a compound of formula V:
  • each R x , R 1 , A, R 2 and R 4 are as defined generally above and in classes and subclasses described above and herein.
  • the present invention provides a compound of formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j:
  • Scheme 1 above depicts a general method for preparing compounds of formula IV.
  • Scheme 1 depicts compounds having a fluorine substituent (corresponding to the R 3 moiety of formula III)
  • Scheme 1 is amenable to preparing various compounds of formula III and such compounds are also envisioned.
  • the hydroxyl compound 1 is treated with a suitably protected glucuronidate compound 2 having a suitable leaving group to enable the desired coupling to form compound 3.
  • PG 2 , PG 3 , and PG 4 is a suitable hydroxyl protecting group.
  • Suitable hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G.
  • Suitable hydroxyl protecting groups further include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
  • each of PG 2 , PG 3 , and PG 4 may be different or the same.
  • each of PG 2 , PG 3 , and PG 4 is the same such that they are removed by the same conditions.
  • the removal of these protecting groups, also known as "deprotection,” is achieved by methods known in the art, including those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999.
  • the PG 1 group is a suitable carboxylate protecting group.
  • Such protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.
  • Suitable carboxylate protecting groups further include, but are not limited to, substituted Ci_6 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like.
  • ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl wherein each group is optionally substituted.
  • Compounds of the present invention have affinity for and agonist or partial agonist activity at the 2C subtype of brain serotonin receptors and are thus of interest for the treatment of a variety of disorders and/or the alleviation of one or more associated symptoms. Such disorders associated with modulations of the 2C subtype of brain serotonin receptors are described in detail below.
  • the present invention contemplates that compounds of the present invention are associated with a rapid onset of action. In addition, compounds of the present invention lack the side-effect of sexual dysfunction.
  • Compounds of the present invention are useful for treating one or more psychotic disorders, as described herein, without causing diabetogenesis.
  • Diabetogenesis is a side-effect associated with atypical antipsychotic agents. Without wishing to be bound by any particular theory, it is believed that the diabetogenesis associated with atypical antipsychotic agents results from the fact that those agents are 5-HT 2C antagonists.
  • the present compounds are 5-HT 2 c agonists, or partial agonists, and therefore are not associated with diabetogenesis.
  • Compounds of the present invention are useful for treating one or more psychotic disorders such as schizophrenia including paranoid type, disorganized type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise specified; L-DOPA- induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; and psychosis associated with Lewy body disease.
  • Compounds of the present invention are also useful for treating symptoms related to psychotic disorders of the schizophrenic types, including the so called "positive" and "negative” symptoms of schizophrenia.
  • Another embodiment of the present invention provides a method for treating one or more symptoms associated with a psychotic disorder.
  • the present compounds are useful for treating anxiety disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder, and anxiety disorder not otherwise specified.
  • anxiety disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder, and anxiety disorder not otherwise specified.
  • the present compounds are useful for treating bipolar disorders.
  • bipolar disorders include bipolar I disorder, bipolar II disorder, and cyclothymic disorder; bipolar mania, dementia, and depression with psychotic features.
  • the present compounds are also useful for treating (including the preventing) of cycling that may occur between bipolar depression and bipolar mania.
  • compounds of the present invention are administered in combination with one or more anti-psychotic agents.
  • Such anti-psychotic agents are well known in the art and include clozapine (e.g., Clozaril ® ), risperidone (e.g., Risperidal ® ), olanzapine (e.g., Zyprexa ® ), quetiapine (e.g., Seroquel ® ), ziprasidone (e.g., Geodon ® ), aripiprazole, amisulpiride, chlorpromazine, fluphenazine, haloperidol (e.g., Haldol ® ), loxapine, mesoridazine, molindone, perphenazine, pimozide, seroquel, sulpiride, thioridazine, thiothixene, trifluoperazine, and bifeprunox to name a few.
  • clozapine e.g., Clozaril ®
  • risperidone
  • the combination of a compound of the present invention with one or more antipsychotic agents is useful for treating schizophrenia including paranoid type, disorganized type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise specified; L-DOP A-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease; bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; bipolar mania, dementia, and depression with psychotic features.
  • these combinations are useful in the treatment of bipolar disorder, including for example treating the cycling between bipolar depression and bipolar mania.
  • administration of a compound of the present invention with an anti-psychotic agent provide anti-psychotic benefits while eliminating or minimizing certain side affects (e.g., akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and the like) typically observed when the anti-psychotic agent(s) is/are taken alone.
  • certain side affects e.g., akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and the like
  • compounds of the present invention are useful for treating one or more depressive disorders such as major depressive disorder, seasonal affective disorder, dysthymic disorder, substance-induced mood disorder, depressive disorder not otherwise specified, and treatment resistant depression.
  • depressive disorders such as major depressive disorder, seasonal affective disorder, dysthymic disorder, substance-induced mood disorder, depressive disorder not otherwise specified, and treatment resistant depression.
  • Another aspect of the present invention provides a method for treating one or more mood episodes such as major depressive episode, manic episode, mixed episode, and hypomanic episode; and adjustment disorders such as adjustment disorders with anxiety and/or depressed mood.
  • mood episodes such as major depressive episode, manic episode, mixed episode, and hypomanic episode
  • adjustment disorders such as adjustment disorders with anxiety and/or depressed mood.
  • Compounds of the present invention are also useful for treating symptoms related to depressive disorders including somatic symptoms such as neuropathic pain and sexual dysfunction.
  • somatic symptoms include hopelessness, helplessness, anxiety and worries, memory complaints with or without objective signs of cognitive impairment, loss of feeling of pleasure (anhedonia), slowed movement, irritability, and lack of interest in personal care, such as poor adherence to medical or dietary regimens.
  • the present invention provides a method of treating sexual dysfunction related to depression. In other embodiments, the present invention provides a method of treating sexual dysfunction associated with administering a serotonin reuptake inhibitor (SRI) for treating a depressive or other disorder. Such methods of treating sexual dysfunction are described in detail below.
  • SRI serotonin reuptake inhibitor
  • compounds of the present invention are administered in combination with one or more antidepressive agents.
  • Suitable antidepressant agents include, for example, serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs), combined serotonin- norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists, alpha. -adrenoreceptor antagonists or other compounds including atypical antidepressants.
  • SRIs serotonin reuptake inhibitors
  • NRIs norepinephrine reuptake inhibitors
  • SNRIs combined serotonin- norepinephrine reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • RIMAs reversible inhibitors of monoamine oxidase
  • PDE4
  • Additional antidepressants for administering in combination with compounds of the present invention include triple uptake inhibitors such as DOV 216303 and DOV 21947...; melatonin agonists such as agomelotine, super neurotransmitter uptake blockers (SNUBs; e.g., NS-2389 from Glaxo SmithKline and Neurosearch; (R)-DDMA from Sepracor), and/or substance P/neurokinin receptor antagonists (e.g., aprepitant/MK-869 from Merck; NKP-608 from Novartis; CPI- 122721 from Pfizer; R673 from Roche; TAK637 from Takeda; and GW-97599 from Glaxo SmithKline).
  • Another class of antidepressant agents for administering in combination with compounds of the present invention are noradrenergic and specific serotonergic antidepressants (NaSSAs).
  • NaSSAs noradrenergic and specific serotonergic antidepressants
  • Suitable NRIs for administering in combination with compounds of the present invention include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine (See United States Patent 2,554,736, incorporated herein by reference in its entirety) and trimipramine, and pharmaceutically acceptable salts thereof.
  • Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
  • NRI for administering in combination with compounds of the present invention is reboxetine (EdronaxTM; 2-[.alpha.-(2-ethoxy)phenoxy-benzyl]morpholine, usually administered as the racemate; See United States Patent. 4,229,449, incorporated herein by reference in its entirety).
  • Suitable SSRIs for administering in combination with compounds of the present invention include: citalopram (l-[3-(dimethylamino)propyl]-(4-fluorophenyl)-l,3-dihydr-o-5- isobenzofurancarbonitrile; See United States Patent 4,136,193; Christensen et al, Eur. J. Pharmacol. 41 :153, 1977; Dufour et al., Int. Clin. Psychopharmacol.
  • fluoxetine N- methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, marketed in the hydrochloride salt form and as the racemic mixture of its two isoforms; see, for example, United States Patent 4,314,081; Robertson et al., J. Med. Chem.
  • paroxetine trans-(-)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fluo- rophenyl)piperidine; See United States Patent 3,912,743; United States Patent 4,007,196; Lassen, Eur. J. Pharmacol. 47:351, 1978; Hassan et al., Brit. J. CHn. Pharmacol. 19:705, 1985; Laursen et al., Acta Psychiat. Scand.
  • Suitable MAOIs for administering in combination with compounds of the present invention include: isocarboxazid, phenelzine, selegiline and tranylcypromine, and pharmaceutically acceptable salts thereof.
  • Suitable reversible MAOIs for administering in combination with compounds of the present invention include: moclobemide (4-chloro-N-[2-(4-morpholinyl)-ethyl]benzamide; See United States Patent 4,210,754, incorporated herein by reference in its entirety), selegiline, and pharmaceutically acceptable salts thereof.
  • Suitable SNRIs for administering in combination with compounds of the present invention include venlafaxine (see United States Patent 4,535,186, incorporated herein by reference in its entirety; see also United States Patents 5,916,923, 6,274,171, 6,403,120, 6,419,958, 6,444,708, each of which is incorporated herein by reference in its entirety), and pharmaceutically acceptable salts and analogs, including the O-desmethylvenlafaxine succinate salt; milnacipran (N,N-diethyl-2-aminomethyl-l-phenylcyclopropanecarboxamide; see United States Patent 4,478,836; Moret et al., Neuropharmacology 24:1211-19, 1985, each of which is incorporated herein by reference in its entirety); nefazodone (available from Bristol Myers Squibb and Dr.
  • Suitable CRF antagonists for administering in combination with compounds of the present invention include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
  • Suitable atypical antidepressants for administering in combination with compounds of the present invention include: bupropion (WellbutrinTM; (.+-.)-l-(3-chlorophenyl)-2-[(l,l-dim- ethylethyl)amino]-l-propanone), lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
  • Another suitable atypical antidepressant is sibutr amine.
  • antidepressants for administering in combination with compounds of the present invention include, but are not limited to, adinazolam, alaproclate, alnespirone, amineptine, amitriptyline, amitriptyline/chlordiazepoxide combination, amoxapine, aprepitant, atipamezole, azamianserin, apelinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, buproprion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clomipramine, clovoxamine, dazepinil, deanol, demexiptiline, desipramine, O- desmethylvenlafaxine, dibenzepin, dothiepin, doxepin, droxidopa, duloxetine, elzasonan,
  • Suitable classes of anti-anxiety agents for administering in combination with compounds of the present invention include 5-HT IA agonists or antagonists, especially 5-HT IA partial agonists, neurokinin recepter (NK) antagonists (e.g., saredutant and osanetant) and corticotropin releasing factor (CRF) antagonists.
  • Suitable 5-HT IA receptor agonists or antagonists that may be used in the present invention include, in particular, the 5-HT IA receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • An example of a compound with 5-HT IA receptor antagonist/partial agonist activity is pindolol.
  • new 5HT IA agonists variza, alnespirone, gepirone, sunepitron, MKC242, vilazodone, eptapirone, and ORG 12962 from Organon; new 5HT IA antagonists such as robalzotan; new 5-HT IB agonists such as elzasonan; new 5HT 2 antagonists such as YM-992 (from Yamanouchi Pharmaceuticals) and nemif ⁇ tide.
  • inventive combinations may be administered in conjunction with one or more other agents that are useful in treating depression or other mood disorders.
  • inventive combinations may be administered with one or more other pharmaceutical agents active in treating any other symptom or medical condition present in the mammal that is related or unrelated to the depression or mood disorder being experienced by the mammal.
  • pharmaceutical agents include, for example, anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, pain- relieving agents, anti-psychotic agents, gastrointestinal agents, etc., or combinations thereof.
  • Other pharmaceutical agents useful in the practice of the present invention include, for example, adjunctive therapies typically used to enhance the effects of an antidepressant.
  • adjunctive agents may include, for instance, mood stabilizers (e.g., lithium, valproic acid, carbamazepine, etc.); pindolol, stimulants (e.g., methylphenidate, dextroamphetamine, etc.); or thyroid augmenting agents (e.g., T3); anti-psychotics, anti-anxiety agents (e.g., benzodiazepines), and/or agents that relieve sexual dysfunction (e.g., buspirone, which also has anti-anxiety effects; dopaminergic agents such as amantadine, pramipexole, bupropion, etc.).
  • mood stabilizers e.g., lithium, valproic acid, carbamazepine, etc.
  • pindolol e.g., stimulants (e.g., methylphenidate, dextroamphetamine, etc.); or thyroid augmenting agents (e.g., T3)
  • PMS premenstrual syndrome
  • PMDD premenstrual dysphoric disorder
  • Parkinson's disease chronic fatigue syndrome
  • anorexia nervosa disorders of sleep (e.g., sleep apnea)
  • mutism disorders of sleep
  • PMDD Premenstrual dysphoric disorder
  • PMDD is a severe form of PMS. Like PMS, PMDD typically occurs the week before the onset of menstruation and disappears a few days after. PMDD is characterized by severe monthly mood swings and physical symptoms that interfere with everyday life, especially a woman's relationships with her family and friends. PMDD symptoms go far beyond what are considered manageable or normal premenstrual symptoms.
  • PMDD is a combination of symptoms that may include irritability, depressed mood, anxiety, sleep disturbance, difficulty concentrating, angry outbursts, breast tenderness and bloating.
  • the diagnostic criteria emphasize symptoms of depressed mood, anxiety, mood swings or irritability.
  • the condition affects up to one in 20 American women who have regular menstrual periods.
  • the present invention provides a method for treating one or more symptoms associated with PMDD.
  • SSRIs selective serotonin reuptake inhibitors
  • the present invention provides a method for treating PMDD, or one or more symptoms associated with PMDD, by administering a compound of formula I in combination with an SSRI.
  • the SSRI is fluoxetine, venlafaxine, paroxetine, duloxetine, or sertraline.
  • compounds of the present invention are useful for treating a variety of eating disorders.
  • the eating disorder is hyperphagia, bulimia or anorexia nervosa.
  • compounds of the present invention are useful for treating gastrointestinal disorders, such as malfunction of gastrointestinal motility or intestinal propulsion.
  • Compounds of the present invention are also useful in connection with weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression).
  • Such methods are particularly useful for treating obesity with its consequent comorbidities including diabetes insipidus, Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality.
  • compounds of the present invention are administered in combination with one or more anti-obesity agents.
  • anti-obesity agents include apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, l l ⁇ -hydroxy steroid dehydrogenase- 1 (l l( ⁇ -HSD type 1) inhibitors, PYY 3 .
  • MCR-4 agonists cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, R3 adrenergic receptor agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists (e.g., rimonabant), melanin concentrating hormone antagonists, leptins (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
  • anorectic agents such as a bombesin agonist
  • Neuropeptide-Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analog thereof such as glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon- like peptide- 1 receptor agonists, ciliary neurotrophic factors (such as Axokine TA ), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists.
  • anorectic agents such as a bombesin agonist
  • Neuropeptide-Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • a compound of the present invention is administered in combination with an anti-obesity agent selected from orlistat, sibutramine, bromocriptine, ephedrine, leptin, rimonabant, pseudoephedrine, PYY3.36 or an analog thereof, and 2-oxo-N- (5-phenyipyrazinyl)spiro-[isobenzofuran-l(3H),4 -piperidine]-l -carboxamide.
  • an anti-obesity agent selected from orlistat, sibutramine, bromocriptine, ephedrine, leptin, rimonabant, pseudoephedrine, PYY3.36 or an analog thereof, and 2-oxo-N- (5-phenyipyrazinyl)spiro-[isobenzofuran-l(3H),4 -piperidine]-l -carboxamide.
  • an anti-obesity agent selected from orlistat,
  • a compound of the present invention is administered in combination with one or more agents for treating diabetes and associated conditions.
  • a compound of the present invention is administered in combination with one or more such agents including insulin and insulin analogs (e.g., LysPro Insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-3O)-NH 2 ; sulfonylureas and analogs thereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; W 2- antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166
  • insulin and insulin analogs e.g
  • a compound of the present invention is administered in combination with one or more lipid- lowering agents: benfluorex: vanadate and vanadium complexes (e.g., Nagiivan ® ) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox, WAG 994, pramlintide (Symlin” ), AC 2993, nateglinide, aldose reductase inhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium- hydrogen exchanger type 1 (NNE-I) inhibitors and/or cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, especially a HMG-CoA reductase inhibitor, or a HMG-CoA synthas
  • benfluorex van
  • a compound of the present invention is administered in combination with one or more naturally occurring compounds that acts to lower plasma cholesterol levels.
  • Such naturally occurring compounds are commonly referred to as nutraceuticals and include, for example, garlic extract, Hoodia plant extracts, and niacin.
  • compounds of the present invention are useful for inducing, assisting or maintaining desirable bladder control in a mammal. The methods are particularly useful for treating a mammal that is experiencing or susceptible to bladder instability or urinary incontinence.
  • Inventive methods include prevention, treatment or inhibition of bladder-related urinary conditions and bladder instability, including idiopathic bladder instability, nocturnal enuresis, nocturia, voiding dysfunction and urinary incontinence (including, for example, stress incontinence, urge incontinence, and/or mixed incontinence).
  • bladder instability secondary to prostate hypertrophy is a method for enhancing urethral tone and reducing undesirable urine leakage even in an otherwise healthy person.
  • the inventive methods are applicable to alleviating urine leakage often occurring in women during the first year after childbirth.
  • the present compounds are useful for treating urine retention or detrusor sphinctor dyssynergia.
  • Patients suffering from urine retention include those suffering from spinal cord injuries or male patients with benign prostatic hyperplasia.
  • a compounds of the present invention is also useful in promoting the temporary delay of urination whenever desirable. Such compounds may be utilized in accordance with the present invention to stabilize the bladder in any applicable context. Inventive methods therefore may be utilized to allow a recipient to control the urgency and frequency of urination.
  • compounds of the present invention are administered to a mammal in need thereof for the treatment, prevention, inhibition and/or amelioration of urge urinary incontinence (also known as bladder instability, neurogenic bladder, voiding dysfunction, hyperactive bladder, detrusor overactivity, detrusor hyper-reflexia or uninhibited bladder) or mixed urinary incontinence.
  • urge urinary incontinence also known as bladder instability, neurogenic bladder, voiding dysfunction, hyperactive bladder, detrusor overactivity, detrusor hyper-reflexia or uninhibited bladder
  • Inventive uses include, but are not limited to, those for bladder activities and instabilities in which the urinary urgency is associated with prostatitis, prostatic hypertrophy, interstitial cystitis, urinary tract infections or vaginitis.
  • the methods of this invention may also be used to assist in inhibition or correction of the conditions of Frequency-Urgency Syndrome, and lazy bladder, also known as infrequent voiding syndrome.
  • Compounds of the present invention may also be used to treat, prevent, inhibit, or limit the urinary incontinence, urinary instability or urinary urgency associated with or resulting from administrations of other medications, including diuretics, vasopressin antagonists, anticholinergic agents, sedatives or hypnotic agents, narcotics, alpha-adrenergic agonists, alpha- adrenergic antagonists, or calcium channel blockers.
  • Compounds of the present invention are useful for inducing or assisting in urinary bladder control or preventing or treating the maladies described herein in humans in need of such relief, including adult and pediatric uses. They may also be utilized for veterinary applications, particularly including canine and feline bladder control methods. If desired, the methods herein may also be used with farm animals, such as ovine, bovine, porcine and equine breeds. [00114] According to the present invention, compounds of the present invention may be administered alone to modulate bladder activity, or alternatively may be administered in combination with (whether simultaneously or sequentially) one or more other pharmaceutical agents useful in the modulation of bladder activity.
  • the compounds of the present invention may be administered in combination with one or more other pharmaceutical agents useful in the treatment or prevention of one or more other symptoms, disorders, or diseases suffered by the individual in need of bladder activity modulation.
  • Other pharmaceutical agents useful in the modulation of bladder activity, and particularly for treatment, prevention, inhibition, and/or amelioration of urinary incontinence include, for example, desmopressin acetate (available as DDA VP® Nasal Spray and DDAVP® tablets from Aventis Pharmaceuticals), as well as a desmopressin acetate rhinal tube (available from Ferring Pharmaceuticals Inc.).
  • tolterodine tartrate available as Detroltm tablets from Pharmacia & Upjohn
  • oxybutinin chloride available in the form of Ditropan® tablets and syrup and Ditropan XL® extended release tablets from ALZA Pharmaceuticals
  • propanthaline bromide available in tablet form from Roxane Laboratories, Inc.
  • hyoscyamine and hyoscyamine sulfate available, respectively, as Cystopaz® tablets and Cystopaz-M® timed release capsules from PolyMedica Pharmaceuticals (U.S.A.), Inc.
  • hyoscyamine hydrobromide flavoxate HCl (available in Urispas® 100 mg tablets from ALZA Pharmaceuticals), imipramine HCl (available in 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuticals, Inc.), phenylpropanolamine, midodrine HCl (available in 2.5 mg and 5 mg Proamatine® tablets from Shire US Inc.
  • Each of these medicaments may be administered in the pharmaceutically effective amounts and regimens known in the art, including those listed in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Company, Inc. at Monvale, NJ 07645-1742, the relevant portions of which are incorporated herein by reference.
  • Yet other pharmaceutical agents that can act to modulate bladder activity include, for example, other regulators of the 5HT 2C receptor.
  • United States Patent Publication Number 2004/0235856 describes a variety of 5HT 2 c receptor modulators that are useful in accordance with the practice of the present invention, the entirety of which is hereby incorporated herein by reference. Additional 5HT 2 c agonists are exemplified in Bishop et al., Expert Opin. Ther. Patent 13:1691-1705, 2003, the entire contents of which are incorporated herein by reference.
  • Still other pharmaceutical agents that can act to modulate bladder activity include, for example, modulators of one or more KCNQ potassium channels.
  • compounds of the present invention are administered in conjunction with one or more agonists of KCNQ 2/3 or KCNQ3/5.
  • KCNQ modulators include, for example, compounds described in United States Patent Number 5,384,330 and those described in United States Patent Number 5,565,483, as well as those described in United States Patent Publication Number 2002/0183395 (now abandoned); and United States Patent Publication Number 2004/0029949, now U.S. Patent Number 7,015,242. The entire contents of each of these patents and patent applications is incorporated herein by reference.
  • compounds of the present invention are administered with retigabine.
  • compounds of the present invention are administered in conjunction with one or more compounds which act as vasopressin agonists including, but not limited to those described in U.S. Patent No. 6,194,407 (Failli et al), U.S. Patent No. 6,090,803 (Failli et al.), U.S. Patent No. 6,096,736 (Ogawa et al.), and U.S. Patent No. 6,096,735 (Ogawa et al.).
  • compounds of formula I may be used to treat, prevent, or alleviate dependence, withdrawal, or symptoms thereof for any of a variety of substances including, for example, recreational substances (e.g., alcohol, tobacco [for example, nicotine]), pharmacologic agents (e.g., pain relievers [for example, Vicodin ® , Lortab ® , Lorcet ® , Percocet ® , Percodan ® , Tylox ® , Hydrocodone, OxyContin ® , methadone, Tramadol, etc], tranquilizers, stimulants, or sedatives), and illicit drugs (e.g., marijuana, heroine, cocaine, ecstasy, LSD, PCP, methamphetamine, etc
  • substance abuse may be defined with reference to criteria set form in the Diagnostic and Statistical Manual of Mental Disorders, 4 th Ed. (1994) ("DSM- IV"), which was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association.
  • DSM- IV Diagnostic and Statistical Manual of Mental Disorders, 4 th Ed. (1994)
  • a feature of substance abuse is a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances.
  • substance abuse is defined as maladaptive pattern of substance abuse leading to clinicalyl significant impairment or distress, as manifested by one(or more) of the following, occurring within a 12-month period: (1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home; (2) recurrent substance use in situations in which it is physically hazardous; (3) recurrent substance-related legal problems; and (4) continued substance use despite having persistent or recurrent social or interpersonal problems cause or exacerbated by the effects of the substance.
  • the DMS-IV requires that the symptoms of substance abuse do not meet the criteria for substance dependence.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • the criteria for substance dependence set forth in DSM-IV is a pattern of substance use, leading to clinically significant impairment or distress as manifested by at least three selected from the following group, occurring at any time within the same twelve month period: (1) tolerance as defined by either (a) a need for substantially increased amounts of the substance to achieve the desired effect; or (b) substantially diminished effect with continued use of the same amount of the substance; (2) withdrawal, as demonstrated by either (a) the characteristic withdrawal syndrome for the specific substance; or (b) the same, or a closely related substance is taken to relieve or avoid withdrawal symptoms; (3) the substance is often taken in larger amounts or over a longer period then was intended; (4) there is a persistent desire or unsuccessful efforts to cut down or control substance use; (5) a great deal of time is spent in activities to obtain the substance, use the substance, or recover from its effects; (6) important social, occupational or recreational activities are given up or reduced because of substance use; and (7) the substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or
  • Substance dependence can be with physiological dependence; that is evidence of tolerance or withdrawal is present, or without physiological dependence, where no evidence of tolerance or withdrawal is present.
  • DSM-IV includes remission. These types of remission are based on the interval of time that has elapsed since the cessation of dependencies and whether there is continued presence of one or more of the symptoms included in the criteria for dependencies.
  • compounds of the present invention are useful for treating alcoholism (e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake) and/or tobacco abuse (e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking).
  • alcoholism e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake
  • tobacco abuse e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking.
  • NASH National Survey on Drug Use and Health
  • drugs are grouped under the hallucinogens category, including LSD, PCP, peyote, mescaline, mushrooms, and "Ecstasy” (MDMA).
  • Inhalants include a variety of substances, such as amyl nitrite, cleaning fluids, gasoline, paint, and glue.
  • the four categories of prescription-type drugs cover numerous drugs available through prescriptions and sometimes illegally "on the street.” Methamphetamine is considered a type of stimulant. Respondents are asked to report only uses of drugs that were not prescribed for them or drugs they took only for the experience or feeling they caused. Over-the-counter drugs and legitimate uses of prescription drugs are not included.
  • NSDUH reports combine the four prescription-type drug groups into a category referred to as "any psychotherapeutics.”
  • the NSDUH categorizes alcohol abuse through use of questions about the frequency of the consumption of alcoholic beverages, such as beer, wine, whiskey, brandy, and mixed drinks.
  • An extensive list of examples of the kinds of beverages covered is given to respondents prior to the question administration.
  • a "drink" is defined as a can or bottle of beer, a glass of wine or a wine cooler, a shot of liquor, or a mixed drink with liquor in it. Times when the respondent only had a sip or two from a drink are not considered as consumption. For this report, estimates for the prevalence of alcohol use are reported primarily at three levels defined for both males and females and for all ages as follows: Current use - At least one drink in the past 30 days (includes binge and heavy use).
  • the NSDUH also characterizes the use of tobacco products, including cigarettes, chewing tobacco, snuff, cigars, and pipe tobacco. For analytic purposes, data for chewing tobacco and snuff are combined as "smokeless tobacco.” Cigarette use is defined as smoking “part or all of a cigarette.” Questions to determine nicotine dependence among current cigarette smokers also are included in NSDUH. Nicotine dependence is based on criteria from the Nicotine Dependence Syndrome Scale (NDSS) or the Fagerstrom Test of Nicotine Dependence (FTND).
  • NDSS Nicotine Dependence Syndrome Scale
  • FTND Fagerstrom Test of Nicotine Dependence
  • compounds of the present invention are useful for treating withdrawal from drug addiction including addiction to nicotine, alcohol, and other substances of abuse.
  • Individuals often suffer the symptoms of nicotine withdrawal as a consequence of the discontinued use of tobacco in any form, including, but not limited to smoking of cigarette, cigar, or pipe tobacco, or the oral or intranasal ingestion of tobacco or chewing tobacco.
  • Such oral or intranasal tobacco includes, but is not limited to snuff and chewing tobacco.
  • the cessation of nicotine use or reduction in the amount of nicotine use is often followed within 24 hours by symptoms including dysphoric, depressed mood; light-headedness; insomnia; irritability, frustration or anger; anxiety; nervous tremor; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain; and the craving for tobacco or nicotine.
  • symptoms including dysphoric, depressed mood; light-headedness; insomnia; irritability, frustration or anger; anxiety; nervous tremor; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain; and the craving for tobacco or nicotine.
  • opioid withdrawal condition typically self- administration, through injection or orally, through smoking or intranasal ingestion, often results in the presence of a characteristic opioid withdrawal condition.
  • This withdrawal condition can also be precipitated by administration of an opioid antagonist such as naloxone or naltrexone after opioid use.
  • opioid antagonist such as naloxone or naltrexone after opioid use.
  • Opioid withdrawal is characterized by symptoms that are generally opposite to the opioid agonist effects. These withdrawal symptoms may include anxiety; restlessness; muscle aches, often in the back and legs; craving for opioids; irritability and increased sensitivity to pain; dysphoric mood; nausea or vomiting; lacrimation; rhinorrhoea; papillary dilation; piloerection; sweating; diarrhea; yawning; fever; and insomnia.
  • the present invention is most preferably used to alleviate one or more symptoms attributed to opioid withdrawal when such symptoms are not due to a general medical condition and are not better accounted for by another medical disorder.
  • Ethanol withdrawal conditions are characterized by symptoms that begin when blood concentrations of ethanol decline sharply, within 4 to 12 hours after ethanol use has been stopped or reduced. These ethanol withdrawal symptoms include craving for ethanol; autonomic hyperactivity (such as sweating or pulse rate greater than 100); hand tremor; insomnia; nausea; vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; and grand mal seizures. These symptoms often cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • a compound of the present invention is administered in combination with one or more agents useful for treating substance abuse.
  • a compound of the present invention is administered in combination with one or more agents to treat tobacco abuse.
  • agents include nicotine receptor partial agonists bupropion hypochloride (ZybanTM) and nicotine replacement therapies.
  • a compound of the present invention is administered in combination with one or more agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone, Re ViaTM), nalmefene, disulf ⁇ ram (AntabuseTM), and acamprosate (CampralTM).
  • opioid antagonists e.g., naltrexone, Re ViaTM
  • nalmefene e.g., nalmefene
  • disulf ⁇ ram e.g., ntabuseTM
  • acamprosate e.g., acamprosate
  • a compound is administered in combination with one or more agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • therapy utilizing compounds of the present invention is administered concomitantly with, in connection with, and/or subsequent to an educational and/or behavioral modification program to enhance continued abstinence from substance dependence or abuse.
  • the method of the present invention may be particularly useful in treating symptoms of withdrawal often observed in rehabilitation or other treatment programs. Therefore, the programs can be more effective by focusing on educational and behavioral modification goals, further reducing the incidence of program non-completion.
  • compounds of the present invention are useful for treating one or more intellectual deficit disorders comprising administering a compound of the present invention.
  • intellectual deficit disorders include dementia, such as dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder; Alzheimer's disease, and memory deficit, attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults.
  • ADD attention deficit disorders
  • the present invention provides a method of treating ADD and/or ADHD in a pediatric patient comprising administering to said patient a compound of formula I or pharmaceutical composition thereof.
  • the present invention provides a method of treating one or more cognition disorders.
  • the cognition disorder is a learning disorder.
  • learning disorders are known in the art and include autism, dyslexia, Asperger's syndrome, a neurobiological disorder similar to autism and characterized by serious deficits in social and communication skills; specific learning disability, a disorder in one or more of the basic psychological processes involved in understanding or in using spoken or written language, which may manifest itself in an imperfect ability to listen, think, speak, read, write, spell or to do mathematical calculations; dysgraphia, a disorder that causes difficulty with forming letters or writing within a defined space; dyscalculia, a disorder that causes people to have problems doing arithmetic and grasping mathematical concepts; dyspraxia, a problem with the body's system of motion that interferes with a person's ability to make a controlled or coordinated physical response in a given situation; visual perceptual deficit, difficulty receiving and/or processing accurate information from the sense of sight, although there is nothing wrong with vision
  • the present invention provides a method for treating one or more impulsivity disorders (e.g. borderline personality disorder), disruptive behavior disorders, or impulse control disorders.
  • the present invention provides a method for treating Tourette's syndrome (TS), an inherited, neurological disorder characterized by repeated and involuntary body movements (tics) and/or uncontrollable vocal sounds.
  • TS Tourette's syndrome
  • the present invention provides a method for treating one or more behavioral addictions and addictive disorders. Behavioral addictions and addictive disorders result from the intoxication one senses from the release of brain chemicals (e.g., serotonin, adrenaline, epinepherine, etc.) during certain activities.
  • brain chemicals e.g., serotonin, adrenaline, epinepherine, etc.
  • a compound of the present invention is administered in combination with one or more cognitive improvement agents.
  • Such agents are well known in the art and include donepezil hydrochloride (AirceptTM) and other acetylcholinesterase inhibitors; galantamine, neuroprotective agents (e.g., memantine); ADD/ADHD agents (e.g., methylphenidate (Ritalin 1 ""), atomoxetine (StratteraTM), methylphenidate, sustained release (ConcertaTM) and amphetamine/dextroamphetamine (AdderallTM).
  • AirceptTM donepezil hydrochloride
  • other acetylcholinesterase inhibitors galantamine
  • neuroprotective agents e.g., memantine
  • ADD/ADHD agents e.g., methylphenidate (Ritalin 1 ""), atomoxetine (StratteraTM), methylphenidate, sustained release (ConcertaTM) and amphetamine/dextroamphetamine (AdderallTM).
  • the present invention provides a method for treating sexual dysfunction comprising administering a compound of the present invention.
  • the sexual dysfunction is associated with a depressive disorder.
  • the sexual dysfunction is associated with treatment of a disorder by administration of a serotonin reuptake inhibitor.
  • Compounds of the present invention are useful for treating sexual dysfunction in the male and in the female.
  • Such disorders include male erectile dysfunction (MED) and female sexual dysfunction (FSD), e.g. female sexual arousal disorder (FSAD).
  • the present invention provides a method for treating one or more disorders associated with sexual dysfunction including: HSDD, characterized by a deficiency, or absence of, sexual fantasies and desire for sexual activity; FSAD, characterized by a persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement; FOD characterized by persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase; Sexual Pain Disorders such as dyspareunia and vaginismus; and/or HSDD characterized by a woman who has no or little desire to be sexual, and has no or few sexual thoughts or fantasies.
  • HSDD characterized by a deficiency, or absence of, sexual fantasies and desire for sexual activity
  • FSAD characterized by a persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement
  • FOD characterized by persistent or recurrent delay in
  • a compound of the present invention is administered in combination with one or more agents for treating male sexual dysfunction (e.g., male erectile dysfunction).
  • agents include a dopaminergic agent (e.g. D2, D3 or D4 agonists and apomorphine); an NPY (neuropeptide Y) (preferably an NPY-I and/or NPY-5 inhibitor); a melanocortin receptor agonist or modulator or melanocortin enhancer; an NEP inhibitor; a PDE inhibitor (preferably, a cGMP PDE-5 inhibitor); a bombesin receptor antagonist or modulator, and a soluble secreted endopeptidase inhibitor (SEPi).
  • a dopaminergic agent e.g. D2, D3 or D4 agonists and apomorphine
  • an NPY neuropeptide Y
  • a melanocortin receptor agonist or modulator or melanocortin enhancer e.g., an NPY-I and
  • a compound of the present invention is administered in combination with one or more agents for treating male sexual dysfunction such as alprostadil or sildenafil.
  • a compound of the present invention is administered in combination with one or more agents for treating female sexual dysfunction.
  • estrogen receptor modulators e.g., estrogen agonists and/or estrogen antagonists
  • testosterone replacement agents include testosternone (Tostrelle), dihydrotestosterone, dehydroepiandrosterone (DHEA), a testosterone implant
  • DHEA dehydroepiandrosterone
  • MPA dehydroandrostendione
  • Estrace Estrofem
  • MCA medroxyprogesterone acetate
  • compounds of the present invention are useful for treating any of a variety of different types of pain experienced by mammals, such as humans.
  • the compounds of the present invention may be used to treat treating acute pain (short duration) or chronic pain (regularly reoccurring or persistent), whether centralized or peripheral.
  • Examples of pain that can be acute or chronic and that can be treated in accordance with the methods of the present invention include inflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain, or headaches such as migraines or tension headaches, or combinations of these pains.
  • a pain caused by inflammation may also be visceral or musculoskeletal in nature.
  • one or more compounds of the present invention is/are administered in mammals to treat chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and/or perineal regions or pancreatitis; musculoskeletal pain associated with for example the lower or upper back, spine, f ⁇ bromylagia, temporomandibular joint, or myofascial pain syndrome; bony pain associated with for example bone or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such migraine or tension headaches; or pain associated with infections such as HIV, sickle cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.
  • chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic
  • the compounds of the present invention are used to treat chronic pain that is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, headache, cancer pain or inflammatory pain or combinations thereof, in accordance with the methods described herein.
  • Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury.
  • Neuropathic pain may be associated with for example diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections such as shingles or HIV, or combinations thereof.
  • Inventive treatment methods further include treatments in which the neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns or central pain conditions related to thalamic conditions.
  • Neuropathic pains described above may also be, in some circumstances, classified as "painful small fiber neuropathies” such as idiopathic small-fiber painful sensory neuropathy, or "painful large fiber neuropathies” such as demylinating neuropathy or axonal neuropathy, or combinations thereof.
  • pains are described in more detail, for example, in the J. Mendell et al, N. Engl. J. Med. 2003, 348:1243-1255, which is hereby incorporated by reference in its entirety.
  • the compounds useful in the present invention may be administered to totally or partially inhibit a neuropathic pain condition from developing.
  • compounds of the present invention may be administered to a mammal who is at risk for developing a neuropathic pain condition such as a mammal who has contracted shingles or a mammal who is being treated for cancer.
  • the compounds useful in the present invention may be administered prior to or during a surgical procedure to partially or totally inhibit development of pain associated with the surgical procedure.
  • somatic pain that can be treated in accordance with the methods of the present invention includes pain associated with structural or soft tissue injury experienced during surgery, dental procedures, burns, or traumatic body injuries.
  • visceral pain that can be treated in accordance with the methods of the present invention include those types of pain associated with or resulting from maladies of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, or biliary tract disorders, or combinations thereof.
  • the pain treated according to the methods of the present invention may also be related to conditions of hyperalgesia, allodynia, or both. Additionally, chronic pain to be treated in accordance with the present invention may be with or without peripheral or central sensitization. [00150]
  • the present invention also provides use of the compounds of the present invention to treat acute and/or chronic pains associated with female conditions, which may also be referred to as female-specific pain.
  • Such types of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes.
  • a compound of the present invention is administered in combination with a pain relieving agent.
  • pain relieving agents include, but are not limited to, analgesics such as non-narcotic analgesics or narcotic analgesics; anti-inflammatory agents such as nonsteroidal anti-inflammatory agents (NSAIDs), steroids or anti-rheumatic agents; migraine preparations such as beta adrenergic blocking agents, ergot derivatives, or isometheptene; tricyclic antidepressants such as amitryptyline, desipramine, or imipramine; anti-epileptics such as gabapentin, carbamazepine, topiramate, sodium valproate or phenytoin; ⁇ 2 agonists; or selective serotonin reuptake inhibitors/selective norepinepherine uptake inhibitors, or combinations thereof.
  • analgesics such as non-narcotic analgesics or narcotic analgesics
  • agents described herein act to relieve multiple conditions such as pain and inflammation, while other agents may just relieve one symptom such as pain.
  • a specific example of an agent having multiple properties is aspirin, where aspirin is anti-inflammatory when given in high doses, but at lower doses is just an analgesic.
  • the pain relieving agent may include any combination of the aforementioned agents, for example, the pain relieving agent may be a non-narcotic analgesic in combination with a narcotic analgesic.
  • Non-narcotic analgesics useful in the practice of the present invention include, for example, salicylates such as aspirin, ibuprofen (Motrin ® , Advil ® ), ketoprofen (Orudis ® ), naproxen (Naprosyn ® ), acetaminophen, indomethacin or combinations thereof.
  • narcotic analgesic agents that may be used in combination with compounds of the present invention include opioid analgesics such as fentenyl, sufentanil, morphine, hydromorphone, codeine, oxycodone, buprenorphine or pharmaceutically acceptable salts thereof or combinations thereof.
  • anti-inflammatory agents examples include but are not limited to aspirin; ibuprofen; ketoprofen; naproxen; etodolac (Lodine ® ); COX-2 inhibitors such as celecoxib (Celebrex ® ), rofecoxib (Vioxx ® ), valdecoxib (Bextra @) , parecoxib, etoricoxib (MK663), deracoxib, 2-(4-ethoxy-phenyl)- 3-(4-methanesulfonyl-phenyl)-pyrazolo[ 1 ,5-b] pyridazine, 4-(2-oxo-3-phenyl-2,3- dihydrooxazol-4-yl)benzenesulfonamide, darbufelone, flosulide, 4-(4-cyclohexyl-2-methyl-5- oxazolyl)-2-fluoro
  • agents used to treat inflammations include immunosuppressants such as GengrafTM brand cyclosporine capsules, Neoral ® brand cyclosporine capsules or oral solution, or Imuran ® brand azathioprine tablets or IV injection; Indocin ® brand indomethacin capsules, oral suspension or suppositories; Plaquenil ® brand hydroxychloroquine sulfate; or Remicade ® infliximab recombinant for IV injection; or gold compounds such as auranofm or Myochrisyine ® gold sodium thiomalate injection.
  • immunosuppressants such as GengrafTM brand cyclosporine capsules, Neoral ® brand cyclosporine capsules or oral solution, or Imuran ® brand azathioprine tablets or IV injection
  • Indocin ® brand indomethacin capsules, oral suspension or suppositories Plaquenil ® brand hydroxychloroquine sulfate; or
  • disorders of the present invention are useful for treating a variety of disorders.
  • disorders include premenstrual syndrome, motion or motor disorders such as Parkinson's disease and epilepsy; migraines, chronic fatigue syndrome, anorexia nervosa, disorders of sleep (e.g., sleep apnea), and mutism.
  • compounds of the present invention are useful for treating one or more central nervous system deficiencies associated, for example, with trauma, stroke, and spinal cord injuries, neurodegenerative diseases or toxic or infective CNS diseases (e.g., encephalitis or meningitis), or Parkinson's disease.
  • the compounds of the present invention can therefore be used to improve or inhibit further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength. 5.
  • the invention relates to compositions comprising at least one compound of formula I or III, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system.
  • the compositions comprise mixtures of one or more compounds of formula I or III.
  • the invention relates to compositions comprising at least one compound of formula I or III, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety.
  • Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
  • the compounds of formula I or III can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
  • the carrier is a finely divided solid that 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, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • 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 a pharmaceutically acceptable oil or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsif ⁇ ers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the compounds of formula I or III can be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of formula I or III can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of formula I can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable.
  • a variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, pref ⁇ lled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the amount of compound of formula I or III provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • compounds of formula I are provided to a patient suffering from a condition in an amount sufficient to treat or at least partially treat the symptoms of the condition and its complications.
  • An amount adequate to accomplish this is a "therapeutically effective amount" as described previously herein.
  • the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and the size, age, and response pattern of the patient.
  • the treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician.
  • a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the patient.
  • the present invention is directed to prodrugs of compounds of formula I.
  • prodrug as used herein is defined above.
  • 5-HT stands for 5-hydroxytryptamine
  • mCPP stands for meta-chlorophenylpiperazine
  • DOI stands for l-(2,5-dimethoxy-4- iodophenyl)isopropylamine.
  • a CHO (Chinese Hamster Ovary) cell line transfected with the cDNA expressing the human 5-hydroxytryptamine-2C (h5-HT 2 c) receptor is maintained in DMEM (Dulbecco's Modified Eagle Media) supplied with fetal calf serum, glutamine, and the markers: guaninephosphoribosyl transferase (GTP) and hypoxanthinethymidine (HT).
  • GTP guaninephosphoribosyl transferase
  • HT hypoxanthinethymidine
  • the harvested cells are suspended in half volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at low speed (900 x g). This operation is repeated once.
  • the collected cells are then homogenized with a polytron at setting #7 for 15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA.
  • the homogenate is centrifuged at 900 x g for 15 min to remove nuclear particles and other cell debris. The pellet is discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min.
  • the resulting pellet is resuspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 ⁇ L volumes.
  • Bovine Serum Albumin (BSA) is used as the standard in the protein determination by the method of Lowry et al, (J. Biol. Chem., 193:265 (1951).
  • the volume of the suspended cell membranes is adjusted with 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCl 2 to give a tissue protein concentration of 1-2 mg per ml of suspension.
  • the preparation membrane suspension (many times concentrated) is aliquoted in 1 ml volumes and stored at -70 C until used in subsequent binding experiments.
  • Binding measurements are performed in a 96 well microtiter plate format, in a total volume of 200 ⁇ L. To each well is added: 60 ⁇ L of incubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4 mM CaCl 2 ; 20 ⁇ L of [ 125 I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).
  • the dissociation constant, K D of [ 125 I] DOI at the human serotonin 5 -HT 2C receptor is 0.4 nM by saturation binding with increasing concentrations of [ 125 I] DOI.
  • the reaction is initiated by the final addition of 100 ⁇ L of tissue suspension containing 50 ⁇ g of receptor protein. Nonspecific binding is measured in the presence of 1 ⁇ M unlabeled DOI added in 20.0 ⁇ L volume. Test compounds are added in 20.0 ⁇ L. The mixture is incubated at room temperature for 60 min. The incubation is stopped by rapid filtration. The bound ligand-receptor complex is filtered off on a 96 well unifilter with a Packard ® Filtermate 196 Harvester.
  • Ketanserin 94.8 (70.7 - 127.0) nM
  • CHO cells stably expressing the human 5-HT 2 c receptor are cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and nonessential amino acids.
  • DMEM Dulbecco's modified Eagle's medium
  • Cells are plated at a density of 4OK cells/well in 96-well clear-bottom black- wall plates 24 hours prior to the evaluation of 5-HT 2C receptor- stimulated calcium mobilization.
  • DMEM Dulbecco's modified Eagle's medium
  • HBS Hank's buffered saline
  • Fluorometric imaging plate reader FLIPR, Molecular Devices, Sunnyvale, CA
  • Excitation at 488 nm is achieved with an Argon ion laser and a 510-560 nm emission filter is used.
  • Fluorescence images and relative intensities are captured at 1 second intervals and cells were stimulated by addition of agonist after 10 baseline measurements using the internal fluidics module of the FLIPR. An increase in fluorescence counts corresponds to an increase in intracellular calcium.
  • compounds of the present invention provide an EC50 of ⁇ about 1000 nM. In other embodiments, compounds of the present invention provide an EC50 of ⁇ about 100 nM, in yet other embodiments ⁇ about 20 nM, in still other embodiments ⁇ about 5 nM, and certain embodiments ⁇ about 2 nM. [00175] The following ECso's are provided for various reference compounds in Table 3, below

Abstract

L'invention concerne des composés qui sont des agonistes ou agonistes partiels du sous-type 2C des récepteurs cérébraux de la sérotonine. Les composés présentent la formule I : des sels pharmaceutiquement acceptables de ceux-ci, chacun des A, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Re, Rx, Ry, m, n et chaque groupe == étant tel que défini ici. Ces composés et leurs compositions sont utiles pour traiter divers troubles du système nerveux central tels que la schizophrénie.
PCT/US2007/082450 2006-10-24 2007-10-24 Dérivés de benzodioxane et leurs utilisations WO2008052086A1 (fr)

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WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
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WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
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