WO2006000902A1 - Composes dihydrobenzofurane et leurs utilisations - Google Patents

Composes dihydrobenzofurane et leurs utilisations Download PDF

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Publication number
WO2006000902A1
WO2006000902A1 PCT/IB2005/001853 IB2005001853W WO2006000902A1 WO 2006000902 A1 WO2006000902 A1 WO 2006000902A1 IB 2005001853 W IB2005001853 W IB 2005001853W WO 2006000902 A1 WO2006000902 A1 WO 2006000902A1
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Prior art keywords
compound
alkyl
membered
substituted
fully saturated
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PCT/IB2005/001853
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English (en)
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Yuan-Ching Phoebe Chiang
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Pfizer Products Inc.
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Publication of WO2006000902A1 publication Critical patent/WO2006000902A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to dihydrobenzofuran compounds.
  • the dihydrobenzofuran compounds have been found to act as 5-HT receptor ligands, in particular 5-HT 2c receptor agonists and 5- HT 2a receptor antagonists; therefore, the present invention also relates to their uses in the prevention or treatment of diseases linked to the activation of the 5-HT 2c receptor and/or blocking of the 5-HT 2a receptor in animals.
  • BACKGROUND Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors.
  • Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. As expected, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism and neurodegenerative disorders.
  • the serotonin receptors are currently classified into seven subfamilies (5-HT 1 through 5-HT 7 ). See, Hoyer, D., et al., "VlI International Union of Pharmacology classification of receptors for 5- hydroxytryptamine", Pharmacol. Rev., 56, 157-203 (1994).
  • the subfamilies have been further divided into subtypes.
  • the 5-HT 2 receptor is currently divided into three subtypes: 5-HT 2a , 5-HT 2b and 5- HT 2c .
  • the three subtypes of 5-HT 2 receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (which activates protein kinase C) and inositol trisphosphate (which releases intracellular stores of Ca 2+ ).
  • the 5-HT 2c receptors have a very high density in the choroid plexus, an epithelial tissue that is the primary site of cerebrospinal fluid production. See, Sanders-Bush, E. and S. E.
  • 5-HT 2c receptor agonists or antagonists for use in the treatment of obesity and other related diseases associated with decreased neurotransmission of serotonin in mammals. See, e.g., EP 863136 (azetidine and pyrrolidine derivatives); EP 657426 (tricyclic pyrrole derivatives); EP 655440 (substituted 1-aminoethyl indoles); EP 572863 (pyrazinoindole derivatives); WO98/030548 (aminoalkylindazole compounds); WO 98/56768 (tricyclic pyrrole and pyrazole derivatives); WO 99/43647 (azetidine and pyrrolidine derivatives); WO 99/58490 (aryl-hydronaphthalenalkanamine derivatives); WO 00/12475 (indoline derivatives); WO 00/12482 (indazole derivatives); WO 00/12502 (pyrroloquinoline derivatives); WO 00/12510
  • the present invention provides compounds of Formula (I).
  • the compounds of Formula (!) have been found to be useful as 5-HT 2 receptor ligands (in particular, 5-HT 2a and 5-HT 2c receptor ligands).
  • R 1a is hydrogen or (Ci-C 4 )alkyl, or R 1a taken together with R 1b forms a 5- to 10-membered partially or fully saturated heterocyclic ring containing one to two additional N atoms, where said heterocyclic ring is optionally substituted with one or more independently selected from the group consisting of fluoro, (Ci-C 4 )alkyl, fluoro-substituted (Ci-C 4 )alkyl, and fluoro-substituted(CrC 4 )alkoxy;
  • R 1b is (i) hydrogen, (ii) a partially or fully saturated 3- to 6-membered carbocyclic ring, (iii) a partially or fully saturated 4- to 8-membered heterocyclic ring containing one to two heteroatoms selected from O, N or S, or (iv) a (CrC 8 )alkyl optionally substituted with one or more substituents independently selected from the group consisting of an optional
  • R 1a is hydrogen or (Ci-C 4 )alkyl
  • R 1b is preferably (i) hydrogen, (ii) a fully saturated 3 to 6-membered carbocyclic ring, (iii) a fully saturated 4 to 8-membered heterocyclic ring containing one to two N atoms, or (iv) a (C r C 6 )alkyl optionally substituted with one or more substituents independently selected from the group consisting of (CrC 4 )alkylamino, 3 to 6-membered fully saturated carbocyclic ring, and 4 to 8-membered fully saturated heterocyclic ring containing a N atom; More preferably, R 1b is hydrogen, (C r C 4 )alkyl, or a 3 to 4-membered fully saturated carbocyclic ring.
  • R 1b is hydrogen or (CrC 4 )alkyl.
  • R 4 and R 5 are both preferably hydrogen.
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of hydrogen, (C r C 6 )alkyl, fluoro-substituted (C r C 4 )alkyl, cyano, halo, (C r C 6 )alkoxy, fluoro-substituted (C r C 4 )alkoxy.
  • aryloxy a 3- to 8-membered fully saturated carbocyclic ring, a fully saturated 4- to 8-membered heterocyclic ring, a phenyl substituted with one to three substituents independently selected from R 11 , a 5- 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, or N where said aryloxy and said heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, (C r C 6 )alkyl, fluoro-substituted (Ci-C 4 )alkyl, fluoro-substituted (C 1 - C 4 )alkoxy, acylamino, and aminoacyl, or R 8 and R 9 taken together form a partially or fully saturated 5- to 6- membered carbocyclic ring or a 4- to 8-membered partially or fully saturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, or S
  • R 6 , R 7 , and R 8 are hydrogen; and R 9 is a phenyl substituted with one or more substituents independently selected from halo, cyano, (Ci-C 6 )alkyl, fluoro-substituted (CrC 4 )alkyl, and fluoro-susbsituted (Ci-C 4 )alkoxy.
  • Preferred compounds include: C-(5-chloro-7-o-tolyl-2,3-dihydro-benzofuran-2-yl)-methylamine; C-[7-(2-chloro-phenyl)-5-methyl-2,3-dihydro-benzofuran-2-yl]-methylamine; C-[5-chloro-7-(2-chloro- phenyl)-2,3-dihydro-benzofuran-2-yl]-methylamine; C-[5-chloro-7-(2-fluoro-phenyl)-2,3-dihydro- benzofuran-2-yl]-methylamine; C-(6,7-dimethyl-2,3-dihydro-benzofuran-2-yl)-methylamine; C-(7-chloro-6- trifluoromethyl-2,3-dihydro-benzofuran-2-yl)-methylamine; C-(6,7-dichloro-2,3-dihydro-
  • R 1a When R 1a is taken together with R 1b to form a 5- to 10-membered partially or fully saturated heterocyclic ring containing one to two additional N atoms, where said heterocyclic ring is optionally substituted with one or more independently selected fluoro, (Ci-C 4 )alkyl, fluoro-substituted (C r C 4 )alkyl, and fluoro-substituted(CrC 4 )alkoxy, then R 4 and R 5 are preferably both hydrogen; and R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of hydrogen, (C r C 6 )alkyl, fluoro-substituted (C 1 - C 4 )alkyl, cyano, halo, (Ci-C 6 )alkoxy, fluoro-substituted (C r C 4 )alkoxy.
  • aryloxy a 3- to 8-membered fully saturated carbocyclic ring, a fully saturated 4- to 8-membered heterocyclic ring, a phenyl substituted with one to three substituents independently selected from R 11 , a 5-10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, or N where said aryioxy and said heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, (CrC ⁇ alkyl, fluoro-substituted (C r C 4 )alkyl, fluoro-substituted (C 1 -C 4 JaIkOXy, acylamino, and aminoacyl, or R 8 and R 9 taken together form a partially or fully saturated 5- to 6- membered carbocyclic ring or a 4- to 8-membered partially or fully saturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, or S;
  • R 6 , R 7 , and R 8 are preferably hydrogen; and R 9 is preferably a phenyl substituted with one or more substituents independently selected from halo, cyano, (C r C 6 )alkyl, fluoro-substituted (C r C 4 )alkyl, (C r C 4 )aikoxy, and fluoro-susbsituted (C r C 4 )alkoxy; a pharmaceutically acceptable salt of the compound, or a solvate or hydrate of the compound or the salt.
  • Preferred compounds of this embodiment include: 1-[7-(2-chloro-phenyl)-2,3-dihydro-benzofuran- 2-ylmethyl]-piperazine; 1-[7-(3-chloro-phenyl)-2,3-dihydro-benzofuran-2-ylmethyl]-piperazine; 1-[7-(2- fluoro-phenyl)-2,3-dihydro-benzofuran-2-ylmethyl]-piperazine; 1-[7-(3-fluoro-phenyl)-2,3-dihydro- benzofuran-2-ylmethyl]-piperazine; 1-(7-o-tolyl-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine; 1-(7-m- tolyl-2,3-dihydro-benzofuran-2-y!methyl)-piperazine; 1-[7-(2,5-dichloro-phenyl)-2,3-dihydro-
  • compositions comprising (1) a compound of the present invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier.
  • the composition comprises a therapeutically effective amount of a compound of the present invention.
  • the composition may also contain at least one additional pharmaceutical agent (described herein).
  • Preferred agents include nicotine receptor partial agonists, opioid antagonists (e.g., naltrexone and nalmefene), dopaminergic agents (e.g., apomorphine), attention deficit disorder ((ADD) including attention deficit hyperactivity (ADHD)) agents (e.g., RitalinTM, StratteraTM, ConcertaTM and AdderallTM), anti-psychotic agents (e.g., ziprasidone, risperidone, olanzapine, quetiapine, clozapine, haloperidol, and pharmaceutically acceptable salts thereof) and anti-obesity agents (described herein below which include agents that promote weight loss or weight maintenance).
  • opioid antagonists e.g., naltrexone and nalmefene
  • dopaminergic agents e.g., apomorphine
  • ADHD attention deficit hyperactivity
  • ADHD attention deficit hyperactivity
  • anti-psychotic agents e.g., ziprasidone, ris
  • Yet another embodiment of the present invention includes a method for treating 5-HT 2 (preferably, 5-HT 20 and 5-HT 2a ) receptor-mediated diseases, conditions, or disorders in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof).
  • 5-HT 2 preferably, 5-HT 20 and 5-HT 2a
  • Diseases, conditions, and/or disorders modulated by 5-HT 2 receptor ligands include eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, 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), premenstrual syndrome or late luteal phase syndrome, migraine, panic disorder, anxiety, post-traumatic syndrome, dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age
  • the method is used in the treatment of eating disorders, obesity, sexual dysfunction (male and female), anxiety, depression, and psychosis.
  • One aspect of the present invention is a method for treating obesity or controlling weight gain (including reducing or maintaining weight) comprising the step of administering to an animal in need of such treatment or control a therapeutic amount of a compound of the present invention (or pharmaceutical composition thereof).
  • Another aspect of the present invention is a method for treating psychosis (e.g., schizophrenia and related disorders) comprising the step of administering to an animal in need of such treatment a therapeutic amount of a compound of the present invention (or pharmaceutical composition thereof).
  • Yet another aspect of the present invention is a method for treating female sexual dysfunction (FSD) comprising the step of administering to a female in need of such treatment a therapeutically effective amount of a compound of the present invention (or pharmaceutical composition thereof).
  • the method may further include the administration of one or more additional pharmaceutically active agents for treating FSD (see, e.g., the preferred list of agents below).
  • the FSD treatments include female sexual arousal disorder (FSAD), female orgasmic disorder (FOD), hypoactive sexual desire disorder (HSDD), or sexual pain disorder.
  • a method is provided for treating male erectile dysfunction (MED) comprising the step of administering to a male in need of such treatment a therapeutically effective amount of a compound of the present invention (or pharmaceutical composition thereof).
  • anti-obesity agents include apo-B/MTP inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1) inhibitors, PYY 3-36 and analogs thereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists (e.g., rimonabant), melanin concentrating hormone receptor antagonists, ieptin, leptin analogs, leptin receptor agonists, galanin receptor antagonists, lipase inhibitors, bombesin receptor agonists, neuropeptide-Y receptor antagonists (e.g., anti-obesity agents, anti-pyschotic agents, and agents used for treating sexual dysfunction).
  • Preferred anti-obesity agents include apo-B/MTP inhibitors
  • Preferred anti-psychotic agents include ziprasidone (e.g., GEODON®), risperidone (e.g., RISPERDAL®), olanzapine (e.g., ZYPREXA®), quetiapine (e.g., SEROQUEL®), clozapine (e.g., CLOZARIL®), haloperidol (e.g., HALDOL®) and pharmaceutically acceptable salts thereof.
  • ziprasidone e.g., GEODON®
  • risperidone e.g., RISPERDAL®
  • olanzapine e.g., ZYPREXA®
  • quetiapine e.g., SEROQUEL®
  • clozapine e.g., CLOZARIL®
  • haloperidol e.g., HALDOL®
  • Preferred additional agents used in treating female sexual dysfunction include: (1 ) estrogen receptor modulators (e.g., estrogen agonists, estrogen antagonists or combinations thereof); (2) testosterone replacement agents, testosternone (Tostrelle), dihydrotestosterone, dehydroepiandrosterone (DHEA), a testosterone implant, or combinations thereof; (3) estrogen, a combination of estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA), or a combination of estrogen and a methyl testosterone hormone replacement therapy agent; (4) one or more dopaminergic agents (e.g.
  • D2, D3 or D4 agents (5) one or more of an NPY (neuropeptide Y) inhibitor (e.g., NPY-1 and NPY-5 inhibitors); (6) one or more of a melanocortin receptor modulator or melanocortin enhancer; (7) one or more of an NEP inhibitor; (8) one or more of a PDE inhibitor; and (9) one or more of a bombesin receptor modulator.
  • an NPY neuropeptide Y
  • NPY-1 and NPY-5 inhibitors e.g., NPY-1 and NPY-5 inhibitors
  • Preferred additional pharmaceutical agents used in treating male sexual dysfunction include dopaminergic agents, NPY-1 inhibitors, NPY-5 inhibitors, melanocortin receptor modulators, melanocortin enhancers, NEP inhibitors, cGMP PDE-5 inhibitors, bombesin receptor modulators, and mixtures thereof.
  • the combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
  • kits for use by a consumer to treat diseases, conditions, and/or disorders modulated by 5-HT 2 receptor ligands in an animal.
  • the kit comprises a) a suitable dosage form comprising a compound of the present invention; and b) instructions describing a method of using the dosage form to treat diseases, conditions or disorders that are modulated by 5-HT 2 receptor agonists or antagonists (in particular, 5-HT 2c agonists and/or 5-HT 2a antagonists).
  • Another embodiment includes a pharmaceutical kit comprising: a) a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) a second dosage form comprising (i) an additional pharmaceutical agent described herein, and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and c) a container.
  • a pharmaceutical kit comprising: a) a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) a second dosage form comprising (i) an additional pharmaceutical agent described herein, and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and c) a container.
  • alkyl refers to a hydrocarbon radical of the general formula C n H 2n+ - I .
  • the alkane radical may be straight or branched.
  • (CrC 6 )alkyl refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
  • alkyl portion i.e., alkyl moiety
  • acyl e.g., alkanoyl
  • alkylamino dialkylamino
  • alkylthio group alkyl portion of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group
  • alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls) independently selected from the group of substituents listed below in the definition for "substituted.”
  • Halo-substituted alkyl refers to an alkyl group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, and the like).
  • partially or fully saturated carbocyclic ring refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring.
  • carbocyclic ring is generally a 3- to 8-membered ring (preferably, 3- to 6-membered ring).
  • partially or fully saturated carbocyclic rings include groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbomenyl, bicyclo[2.2.2]octyl, and the like.
  • the partially saturated or fully saturated cycloalkyl group may be unsubstituted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • a substituted carbocyclic ring also includes groups wherein the carbocyclic ring is fused to a phenyl ring (e.g., indanyl).
  • the carbocyclic group may be attached to the chemical entity or moiety by any one of the carbon atoms within the carbocyclic ring system.
  • any cycloalkyl portion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definition as above.
  • the term "partially saturated or fully saturated heterocyclic ring” (also referred to as “partially saturated or fully saturated heterocycle”) refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring.
  • the heterocyclic ring is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen or nitrogen.
  • Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, and the like.
  • Bicyclic rings include groups such as When indicated as being “optionally substituted", the partially saturated or fully saturated heterocycle group may be unsubstiuted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted.”
  • a substituted heterocyclic ring includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl, 2,3-dihydrobenzothiophenyl, 2,3- dihydrobenzothiazolyl, etc.).
  • the heterocyclic group may be attached to the chemical entity or moiety by any one of the ring atoms within the heterocyclic ring system.
  • any heterocycle portion of a group e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.
  • aryl or "aromatic carbocyclic ring” refers to aromatic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • a typical aryl group is a 6- to 10-membered aromatic carbocyclic ring(s).
  • the aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted” (unless specified otherwise).
  • Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.). The aryl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the aromatic ring system.
  • heteroaryl or "heteroaromatic ring” refers to aromatic moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl,
  • the heteroaromatic moiety may consist of a single or fused ring system.
  • a typical single heteroaryl ring is a 5- to 6-membered ring containing one to three heteroatoms independently selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen.
  • the heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted" (unless specified otherwise).
  • the heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl).
  • the heteroaryl portion (i.e., heteroaromatic moiety) of a heteroaroyloxy i.e., (heteroaryl)-C(O)-O-
  • acyl refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups.
  • acyl includes groups such as (CrC 6 )alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C 3 -C 6 )cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.),
  • alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions above.
  • the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.
  • substituted specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament.
  • Suitable substituents for any of the groups defined above include (C r C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, (C r C 6 )alkylidenyl, aryl, heteroaryl, 3- to 6- membered heterocycle, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (CrC 6 )alkoxy, aryloxy, sulfhydryl (mercapto), (CVC ⁇ alkylthio, arylthio, amino, mono- or di-(C r C 6 )alkyl amino, quaternary ammonium salts, amino(C r C 6 )alkoxy, aminocarboxylate (i.e., (CrC 6 )alkyl-O-C(O)-NH-), hydroxy(C 2 - C 6 )alkylamino
  • substituted combinations such as "substituted aryl(C 1 -C 6 )alkyl" either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl groups may be substituted with one or more substituents (typically, one to three substituents except in the case of perhalo substitutions).
  • An aryl or heteroaryl substituted carbocyclic or heterocyclic group may be a fused ring (e.g., indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.).
  • halo refers to a chloro, bromo, fluoro or iodo group.
  • solvate refers to a molecular complex of a compound represented by Formula (I) (including prodrugs and pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and other Class 3 solvents (see, US Federal Drug Administration Guidelines for a list of Class 3 solvents).
  • hydrate refers to the complex where the solvent molecule is water.
  • protecting group or “Pg” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • BOC t- butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9-fluorenylmethylenoxycarbonyl
  • agonist unless indicated otherwise includes both partial and full agonists. Full agonists are preferred.
  • modulator refers to a ligand that increases or decreases the action of an agonist by combining with a distinct site on the receptor macromolecule.
  • therapeutically effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • animal refers to humans, companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • Edible animals refers to food-source animals such as cows, pigs, sheep and poultry.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • treating, “treat”, or “treatment” embrace both preventative, i.e., prophylactic, and palliative treatment.
  • compound(s) of the present invention refers to compounds of Formula (I), prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or the prodrugs, and hydrates or solvates of the compounds, the salts, and/or the prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.
  • DETAILED DESCRIPTION Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aidrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie. 4. Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • Aidrich Chemicals Manton Chemicals
  • Wl Aidrich Chemicals
  • Suitable amino- protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • BOC f-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9-fluorenylmethyleneoxycarbonyl
  • Scheme I illustrates the general procedures for preparing a compound of the present invention where R 2 , R 3 , R 4 and R 5 are all hydrogen, and R 9 is an aryl or heteroaryl group (e.g., compound of Formula (I-A)).
  • (l-A-1) Scheme I
  • the allyl ether (1a) can be easily prepared by condensing an allyl halide (e.g., ally! bromide) with the desired alcohol.
  • the allyl ether (1a) can then be rearranged to the corresponding allyl alcohol (1 b) by means of Claisen rearrangement reaction conditions (e.g, heating at an elevated temperature).
  • Cyclization to the 2,3-dihydrofuran (1c) can be accomplished by treating the allyl alcohol (1b) with a peracid (e.g., m-chloroperbenzoic acid) followed by treatment with a base (e.g., alkali hydroxide).
  • a peracid e.g., m-chloroperbenzoic acid
  • a base e.g., alkali hydroxide
  • the alcohol functionality is protected with an alcohol protecting group (e.g., mesylate) and then the aryl or heteroaryl group (R 9 ) is introduced via metal-mediated cross-coupling reactions such as the Suzuki reaction (See: A. Suzuki in Metal-Catalyzed Cross-Coupling Reactions: F. Diederich and PJ. Stang, Eds.; Wiiey-VCH Verlag, Weinheim, Germany, Chapter 2 (1998) and N.
  • intermediate (1e) may be produced by Suzuki reaction of intermediate (1d) with a compound of Formula R 9 -B(OH) 2 in the presence of a complex or salt of palladium (e.g., Pd(PPh 3 ) 4 , Pd(OAc) 2 ), a base (e.g., cesium carbonate, sodium carbonate, cesium fluoride, potassium phosphate), and a suitable solvent (e.g., toluene, water, dioxane, N,N-dimethylformamide (DMF), or dimethoxyethane (DME)) in the presence or absence of added ligand (e.g., dppf, dppb).
  • a complex or salt of palladium e.g., Pd(PPh 3 ) 4 , Pd(OAc) 2
  • a base e.g., cesium carbonate, sodium carbonate, cesium fluoride, potassium phosphate
  • a suitable solvent e.g., tol
  • Preferred reaction temperatures range from about 0 0 C to about 120 0 C.
  • the amine (l-A-1) can be prepared by treating the mesylate (1e) with ammonium hydroxide in a suitable solvent (e.g., acetonitrile (ACN), dioxane, DMF, or N- methylprrolidone (NMP)) at about 25 0 C to about 120 0 C.
  • a suitable solvent e.g., acetonitrile (ACN), dioxane, DMF, or N- methylprrolidone (NMP)
  • an amine or protected amine functionality may be introduced prior to the Suzuki reaction by treating intermediate (1d) with the desired amine in the presence of a weak base (e.g., triethylamine or potassium carbonate).
  • a weak base e.g., triethylamine or potassium carbonate.
  • any remaining protecting groups may then be removed using conventional methods well-known to those skilled in the art to produce the compound of Formula (l-A-2).
  • Numerous amine compounds of Formula R 1a R 1b NH are available from commercial sources or prepared by known methods readily available to those skilled in the art.
  • Scheme III illustrates the general procedures for preparing a compound of the present invention where R 7 is an aryl or heteroaryl group (e.g., compound of Formula (I-B)).
  • a bromo group may be introduced in the 5-position using a conventional bromination agent (e.g., N-bromosuccinimide (NBS)).
  • N-bromosuccinimide (NBS) N-bromosuccinimide
  • the aryl or heteroaryl group (R 7 ) can then be introduced via a metal- mediated cross-coupling reaction such as the Suzuki reaction described above in Scheme I.
  • the amino- protecting group may be removed using standard procedures well-known to those skilled in the art.
  • a BOC-protected intermediate (3b) can be treated with trifluoroacetic acid in an aprotic solvent (e.g., methylene chloride).
  • halo group on the aryl ring may then be removed by hydrogenation (e.g., Pd/C catalyzed hydrogenation) to produce the compound of Formula (I-B).
  • Scheme IV illustrates the general procedures for preparing a compound of the present invention where R 9 is an aryl or heteroaryl group (e.g., compound of Formula (1-C)).
  • the bromo group may be introduced at the 7 position using standard bromination procedures (e.g., N-bromosuccinimide).
  • the alcohol functionality is protected with an alcohol protecting group (e.g., mesylate) and then the aryl or heteroaryl group (R 9 ) is introduced via metal-mediated cross-coupling reactions such as the Suzuki reaction described above in Scheme I to produce intermediate (4c).
  • the amino group can then be introduced by treating the mesylate (4c) with the desired amine (R 1a R 1b NH).
  • Scheme V illustrates the general procedures for preparing a compound of the present invention where n is 2 (e.g., compound of Formula (I-D)).
  • the mesylate intermediate (1e) can be converted to the corresponding cyano intermediate (5a) using traditional substitution with a cyanide.
  • intermediate (1e) is reacted with an alkali metal cyanide (e.g., NaCN) in the presence of an appropriate solvent.
  • the cyano group may then be reduced to the primary amine to produce a compound of Formula (I-D).
  • the cyano group may be reduced with a hydroborane (e.g., BH 3 S(CH 3 ) 2 ).
  • the primary amino group may be further derivatized by alkylation to the secondary or tertiary amine using standard procedures well-known to those skilled in the art.
  • salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound, or prodrug with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanoi, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • suitable pharmaceutically acceptable solvents include the Class 3 solvents listed in the United States Federal Drug Administration Guidelines.
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I), a pharmaceutically acceptable salt of the compound, or a hydrate or solvate of the compound or salt. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a prodrug could be formed by replacing the hydrogen atom in the amine group with a group such as an alkyl group, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (CrC 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl-natural ⁇ -aminoacyl, -C(OH)C(O)OY' wherein Y' is H, (C r C 6 )alkyl or benzyl, -C(OY 0 )Yi wherein Y 0 is (C 1 -C 4 ) alkyl and Y 1 is (CrC 6 )alkyl, carboxy(C r C 6 )alkyl, amino(C r C 4 )alkyl or mono-N- or di- N,N-(Cr)
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 18 F, and 36 CI, respectively.
  • Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances
  • lsotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • Compounds of the present invention are useful 5-HT 20 agonists and/or 5-HT 2a antagonists; therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients described above.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings..
  • the present invention further provides methods of treating 5-HT 2 receptor-mediated diseases, conditions, or disorders in an animal in need of such treatment that include administering to the animal (preferably, a human) a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the method is particularly useful for treating 5- HT 20 receptor-mediated diseases, conditions, or disorders.
  • the compounds of the present invention act as potent full agonists at the 5-HT 20 receptor, and as antagonists or very weak partial agonists at the 5-HT 2a and 5-HT 2b receptors.
  • the compounds of the present invention are functionally selective for 5-HT 2c against 5-HT 2a and 5-HT 2b , by virtue of their much higher agonistic potency (lower EC 50 ) for 5-HT 20 than that observed for 5-HT 2a and/or 5-HT 2b or their lack of agonistic activity at 5-HT 2a and/or 5-HT 2b .
  • Receptor binding data or binding selectivity data may not always correlate with or reflect functional data or functional selectivity data.
  • a compound may be selective for the 5-HT 20 receptor when functional assays are analyzed, but in the binding assays the compound may have the same potency at other 5-HT receptors.
  • selective as used herein in relation to the present invention with respect to methods of treatment means "functionally selective".
  • Diseases, conditions, and/or disorders modulated by 5HT 2 receptor ligands include eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, 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), premenstrual syndrome or late luteal phase syndrome, migraine, panic disorder, anxiety, post-traumatic syndrome, dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age
  • the compounds of the present invention described herein are useful in treating 5-HT 2 receptor-mediated diseases, conditions, or disorders. Consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of from about 0.1 mg to about 1 ,000 mg per day (preferably, about 1 mg to about 500 mg per day, more preferably, about 25 mg to about 250 mg per day, most preferably about 5 mg to about 100 mg per day). For a normal adult human having a body weight of about 70 kg, a dosage in the range of from about 0.01 mg to about 20 mg per kilogram body weight is typically sufficient.
  • the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
  • the compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases/conditions described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided.
  • Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1) inhibitors, PYY 3-36 and analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 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, lip
  • anorectic agents such as a bombesin agonist
  • Neuropeptide-Y receptor antagonists e.g., NPY Y5 receptor antagonists, such as the spiro compounds described in US Patent Nos. 6,566,367; 6,649,624; 6,638,942; 6,605,720; 6,495,559; 6,462,053; 6,388,077; 6,335,345; and 6,326,375; US Publication Nos. 2002/0151456 and 2003/036652; and PCT Publication Nos. WO 03/010175.
  • thyromimetic agents dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti- related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists.
  • AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • human agouti- related proteins AGP
  • ghrelin receptor antagonists histamine 3 receptor antagonists or inverse agonists
  • neuromedin U receptor agonists such as AxokineTM available from Regener
  • anti-obesity agents including the preferred agents set forth hereinbelow, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • anti-obesity agents selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, rimonabant, pseudoephedrine, PYY 3-36 Or an analog thereof, and 2-oxo-N-(5-phenylpyrazinyl)spiro-[isobenzofuran-1 (3H),4'-piperidine]-1 '-carboxamide.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; rimonabant can be prepared as described in U.S. Pat. No. 5,624,941 ; PYY 3-36 (including analogs thereof) can be prepared as described in US Publication No.
  • NPY Y5 receptor antagonist 2-oxo-N-(5- phenylpyrazinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide can be prepared as described in US Publication No. 2002/0151456.
  • 03/082190 that may be useful in combination with a compound of the present invention are selected from the group consisting of: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1 (3H), 4'-piperidine]-1'- carboxamide; 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)-spiro-[isobenzofuran-1 (3H), 4'- piperidine]-1'-carboxamide; N- [5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H), [4 1 - piperidine]-1'-carboxamide; frans-3'-oxo-N-(5-phenyl-2-pyrimidinyl)] spiro[cyclohexane-1 ,1'(3'H)- isobenzofur
  • tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename ZybanTM) and nicotine replacement therapies
  • ADD/ADHD agents e.g., RitalinTM, StratteraTM, ConcertaTM and AdderallTM
  • agents to treat alcoholism
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).
  • AA Alcohol Anonymous
  • other useful nicotine receptor partial agonists are described in US Patent Nos. 6,235,734; 6,410,550; and 6,462,035; all of which are incorporated herein by reference.
  • anti-inflammatory agents e.g., COX-2 inhibitors
  • antidepressants e.g., fluoxetine hydrochloride (ProzacTM)
  • cognitive improvement agents e.g., donepezil hydrochloride (AirceptTM) and other acetylcholinesterase inhibitors
  • neuroprotective agents e.g., memantine
  • insulin and insulin analogs e.g., LysPro insulin
  • the compounds of the present invention may also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels.
  • a naturally occurring compound that acts to lower plasma cholesterol levels.
  • Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts, and niacin.
  • the compounds of the present invention have also been shown to be potent 5-HT 2a antagonists in vivo. Consequently, the compounds of the present invention may be used to treat psychotic disorders of the schizophrenic types, and in particular the compounds would be useful for removing or ameliorating such symptoms as anxiety, agitation, excessive aggression, tension, and social or emotional withdrawal in psychotic patients.
  • the compounds may also be useful in the blocking of serotonin-induced contractions of bronchial tissues and of blood vessels, arteries as well as veins.
  • the compounds of the present invention may also be useful as sedating-, anxiolytic-, anti-agressive-, anti-stress-, muscular protectant- and cardiovascular protectant agents and, consequently, they would be useful to protect warm-blooded animals, for example, in stress situations, e.g., during transport periods and the like situations. Additionally, the compounds of the present invention may be useful as protectors of endotoxine shocks and as antidiarrhoeals.
  • Suitable antipsychotic agents which may be used in combination with the compounds of the present invention include ziprasidone (e.g., GEODON®), risperidone (e.g., RISPERDAL®), olanzapine (e.g., ZYPREXA®), quetiapine (e.g., SEROQUEL®), clozapine (e.g., CLOZARIL®), haloperidol (e.g., HALDOL®) and pharmaceutically acceptable salts thereof.
  • ziprasidone e.g., GEODON®
  • risperidone e.g., RISPERDAL®
  • olanzapine e.g., ZYPREXA®
  • quetiapine e.g., SEROQUEL®
  • clozapine e.g., CLOZARIL®
  • haloperidol e.g., HALDOL®
  • Ziprasidone (5-(2-(4-(1 ,2-benzisothiazol-3-yl)-piperazinyl)ethyl)-6-chloro-1 , 3-dihydro-2H-indol-2-one hydrochloride) may be purchased or prepared using the methods described in U.S. Patent Nos. 4,831 ,031 ; 5,312,925; and 6,150,366.
  • Risperidone (3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8, 9- tetrahydro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one) may be purchased or prepared using the methods described in U.S. Patent Nos. 4,804,663; 5,453,425; and 5,616,587.
  • Olanzapine (2-Methyl-10-(4-methyl- 1-piperazinyl)-4H-thieno-[2,3-b][1 ,5]benzodiazepine) may be purchased or prepared using the procedures described in U.S. Patent No.
  • Quetiapine (11-[4-[2-(2-Hydroxyethoxy)ethyl]-1- piperazinyl]dibenzo[b,f][1 ,4 ]thiazepine) may be purchased or prepared using the procedures described in U.S. Patent No. 4,879,288.
  • the compounds of the present invention may be used in the treatment of sexual dysfunction.
  • Sexual dysfunction (SD) is a significant clinical problem, which can affect both males and females.
  • the causes of SD may be both organic as well as psychological.
  • SD Organic aspects of SD are typically caused by underlying vascular diseases, such as those associated with hypertension or diabetes mellitus, by prescription medication and/or by psychiatric disease such as depression.
  • Physiological factors include fear, performance anxiety and interpersonal conflict. SD impairs sexual performance, diminishes self-esteem and disrupts personal relationships thereby inducing personal distress.
  • SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (Melman et al 1999). FSD is best defined as the difficulty or inability of a woman to find satisfaction in sexual expression.
  • Male sexual dysfunction is generally associated with erectile dysfunction, also known as male erectile dysfunction (MED) (Benet et al 1994 - Male Erectile dysfunction assessment and treatment options. Comp. Ther. 20: 669-673.).
  • the compounds of the invention are particularly beneficial for the prophylaxis and/or treatment of sexual dysfunction in the male (e.g. male erectile dysfunction - MED) and in the female - female sexual dysfunction (FSD), e.g. female sexual arousal disorder (FSAD). It is known that some individuals can suffer from male erectile dysfunction (MED).
  • MED is defined as: "the inability to achieve and/or maintain a penile erection for satisfactory sexual performance" (NIH Consensus Development Panel on Impotence, 1993)"
  • the categories of female sexual dysfunction (FSD) are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (see S R Leiblum, (1998), Definition and Classification of Female Sexual Disorders, Int. J. Impotence Res.. 10, S104-S106). Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli.
  • Arousal includes the vascular response to sexual stimulation, an important component of which is genital engorgement and increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity and a subjective excitement response.
  • Orgasm is the release of sexual tension that has culminated during arousal.
  • FSD occurs when a woman has an absent, inadequate or unsatisfactory response in any one or more of these phases, usually desire, arousal or orgasm.
  • the American Psychiatric Association classifies female sexual dysfunction (FSD) into four classes: FSAD, hypoactive sexual desire disorder (HSDD), female orgasmic disorder (FOD), and sexual pain disorders (e.g.
  • DSM-IV defines the four classes as follows: HSDD - Persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity. The judgment of deficiency or absence is made by the clinician, taking into account factors that affect functioning, such as age and the context of the persons life.
  • FSAD Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement.
  • FOD Persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase.
  • the diagnosis of FOD should be based on the clinician's judgment that the woman's orgasmic capacity is less than would be reasonable for her age, sexual experience, and the adequacy of the sexual stimulation she receives.
  • Sexual Pain Disorders such as Dyspareunia and Vaginismus.
  • HSDD is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies.
  • This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause.
  • Other causes in both pre-menopausal woman (i.e. woman who are pre-menopausal and who have not have hysterectomies) as well as post-menopausal women include illness, medications, fatigue, depression and/or anxiety.
  • Factors having a potential (conscious or sub ⁇ conscious) psychological impact such as relationship difficulties or religious factors may be related to the presence of/development of HSDD in females.
  • DSM Diagnostic and Statistical Manual
  • FSAD Female Sexual Arousal Disorder
  • FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post-menopausal ( ⁇ hormone replacement therapy (HRT)) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital (UG) disorders.
  • FSAD FSAD
  • the primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation.
  • the secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm. It has recently been hypothesized that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein et al., Int. J. Impot. Res.. 10, S84-S90.1998) with animal data supporting this view (Park et al., Int. J. Impot. Res., 9, 27-37, 1997).
  • Drug candidates for treating FSAD which are under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to male genitalia.
  • the compounds of the present invention are advantageous by providing a means for restoring a normal sexual arousal response - namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity.
  • the present invention provides a means to restore, or potentiate, the normal sexual arousal response.
  • female genitalia herein we mean: "The genital organs consist of an internal and external group. The internal organs are situated within the pelvis and consist of ovaries, the uterine tubes, uterus and the vagina. The external organs are superficial to the urogenital diaphragm and below the pelvic arch. They comprise the mons pubis, the labia majora and minora pudendi, the clitoris, the vestibule, the bulb of the vestibule, and the greater vestibular glands" (Gray's Anatomy, CD. Clemente, 13 th American Edition). RJ. Levin teaches us that because "...
  • FSAD is characterized by inadequate genital response to sexual stimulation.
  • the genitalia do not undergo the engorgement that characterizes normal sexual arousal.
  • the vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded.
  • Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis.
  • Other causes result from treatment with diuretics, antihistamines, antidepressants e.g. selective serotonin reuptake inhibitors (SSRIs) or antihypertensive agents.
  • FOD is the persistent or recurrent difficulty, delay in or absence of attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress.
  • the present invention additionally provides a method for the treatment and/or prevention of male sexual dysfunction (MSD), in particular male erectile dysfunction (MED) via treatment with a compound of the present invention as detailed hereinbefore.
  • the present invention additionally provides a method for the treatment and/or prevention of male sexual dysfunction via treatment with a combination of a compound of the present invention and at least one additional pharmaceutical agent.
  • Preferred additional pharmaceutical agents used in treating male sexual dysfunction include: (1) one or more dopaminergic agents (e.g. D2, D3 or D4 agonists and apomorphine); (2) one or more of an NPY (neuropeptide Y) (preferably an NPY-1 and/or NPY-5 inhibitor); (3) one or more of a melanocortin receptor agonist or modulator or melanocortin enhancer; (4) one or more of an NEP inhibitor; (5) one or more of a PDE inhibitor (preferably, a cGMP PDE-5 inhibitor); and (6) one or more of a bombesin receptor antagonist or modulator.
  • dopaminergic agents e.g. D2, D3 or D4 agonists and apomorphine
  • an NPY neuropeptide Y
  • melanocortin receptor agonist or modulator or melanocortin enhancer e.g., a melanocortin receptor agonist or modulator or melanocortin enhancer
  • Men who display an insufficient response or lack of response to treatment with ViagraTM may benefit either from therapy based on treatment with compounds of the present invention alone or via combination therapy based on compound(s) of the present invention and a cGMP PDE5i, such as for example sildenafil.
  • Patients with mild to moderate MED should benefit from combined treatment based on compound(s) of the present invention alone or in combination with a NEPi, and patients with severe MED may also respond. Mild, moderate and severe MED will be terms known to the man skilled in the art, but guidance can be found in: The Journal of Urology, vol 151 , 54-61 (Jan 1994).
  • MED patient groups which are described in more detail in Clinical Andrology vol 23,no.4, p773- 782, and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction - Current Investigation and Management, published by Mosby-Wolfe, are as follows: psyhcogenic, endocrinologic, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to cavernosal factors, particularly venogenic causes.
  • Suitable cGMP PDE5 inhibitors for the use in combination with a compound of the present invention for the treatment of MED according to the present invention include: the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27112; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27113; the indole-1 ,4-diones disclosed in WO95/19978 and the triazin-4-ones disclosed in published international application WO99/24433.
  • the present invention provides a composition for the treatment of MED comprising a compound of the present invention and sildenafil.
  • a composition for the treatment of MED comprising a compound of the present invention and sildenafil.
  • the suitability of any particular cGMP PDE5 inhibitor for use in combination with a compound of the present invention can be readily determined by evaluation of its potency and selectivity using literature methods followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc in accordance with standard pharmaceutical practice.
  • Preferred cGMP PDE5 inhibitors for use herein have an IC 50 at less than 100 nanomolar, more preferably, at less than 50 nanomolar, more preferably still at less than 10 nanomolar.
  • the cGMP PDE5 inhibitors for use in the pharmaceutical combinations according to the present invention are selective for the PDE5 enzyme.
  • they have a selectivity of PDE5 over PDE3 of greater than 100 more preferably greater than 300.
  • the PDE5 has a selectivity over both PDE3 and PDE4 of greater than 100, more preferably greater than 300.
  • Selectivity ratios may readily be determined by the skilled person.
  • !C 50 values for the PDE3 and PDE4 enzyme may be determined using established literature methodology, see S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171.
  • NEP inhibitors wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , which has an IC 50 of less than 10OnM (e.g. ompatrilat, candoxatril, candoxatrilat, sampatrilat).
  • Suitable NEP inhibitor compounds are described in EP-A- 1097719.
  • Particularly preferred NEPi compounds for use as auxiliary agents in the treatment of MED according to the present invention are those described in International Patent application WO 02/079143.
  • the present invention provides a composition for the treatment of MED comprising a compound of the present invention and (S)-2-[(1- ⁇ [3-(4- chlorophenyl)propyl]carbamoyl ⁇ cyclo-pentyl)methyl]-4-methoxybutanoic acid.
  • a compound of the present invention for the treatment of female sexual dysfunction (FSD).
  • FSD female sexual dysfunction
  • a compound of the present invention for the treatment of female sexual dysfunction (FSD)
  • FSD female sexual dysfunction
  • the one or more additional active agents is/are selected from the group consisting of: 1) estrogen receptor modulators (e.g., estrogen agonists and/or estrogen antagonists); 2) testosterone replacement agents and/or testosternone (Tostrelle) and/or dihydrotestosterone and/or dehydroepiandrosterone (DHEA) and/or a testosterone implant; 3) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (as a combination), or a combination of estrogen and a methyl testosterone hormone replacement therapy agent; 4) one or more dopaminergic agents; 5) one or more NPY (neuropeptide Y) inhibitors; 6) one or more melanocortin receptor modulators or melanocortin enhancers; 7) one or more NEP (neutral endopeptidase) inhibitors; 8) one or more PDE (phosphodiesterase) inhibitors; and 9) one or more bombesin receptor modulators
  • the FSD is female sexual arousal disorder (FSAD).
  • the FSD is female orgasmic disorder (FOD).
  • the FSD is hypoactive sexual desire disorder (HSDD).
  • the FSD is a sexual pain disorder, preferably Dyspareunia or Vaginismus.
  • estrogen receptor modulators include raloxifene or lasofoxifene, (-)-cis-6-phenyl-5- [4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof (compound (a) below), the preparation of which is detailed in US Patent No. 5,552,412 (equivalent to WO 96/021656) and incorporated herein by reference.
  • testosterone replacement agent is dehydroandrostendione.
  • hormone replacement therapy agents include Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, EIIeste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, and Tibolone.
  • dopaminergic agents include apomorphine or a selective D2, D3 or D2/D 3 agonist such as, pramipexole and ropirinol (as claimed in WO-0023056), L-Dopa or carbidopa, PNU95666 (as disclosed in WO-0040226 and US Patent No. 6,455,564).
  • NPY (neuropeptide Y) inhibitors include NPY1 or NPY5 inhibitors, preferably NPY1 inhibitor.
  • said NPY inhibitors (including NPY Y1 and NPY Y5) having an IC50 of less than 10OnM, more preferably less than 50 nM.
  • Suitable NPY, and in particular NPY1 inhibitor compounds are described in EP-A-1097718.
  • Examples of a melanocortin receptor agonist or modulator or melanocortin enhancer include melanotan II, PT-14, PT-141 or compounds disclosed in WO-09964002, WO-00074679, WO-09955679, WO-00105401 , WO-00058361 , WO-00114879, WO-00113112 or WO-09954358.
  • Suitable NEP inhibitors are as described hereinabove.
  • the present invention provides a composition for the treatment of FSD comprising a compound of the present invention and (S)-2-[(1- ⁇ [3-(4- chlorophenyl)propyl]carbamoyl ⁇ cyclo-pentyl)methyl]-4-methoxybutanoic acid.
  • Preferred PDE inhibitors include a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably a PDE2 or PDE5 inhibitor and more preferably a PDE5 inhibitor (as described hereinabove), most preferably sildenafil.
  • the present invention provides a composition for the treatment of FSD comprising a compound of the present invention and sildenafil.
  • bombesin receptor antagonists or modulators would be antagonists or modulators for BB 1 , including those described in WO 02/40008. Also preferred are bombesin BB 2 , BB 3 , or BB 4 receptor antagonists. Preferred bombesin receptor antagonists are also mentioned as "auxiliary agents" in WO 02/47670. It should be noted that a full list of possible “additional active agents” can be found in WO 02/ 47670 and are described as “auxiliary agents” therein. In accordance with yet another aspect of the present invention, other 5-HT 2c receptor agonists may be used in addition to a compound of the present invention.
  • Such 5-HT 20 receptor agonists include, but are not limited to, those disclosed in Chaki and Nakazato - Expert Opin. Ther. Patents (2001). 11(11 ):1677-1692 (see especially Section 3.9 - 5HT 20 on page 1687 and Figure 7 on page 1686), or Isaac - Drugs of the Future (2001 ), 26(4):383-393 (see especially Figure 2 on page 385).
  • the aforementioned publications are incorporated herein by reference in their entireties.
  • the 5-HT 2c receptor agonists are selective 5-HT 2c receptor agonists.
  • the term "selective" as used herein with respect to methods of treatment means "functionally selective".
  • the present invention additionally provides the use of the compounds of the present invention as 5-HT 2c receptor agonists, preferably selective 5-HT 2c receptor agonists, for the treatment of FSD, preferably FSAD, FOD, HSDD or a sexual pain disorder (such as Dyspareunia or Vaginismus).
  • a compound of the present invention or a combination of a compound of the present invention and at least one additional pharmaceutical agent is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
  • the compound of the present invention and at least one other pharmaceutical agent may be administered either separately or in the pharmaceutical composition comprising both.
  • such administration be oral. However, if the subject being treated is unable to swallow, or oral administration is otherwise impaired or undesirable, parenteral or transdermal administration may be appropriate.
  • parenteral or transdermal administration may be appropriate.
  • a combination of a compound of the present invention and at least one other pharmaceutical agent when administered together, such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred.
  • a compound of the present invention and the additional pharmaceutical agent can be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
  • the administration of each can be by the same or by different methods.
  • a compound of the present invention or a combination of a compound of the present invention and at least one additional pharmaceutical agent is preferably administered in the form of a pharmaceutical composition.
  • a compound of the present invention or a combination can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral, (for example, intravenous, intramuscular, or subcutaneous) intracisternal, intravaginal, intraperitoneal, intravesical, local (for example, powder, ointment or drop), or buccal, or nasal, dosage form.
  • compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers or diluents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain excipients such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • a compound of the present invention or a combination is admixed with at least one inert customary pharmaceutical excipient, diluent or carrier, such as sodium citrate or dicalcium phosphate or (a) fillers or extenders (e.g., starches, lactose, sucrose, mannitol, silicic acid and the like); (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like); (c) humectants (e.g., glycerol and the like); (d) disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca
  • Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the present invention and/or the additional pharmaceutical agent in a delayed manner.
  • Examples of embedding compositions that can be used are polymeric substances and waxes.
  • the drug can also be in micro ⁇ encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oii, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
  • the liquid compositions can also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the compound of the present invention or the combination, may further comprise suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the present invention or a combination with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • Dosage forms for topical administration of the compounds of the present invention and combinations may comprise ointments, powders, sprays and inhalants.
  • the drugs are admixed under sterile condition with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also intended to be included within the scope of the present invention.
  • the dosage of the additional pharmaceutical agent will be generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • the dosage range of an anti-obesity agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day.
  • a daily dose that is administered orally to an animal is between about 0.01 and about 1 ,000 mg/kg of body weight, preferably between about 0.01 and about 300 mg/kg of body weight.
  • a compound of the present invention (or combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply.
  • the compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).
  • a compound of the present invention (or combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate.
  • a premix or concentrate of the compound in a carrier is more commonly employed for the inclusion of the agent in the feed.
  • Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds.
  • a particularly effective carrier is the respective animal feed itself; that is, a small portion of such feed.
  • the carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended.
  • the compound is thoroughly blended into the premix and, subsequently, the feed.
  • the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier.
  • a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like
  • the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.
  • High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet.
  • such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the present invention.
  • the mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity. If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.
  • Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the present invention with a sufficient amount of animal feed to provide from about 10 "3 to about 500 ppm of the compound in the feed or water.
  • the preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of a compound of the present invention (or combination) per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed.
  • the preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of a compound of the present invention (or combination) per ton of feed.
  • the compounds of the present invention (or combination) may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean meat to fat ratio is sought.
  • parenteral administration involves injection of a sufficient amount of a compound of the present invention (or combination) to provide the animal with about 0.01 to about 20 mg/kg/day of body weight of the drug.
  • the preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from about 0.05 to about 10 mg/kg/day of body weight of drug.
  • Paste formulations can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
  • Pellets containing an effective amount of a compound of the present invention, pharmaceutical composition, or combination can be prepared by admixing a compound of the present invention or combination with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
  • a diluent such as carbowax, carnuba wax, and the like
  • a lubricant such as magnesium or calcium stearate
  • implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
  • the present invention has several advantageous veterinary features.
  • the instant invention provides the means by which this may be accomplished.
  • utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.
  • Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. EXAMPLES Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc.
  • Atmospheric pressure chemical ionization mass spectra were obtained on a FisonsTM Platform Il Spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK).
  • Chemical ionization mass spectra were obtained on a Hewlett-PackardTM 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, CA).
  • Electrospray ionization mass spectra were obtained on a WatersTM ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35 CI/ 37 CI-containing ions and 1 :1 for 79 Br/ 81 Br-containing ions) and the intensity of only the lower mass ion is given. In some cases only representative 1 H NMR peaks are given. MS peaks are reported for all examples.
  • Preparative thin-layer chromatography was performed using Analtech silica gel GF with UV254 indicator (Analtech Inc., Newark, DE) 20 cm x 20 cm X 1mm plates. When needed multiple plates are used. After eluting the plates with the indicated solvent, the desired band is marked under UV light, and scrapped off.
  • the desire product is extracted from the silica using a polar solvent system (e.g., 20% methanol in methylene chloride).
  • a polar solvent system e.g. 20% methanol in methylene chloride
  • the reaction mixture was then cooled to ambient temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was dissolved in a 1 :1 mixture of DMSO (500 microliters) to DMF (500 microliters). The crude material was purified using a Shimadzu preparative HPLC.
  • a XTERA 50 X 50 mm column was used eluting with a gradient of 15 %, 0.1 % formic acid in acetonitrile (85 %, O.I % aqueous formic acid) to 100 %, 0.1 % formic acid in acetonitrile (0 %, 0.1 % aqueous formic acid) over 6 minutes with a flow rate of 75 ml/minute detecting at a wavelength of 220 nm. The fractions were collected and concentrated in vacuo to afford the title compound Hb (42.0 mg). MS (ES +' ) CaIc: 428.2, Found: 429.3 (M+1).
  • BIOLOGICAL ASSAYS The utility of the compounds of the present invention in the practice of the instant invention was evidenced by activity in one or more of the protocols described hereinbelow.
  • the following acronyms are used hereinbelow.
  • DMEM Dulbecco's Modified Eagle Medium HEPES - N-2-hydroxyethyl-piperazine-N'-2-ethane sulfonate
  • EDTA Ethylenediaminetetraacetic acid
  • EGTA Ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N ⁇ N'-tetraacetic acid
  • PEI Polyethyleneimine DMSO - Dimethylsulfoxide Fluo 4-AMTM - Fluorescent probe available from Molecular Probes, Inc., Eugene, OR PerkinElmerTM refers to PerkinElmer Life and Analytical Sciences, Inc., Boston, MA SigmaTM refers to Sigma-Aldrich Corp., St. Louis, MO
  • 5HT 2c Binding Procedure Affinity of compounds at the serotonin 5HT 20 binding site is determined by competition binding in Swiss 3T3 mouse cells (available from the American Type Culture Collection (ATCC), Manassas, VA) transfected with the human 5HT 2c receptor against 3 H-5HT.
  • Cells are grown in DMEM high glucose medium, (switched to medium containing 10% dialyzed fetal bovine serum 18 hours prior to harvest), harvested, centrifuged, and resuspended in Homogenization buffer (10 mM HEPES, pH 7.5, 1 mM EDTA, 1 mM EGTA containing the following protease inhibitors: 0.1 mg/ml benzamidine (SigmaTM B 6506), 0.1 mg/ml bacitracin (SigmaTM B 0125), 0.005 mg/ml leupeptin (SigmaTM L 8511 ), 0.5 mg/ml aprotinin (SigmaTM A 1153).
  • Homogenization buffer 10 mM HEPES, pH 7.5, 1 mM EDTA, 1 mM EGTA containing the following protease inhibitors: 0.1 mg/ml benzamidine (SigmaTM B 6506), 0.1 mg/ml bacitracin (SigmaTM B 01
  • Cells are incubated in a centrifuge tube on ice for 10 minutes, then homogenized using four 10-second bursts of a PolytronTM homogenizer (BrinkmanTM, Westbury, NY), and then centrifuged at 1000 x g for 10 minutes at 4 0 C. The supernatant was carefully removed and transferred to new centrifuge tubes, then centrifuged for 20 minutes at 25,000 x g at 4 0 C. The supernatant was removed and discarded, while the pellet was resuspended in homogenization buffer, then centrifuged for 20 minutes at 25,000 x g at 4 °C.
  • Binding activity of test compounds to the 5HT 2c receptor was determined in 96-well plates containing 2 ⁇ l of test compound (in 100% DMSO) then 100 ⁇ l of 3 H-5HT (Amersham Biosciences, Piscataway, NJ; 2 nM final concentration) which was diluted in assay buffer (50 mM Tris pH 7.7, 10 mM MgCI 2 , 3 mM CaCI 2 , 1 mM EDTA, 10 ⁇ M pargyline, 0.1 % ascorbic acid) followed by 100 ⁇ l of membranes (approximately 10 ⁇ g membrane protein per well) diluted in assay buffer.
  • assay buffer 50 mM Tris pH 7.7, 10 mM MgCI 2 , 3 mM CaCI 2 , 1 mM EDTA, 10 ⁇ M pargyline, 0.1 % ascorbic acid
  • 5HT 2a Binding Procedure Affinity of compounds at the serotonin 5HT 2a binding site is determined by competition binding in NIH 3T3 mouse cells transfected with the rat 5HT 2a receptor using 1251-DOI.
  • Cells are grown in DMEM high glucose medium (switched to medium containing 10% dialyzed fetal bovine serum 18 hours prior to harvest), harvested, centrifuged, and resuspended in Homogenization buffer (10 mM HEPES, pH 7.5, 1 mM EDTA, 1 mM EGTA containing the following protease inhibitors: 0.1 mg/ml benzamidine (SigmaTM B 6506), 0.1 mg/ml bacitracin (SigmaTM B 0125), 0.005 mg/ml leupeptin (SigmaTM L 8511 ), 0.5 mg/ml aprotinin (SigmaTM A1153).
  • Homogenization buffer 10 mM HEPES, pH 7.5, 1 mM EDTA, 1 mM EGTA containing the following protease inhibitors: 0.1 mg/ml benzamidine (SigmaTM B 6506), 0.1 mg/ml bacitracin (SigmaTM B 0125
  • Cells are incubated in a centrifuge tube on ice for 10 minutes, then homogenized using four 10-second bursts of a PolytronTM homogenizer (BrinkmanTM), and then centrifuged at 1000 x g for 10 minutes at 4 0 C. The supernatant was carefully removed and transferred to new centrifuge tubes, then centrifuged for 20 minutes at 25,000 x g at 4 0 C. The supernatant was removed and discarded, while the pellet was resuspended in homogenization buffer, then centrifuged for 20 minutes at 25,000 x g at 4 0 C.
  • test compounds were aliquoted and frozen at -80 0 C. Binding activity of test compounds was determined in 96-well plates containing 2 ⁇ l of test compound (in 100% DMSO) then 100 ⁇ l of [ 125 I]-DOI (catalog number NEX255, PerkinElmerTM Life Sciences; 0.1 nM final concentration) which had been diluted in assay buffer (50 mM HEPES pH 7.4, 0.5 mM EDTA, 0.5 mM EGTA, 37.5 mM KCI, 2.5 mM MgCI 2 ) followed by 100 ⁇ l of 5HT 2a -expressing membranes which had been diluted in assay buffer.
  • assay buffer 50 mM HEPES pH 7.4, 0.5 mM EDTA, 0.5 mM EGTA, 37.5 mM KCI, 2.5 mM MgCI 2
  • 5HT 2b Binding Procedure Affinity of compounds for the human 5HT 2b receptor is determined by competition binding using membranes prepared from Chinese hamster ovary (CHO) cells containing the tetracycline operator (FIp-In Trex system - Invitrogen) that were engineered to express the human 5HT 2b receptor.
  • Membranes were prepared from cells that had been incubated in dialyzed fetal bovine calf serum (FBS) for the previous 18 hours, in the presence of 1 ⁇ M doxicycline, and the membranes were stored at -80 0 C.
  • FBS dialyzed fetal bovine calf serum
  • Cells are incubated in a centrifuge tube on ice for 10 minutes, then homogenized using four 10-second bursts of a PolytronTM homogenizer (BrinkmanTM), and then centrifuged at 1000 x g for 10 minutes at 4 0 C. The supernatant was carefully removed and transferred to new centrifuge tubes, then centrifuged for 20 minutes at 25,000 x g at 4 0 C. The supernatant was removed and discarded, while the pellet was resuspended in homogenization buffer, then centrifuged for 20 minutes at 25,000 x g at 4 0 C.
  • the assay plates were incubated at 37 0 C for 60 minutes, then the assay was terminated by filtration onto 96-well UniFilterTM plates (with GF/C filters - from PerkinElmerTM) which were pre-soaked in 0.3% PEI.
  • the filterplates were washed 2X with cold wash buffer (50 mM Tris, pH 7.4), then dried, scintillation fluid added and radioactivity determined in a Wallac MicrobetaTM plate scintillation counter (PerkinElmerTM).
  • functional assays are able to provide indication of the compound to activate a receptor or block the activation of the receptor as a consequence of prior binding. Activation or blockade of the activation of the receptor are what leads to the physiological activities of the ligands. Agonistic activity at a receptor and antagonistic activity at a receptor are completely different from one another and lead to very different and often opposing pharmacological responses. Consequently, the following assays provide useful information with respect to the mode of activation.
  • 5HT 2b cells were induced in the presence of 1 ⁇ g/ml doxycyclin in culture media with dialyzed serum. Twenty four (24) hours later the cells are loaded with the calcium sensitive dye, Fluo 4-AMTM (4 ⁇ M dissolved in DMSO containing pluronic acid) in serum free DMEM in the presence of probenicid (2.6 mM) for 75 minutes at 37 0 C in a CO 2 incubator. Unincorporated dye is removed by washing 3 times with a HEPES- buffer containing probenicid (2.6 mM) using an EMBLA cell washer (final volume 30 ⁇ l).
  • Plates are added to a fluorometric imaging plate reader (FLIPR 384TM available from Molecular Devices Corporation) individually and fluorescence measurements are taken every 2 seconds over an 90 seconds period. Test compound additions are made simultaneously to all 384 wells after 20 seconds of baseline recording. Concentration-response curves are generated using XLDA and agonist efficacies are generated as % of the response to 10 ⁇ M 5-HT (considered as 100%). Estimation of antagonist potencies (functional Ki's) are generated by measuring inhibition of the test compound response to 5-HT (10 nM for 5-HT 2c and 5HT 2b , 50 nM for 5-HT 2a ) and applying the Cheng Prusoff equation.
  • FLIPR 384TM available from Molecular Devices Corporation
  • OBESITY AND RELATED DISORDERS Spontaneous Food Intake The following screen is used to evaluate the efficacy of test compounds for inhibiting spontaneous food intake in Sprague-Dawley rats.
  • Male Sprague-Dawley rats may be obtained from Charles River Laboratories, Inc. (Wilmington, MA).
  • the rats are individually housed and fed powdered chow. They are maintained on a 12 hour light/dark cycle and received food and water ad libitum.
  • the animals are acclimated to the vivarium for a period of one week before testing is conducted. Rats are transferred to individual test cages 30 hours before the study.
  • the rats are administered test compound or vehicle alone (no compound) 15-30 minutes prior to the onset of the dark cycle.
  • test compounds are dosed at ranges between 0.1 and 100 mg/kg depending upon the compound.
  • the standard vehicle is 0.5% (w/v) methylcellulose or 30% ⁇ - cyclodextrin in water and the standard route of administration is oral. However, different vehicles and routes of administration are used to accommodate various compounds when required.
  • Food intake is monitored using an automated Columbus Instruments system (Columbus, Ohio). Individual rat food intake is recorded continuously at 10-minute intervals, starting at the time of dosing, for a period of at least 12 hours. Compound efficacy is determined by comparing the food intake pattern of compound-treated rats to vehicle.
  • SCHIZOPHRENIA AND RELATED DISORDERS The compounds of the present invention are useful in the treatment of Schizophrenia and related disorders.
  • the compounds of the present invention may be assessed in a number of standard behavioural tests predictive of antipsychotic activity. For example, apomorphine-induced climbing behaviour and hypothermia in mice (see, e.g., Moore, N. A. et al. Psvchopharmacoloqy 94 (2), 263-266 (1988), and 96, 539 (1988)).
  • Conditioned Avoidance Responding (inhibition of CAR) has been a classic and effective test used for the detection of drugs with potential antipsychotic activity, primarily developed to test neuroleptics acting through dopamine receptor blockade).
  • d-Amphetamine locomotor antagonist of the increased activity produced by d-amphetamine to show dopamine receptor blockade
  • PCP locomotor antagonist of the increased activity produced by the activation of dopamine neuronal function by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist; phencyclidine (PCP)
  • NMDA N-methyl-D-aspartate
  • PCP phencyclidine
  • a single 10 watt bulb in each cabinet is controlled by a 24 hour timer, which allows the behavioral to be maintained on any light/dark cycle desired.
  • the plexiglass chambers are fitted with grid floors which are divided into quadrants and a metal touchplate positioned 7 cm from the floor on all four walls of the chamber.
  • Horizontal locomotor activity is measured as the number of cross-overs an animal makes from one quadrant to another within its chamber. When the animal stands up (rears) and makes contact with the metal touchplate it is recorded by the computer as vertical locomotor activity. Subjects are placed in the chambers overnight (approx.15 hours) prior to the experiment. The next day each animal is weighed and treated with the test compound and then immediately returned to the test chamber.
  • subjects are removed from the test chamber and treated with phencyclidine hydrochloride (3.2 mg/kg, sc), or d-Amphetamine sulphate (1 mg/kg, sc) and then immediately returned to the test chamber.
  • Horizontal movements are recorded by a computer for a three-hour test period.
  • each animal is weighed and treated with the test compound one hour prior to being placed in the activity box.
  • the test is always started as soon after the dark cycle (4 pm) as possible so that the effects of the compound can be observed during the animals' most active time.
  • the apparatus is programmed to collect data overnight for a 12-hour period.
  • the computer is programmed to perform statistical analysis at given intervals.
  • a one-way ANOVA is used to determine whether a difference due to treatment exists and is followed by Dunnett's multiple range test to determine differences between the control and experimental groups. Timed intervals of data (cross-overs) are analyzed individually and cumulatively for the duration of the experiment.
  • Conditioned Avoidance Response Male CF rats (Charles River, Fisher-344 strain) are used in all experiments. Weights are approximately 350-400 grams at the time of testing. Animals are housed 2 per cage in environmentally controlled animal quarters (light/dark-4am/4pm).
  • the conditioned avoidance shuttle chambers consist of 8 individual Plexiglas behavior chambers (Coulboum InstrumentsTM) each divided by a guillotine door into two sides, enclosed in sound attenuating cabinets.
  • the Plexiglas chambers are fitted with metal grid floors, which are equipped with scrambled/constant current shockers. Rats are trained to avoid the onset of footshock (1.5 miliampere, preceded for 5 seconds by activation of house lights, que lights, and the opening of the guillotine door) by moving to the opposite side of the chamber. Thirty trials are completed per daily session, and the number of avoidance's (max 30), escapes (max 30), escape failures (max 30), latency to avoid (max 5 sec), latency to escape (max.10 sec), and adaptation crossovers (number of crossovers for a five minute period before the onset of trials, dark chamber) are recorded by the computer program.
  • Inter-trial intervals are 15 seconds with the guillotine door closed.
  • Drug treatment begins (30 minutes prior to session, s.c) when rats have reached criteria of 80% avoidances for a session. Testing is performed during the lights on period of the light/dark cycle, typically between 8am and 10am. Vehicle treatment is performed one day every week and statistical analysis is done comparing each drug treatment on separate days vs. the vehicle treatment that week. Testing is performed during the lights on period of the light/dark cycle, typically between 8am and 10am. The data is analyzed following importation into a spreadsheet using a t-test.
  • ICP Protocol Intra cavernosal pressure (ICP) can be measured in the conscious rat by means of telemetric recording.
  • a catheter is surgically implanted into the corpus cavernosum. The end of the catheter is linked to a device, which senses, processes, and transmits information digitally from within the animal.
  • a receiver converts the radio-frequency signal from the implant to a digital pulse stream that is readable by a data collection system. The PC-based system collects telemetred data from the animal.
  • a model TA11 PA- C40, 8mm catheter implant may be used a with modified 3 mm tip (Data Sciences International Inc.). Secure the implant body to the abdominal wall using non-absorbable sutures and partially close the abdominal incision. Reflect the tip of the penis cranially and retract the caudal incision to optimize the surgical field. Carefully isolate approximately 10mm of the internal structure of the penis from the surrounding tissue. Carefully reflect the corpus spongiosum to one side to give access to the corpus cavernosum. Access the corpus cavernosum using a modified over-the-needle catheter to puncture the tunica. Introduce the catheter tip via the preplaced catheter and advance until fully inserted. Carefully remove the access catheter and apply a suitable tissue adhesive to the insertion site.
  • test compounds are dissolved in 50% ⁇ -cyclodextrin in saline. They are administered at a dose of 5-10mg/kg subcutaneously (s.c).
  • Apomorphine hydrochloride hemihydrate (SigmaTM A-4393) at 60 ⁇ g/kg s.c. is used as a positive control as it has pro-erectile properties. Record ICP over a 15 minute period, starting at 30 minutes post injection i.e. from 30 to 35 minutes and repeat for two further 15 minute periods commencing at 60 minutes post injection and 120 minutes post injection respectively. Record ICP for 15 minutes.
  • a signal from the receiver pad feeds through to the Data Exchange Matrix® and hence to the software (Dataquest ART® acquisition system, Data Sciences International Inc.). Transfer the data via a floppy disk to an Excel spreadsheet for analysis.
  • PDE5 inhibitor for treatment of MED The effects of concomitant administration of a compound of the present invention in combination with a PDE5 inhibitor (PDE5i) on the penile intracavernosal pressure (ICP) in an anaesthetised rabbit model of erection can be measured according to the following protocol.
  • mice Male New Zealand rabbits ( ⁇ 2.5kg) are pre-medicated with a combination of Medetomidine (Domitor®) 0.5ml/kg inramuscularly (i.m.), and Ketamine (Vetalar®) 0.25ml/kg i.m. whilst maintaining oxygen intake via a face mask.
  • the rabbits are tracheotomised using a PortexTM uncuffed endotracheal tube 3 ID (internal diameter), connected to ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 18-20 mi, and a maximum airway pressure of 10 cm H 2 O.
  • Anaesthesia is then switched to Isoflurane® and ventilation continued with O 2 at 2 litres/min.
  • the right marginal ear vein is cannulated using a 23G or 24G catheter, and Lactated Ringer solution perfused at 0.5ml/min.
  • the rabbit is maintained at 3% isoflurane during invasive surgery, dropping to 2% for maintenance anaesthesia.
  • the left jugular vein is exposed, isolated and then cannulated with a PVC catheter (17 gauge / 17G) for the infusion of drugs and the test compounds.
  • the left groin area of the rabbit is shaved and a vertical incision is made approximately 5cm in length along the thigh.
  • the femoral vein and artery are exposed, isolated and then cannulated with a polyvinylchloride (PVC) catheter (17G) for the infusion of drugs and compounds. Cannulation is repeated for the femoral artery, inserting the catheter to a depth of 10 cm to ensure that the catheter reaches the abdominal aorta.
  • PVC polyvinylchloride
  • This arterial catheter is linked to a Gould system to record blood pressure. Samples for blood gas analysis are also taken via the arterial catheter. Systolic and diastolic pressures are measured, and the mean arterial pressure calculated using the formula (diastolic x2 + systolic) ⁇ 3.
  • Heart rate is measured via the pulse oxymeter and a Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc).
  • a ventral midline incision is made into the abdominal cavity. The incision is about 5cm in length just above the pubis. The fat and muscle is bluntly dissected away to reveal the hypogastric nerve which runs down the body cavity. It is essential to keep close to the side curve of the pubis wall in order to avoid damaging the femoral vein and artery which lie above the pubis.
  • the sciatic and pelvic nerves lie deeper and are located after further dissection on the dorsal side of the rabbit. Once the sciatic nerve is identified, the pelvic nerve is easily located.
  • pelvic nerve is loosely applied; anatomy books on the subject fail to identify the nerves in sufficient detail.
  • stimulation of the nerve causes an increase in intracavernosal pressure and cavemosal blood flow, and innervation of the pelvic region.
  • the pelvic nerve is freed away from surrounding tissue and a Harvard bipolar stimulating electrode is placed around the nerve.
  • the nerve is slightly lifted to give some tension, then the electrode is secured in position.
  • Approximately 1 ml of light paraffin oil is placed around the nerve and electrode. This acts as a protective lubricant to the nerve and prevents blood contamination of the electrode.
  • the electrode is connected to a Grass S88 Stimulator.
  • the pelvic nerve is stimulated using the following parameters:- 5V, pulse width 0.5ms, duration of stimulus 20 seconds with a frequency of 16Hz. Reproducible responses are obtained when the nerve is stimulated every 15-20 minutes.
  • Several stimulations using the above parameters are performed to establish a mean control response.
  • the compound(s) to be tested are infused, via the jugular vein, using a Harvard 22 infusion pump allowing a continuous 15. minute stimulation cycle.
  • the skin and connective tissue around the penis is removed to expose the penis.
  • a catheter set (Insyte-W, Becton-Dickinson 20 Gauge 1.1 x 48mm) is inserted through the tunica albica into the left corpus cavemosal space and the needle removed, leaving a flexible catheter.
  • This catheter is linked via a pressure transducer (Ohmeda 5299-04) to a Gould system to record intracavernosal pressure (ICP). Once an intracavernosal pressure is established, the catheter is sealed in place using Vetbond (tissue adhesive, 3M). Heart rate is measured via the pulse oxymeter and a Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc). Intracavernosal blood flow is recorded either as numbers directly from the Flowmeter using Po- ne-mah data acquisition software (Ponemah Physiology Platform, Gould Instrument Systems Inc), or indirectly from Gould chart recorder trace.
  • ICP intracavernosal pressure
  • test compounds are dissolved in 50% ⁇ -cyclodextrin in saline. They are administered at a dose of 5-10mg/kg subcutaneously (s.c).
  • Such benefits include increased efficacy and opportunities to treat MED subgroups that do not respond to other MED mono-therapies.
  • Treatment of FSAD Serotonin 5HT 2 c receptor agonists are known to potentiate pelvic nerve-stimulated increases in female genital blood flow in the anaesthetised rabbit model of sexual arousal.
  • the normal sexual arousal response consists of a number of physiological responses that are observed during sexual excitement. These changes such as vaginal, labial and clitoral engorgement result from increases in genital blood flow. Engorgement leads to increased vaginal lubrication via plasma transudation, increased vaginal compliance (relaxation of vaginal smooth muscle) and increases in vaginal and clitoral sensitivity.
  • FSAD Female sexual arousal disorder
  • ⁇ HRT postmenopausal
  • the primary consequence of FSAD is reduced genital engorgement or swelling which manifests itself as a lack of vaginal lubrication and a lack of pleasurable genital sensation. Secondary consequences include reduced sexual desire, pain during intercourse and difficulty in achieving orgasm.
  • the most common cause of FSAD is decreased genital blood flow resulting in reduced vaginal, labial and clitoral engorgement (Berman, J., Goldstein, I., Werbin, T. et al. (1999a).
  • the present invention provides a means for restoring or potentiating the normal sexual arousal response in women suffering from FSAD, by enhancing genital blood flow. The following describes a method for testing such response.
  • FSAD Method Female New Zealand rabbits (-2.5kg) are pre-medicated with a combination of Medetomidine (Domitor®) 0.5ml/kg intramuscularly (i.m.), and Ketamine (Vetalar®) 0.25ml/kg i.m. while maintaining oxygen intake via a face mask.
  • the rabbits are tracheotomised using a PortexTM uncuffed endotracheal tube 3 ID (internal diameter), connected to ventilator and maintained at a ventilation rate of 30-40 breaths per minute, with an approximate tidal volume of 18-20 ml, and a maximum airway pressure of 10 cm H 2 O.
  • Anaesthesia is then switched to Isoflurane® and ventilation continued with O 2 at 2 l/min.
  • the right marginal ear vein is cannulated using a 23G or 24G catheter, and Lactated Ringer solution perfused at 0.5 ml/min.
  • the rabbit is maintained at 3% Isoflurane® during invasive surgery, dropping to 2% for maintenance anaesthesia.
  • the left groin area of the rabbit is shaved and a vertical incision is made approximately 5 cm in length along the thigh.
  • the femoral vein and artery are exposed, isolated and then cannulated with a PVC catheter (17G) for the infusion of drugs and compounds.
  • Cannulation is repeated for the femoral artery, inserting the catheter to a depth of 10cm to ensure that the catheter has reached the abdominal aorta.
  • This arterial catheter is linked to a Gould system to record blood pressure.
  • Samples for blood gas analysis are also taken via the arterial catheter.
  • Systolic and diastolic pressures are measured, and the mean arterial pressure calculated using the formula (diastolic x2 + systolic) ⁇ 3.
  • Heart rate is measured via the pulse oxymeter and Po-ne-mah data acquisition software system (Ponemah Physiology Platform, Gould Instrument Systems Inc).
  • a ventral midline incision is made into the abdominal cavity. The incision is about 5cm in length just above the pubis.
  • the fat and muscle is bluntly dissected away to reveal the hypogastric nerve which runs down the body cavity. It is essential to keep close to the side curve of the pubis wall in order to avoid damaging the femoral vein and artery, which lie above the pubis.
  • the sciatic and pelvic nerves lie deeper and are located after further dissection on the dorsal side of the rabbit. Once the sciatic nerve is identified, the pelvic nerve is easily located.
  • the term pelvic nerve is loosely applied; anatomy books on the subject fail to identify the nerves in sufficient detail.
  • stimulation of the nerve causes an increase in vaginal and clitoral blood flow, and innervation of the pelvic region.
  • the pelvic nerve is freed away from surrounding tissue and a Harvard bipolar stimulating electrode is placed around the nerve.
  • the nerve is slightly lifted to give some tension, then the electrode is secured in position. Approximately 1 ml of light paraffin oil is placed around the nerve and electrode. This acts as a protective lubricant to the nerve and prevents blood contamination of the electrode.
  • the electrode is connected to a Grass S88 Stimulator.
  • the pelvic nerve is stimulated using the following parameters:- 5V pulse width 0.5 ms, duration of stimulus 10 seconds and a frequency range of 2 to 16 Hz. Reproducible responses are obtained when the nerve is stimulated every 15-20 minutes. A frequency response curve is determined at the start of each experiment in order to determine the optimum frequency to use as a sub-maximal response, normally 4 Hz.
  • a ventral midline incision is made, at the caudal end of the pubis, to expose the pubic area.
  • Connective tissue is removed to expose the tunica of the clitoris, ensuring that the wall is free from small blood vessels.
  • the external vaginal wall is also exposed by removing any connective tissue.
  • One laser Doppler flow probe is inserted 3cm into the vagina, so that half the probe shaft is still visible.
  • a second probe is positioned so that it lay just above the external clitoral wall. The position of these probes is then adjusted until a signal is obtained.
  • a second probe is placed just above the surface of a blood vessel on the external vaginal wall. Both probes are clamped in position.
  • Vaginal and clitoral blood flow is recorded either as numbers directly from the Flowmeter using Po-ne-mah data acquisition software (Ponemah Physiology Platform, Gould Instrument Systems Inc), or indirectly from Gould chart recorder trace. Calibration is set at the beginning of the experiment (0- 125ml/min/100g tissue). All data are reported as mean + standard error of the mean (s.e.m.). Significant changes are identified using Student's t-tests.

Abstract

L'invention concerne des composés dihydrobenzofurane de formule (I), dont des sels, des promédicaments, des hydrates et des solvates de ceux-ci, qui agissent en tant que ligands des récepteurs de 5-HT2, et leurs utilisations dans le traitement de maladies liées à l'activation des récepteurs de 5-HT2 chez les animaux.
PCT/IB2005/001853 2004-06-25 2005-06-13 Composes dihydrobenzofurane et leurs utilisations WO2006000902A1 (fr)

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WO2006116221A2 (fr) * 2005-04-22 2006-11-02 Wyeth Nouvelles combinaisons therapeutiques pour le traitement ou la prevention de troubles psychotiques
WO2006116169A2 (fr) * 2005-04-24 2006-11-02 Wyeth Methodes permettant de moduler la fonction vesicale
WO2007030150A1 (fr) * 2005-04-22 2007-03-15 Wyeth Dérivés d’alkanamine de dihydrobenzofuranyle comme agonistes 5ht2c
WO2007112065A2 (fr) * 2006-03-24 2007-10-04 Wyeth Procédés de traitement de troubles cognitifs et autres troubles
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EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
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EP3878447A1 (fr) 2020-03-11 2021-09-15 InterAx Biotech AG Antagonistes du récepteur bêta adrénergique
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US7396857B2 (en) 2005-04-22 2008-07-08 Wyeth Therapeutic combinations for the treatment or prevention of depression
WO2006116221A2 (fr) * 2005-04-22 2006-11-02 Wyeth Nouvelles combinaisons therapeutiques pour le traitement ou la prevention de troubles psychotiques
WO2007030150A1 (fr) * 2005-04-22 2007-03-15 Wyeth Dérivés d’alkanamine de dihydrobenzofuranyle comme agonistes 5ht2c
WO2006116221A3 (fr) * 2005-04-22 2007-04-12 Wyeth Corp Nouvelles combinaisons therapeutiques pour le traitement ou la prevention de troubles psychotiques
US7470799B2 (en) 2005-04-22 2008-12-30 Wyeth Dihydrobenzofuran derivatives and uses thereof
WO2006116150A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives de dihydrobenzofurane et utilisations associees
US7368477B2 (en) 2005-04-22 2008-05-06 Wyeth Benzofuranyl alkanamine derivatives and uses thereof
US7402687B2 (en) 2005-04-22 2008-07-22 Wyeth Dihydrobenzofuran derivatives and uses thereof
WO2006116169A2 (fr) * 2005-04-24 2006-11-02 Wyeth Methodes permettant de moduler la fonction vesicale
WO2006116169A3 (fr) * 2005-04-24 2006-12-21 Wyeth Corp Methodes permettant de moduler la fonction vesicale
WO2007112065A2 (fr) * 2006-03-24 2007-10-04 Wyeth Procédés de traitement de troubles cognitifs et autres troubles
WO2007112065A3 (fr) * 2006-03-24 2008-02-21 Wyeth Corp Procédés de traitement de troubles cognitifs et autres troubles
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
WO2008073956A3 (fr) * 2006-12-12 2008-07-24 Wyeth Corp Dérivés de sulfonamides cycliques et procédés relatifs à leur utilisation
WO2008073956A2 (fr) * 2006-12-12 2008-06-19 Wyeth Dérivés de sulfonamides cycliques et procédés relatifs à leur utilisation
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EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP3181550A1 (fr) * 2010-07-20 2017-06-21 Bayer Intellectual Property GmbH Benzocycloalcènes en tant qu'agents antifongiques
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