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WO2008027483A1 - Dérivés du benzofuranne utilisés comme modulateurs du récepteur 5-ht2a - Google Patents

Dérivés du benzofuranne utilisés comme modulateurs du récepteur 5-ht2a Download PDF

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Publication number
WO2008027483A1
WO2008027483A1 PCT/US2007/019084 US2007019084W WO2008027483A1 WO 2008027483 A1 WO2008027483 A1 WO 2008027483A1 US 2007019084 W US2007019084 W US 2007019084W WO 2008027483 A1 WO2008027483 A1 WO 2008027483A1
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compound according
alkyl
haloalkyl
patient
methyl
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Peter I. Dosa
Bradley Teegarden
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Arena Pharmaceuticals, Inc.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to benzofuran derivatives which are modulators of the serotonin 5-HT 2A receptor and are useful in the treatment of various diseases and disorders related to, for example, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy, and the like.
  • G Protein coupled receptors share a common structural motif of seven alpha helices
  • transmembrane helices are joined by strands of amino acids having a larger loop between the fourth and fifth transmembrane helix on the extracellular side of the membrane.
  • Another larger loop composed primarily of hydrophilic amino acids, joins transmembrane helices five and six on the intracellular side of the membrane.
  • the carboxy terminus of the receptor lies intracellularly with the amino terminus in the extracellular space. It is thought that the loop joining helices five and six, as well as, the carboxy terminus, interact with the G protein.
  • Gq, Gs, Gi and Go are G proteins that have been identified.
  • G protein coupled receptors exist in the cell membrane in equilibrium between two different states or conformations: an "inactive" state and an “active” state.
  • a receptor in an inactive state is unable to link to the intracellular transduction pathway to produce a biological response.
  • Changing the receptor conformation to the active state allows linkage to the transduction pathway and produces a biological response.
  • a receptor may be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand.
  • Recent discoveries such as, including but not exclusively limited to, modifications to the amino acid sequence of the receptor provide means other than ligands to stabilize the active state conformation. These means effectively stabilize the receptor in an active state by simulating the effect of a ligand binding to the receptor. Stabilization by such ligand-independent means is termed "constitutive receptor activation.”
  • Serotonin receptors Receptors for serotonin 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. Not surprisingly, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism, and neurodegenerative disorders.
  • anti-psychotic treatment approaches focused on the serotonin receptors
  • these types of therapeutics can generally be divided into two classes, the "typical” and the “atypical.” Both have anti-psychotic effects, but the typicals also include concomitant motor-related side effects (extra pyramidal syndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc). Such side effects are thought to be associated with the compounds interacting with other receptors, such as the human dopamine D2 receptor in the nigro-striatal pathway. Therefore, an atypical treatment is preferred. Haloperidol is considered a typical anti-psychotic, and clozapine is considered an atypical anti-psychotic.
  • Serotonin receptors are divided into seven subfamilies, referred to as 5-HTi through 5- HT 7 , inclusive. These subfamilies are further divided into subtypes.
  • the 5-HT 2 subfamily is divided into three receptor subtypes: 5-HT 2A , 5-HT 28 , and 5-HT 2C .
  • the human 5- HT 2C receptor was first isolated and cloned in 1987, and the human 5-HT 2A receptor was first isolated and cloned in 1990. These two receptors are thought to be the site of action of hallucinogenic drugs.
  • antagonists to the 5-HT 2A and 5-HT 2 c receptors are believed to be useful in treating depression, anxiety, psychosis, and eating disorders.
  • U.S. Patent Number 4,985,352 describes the isolation, characterization, and expression of a functional cDNA clone encoding the entire human 5-HT )C receptor (now known as the 5- HT 20 receptor).
  • U.S. Patent Numbers 5,661,024 and 6,541,209 describe the isolation, characterization, and expression of a functional cDNA clone encoding the entire human 5-HT 2A receptor.
  • the 5-HT 2A receptor has been shown to be associated with a number of diseases and disorders, and its modulation is believed to have therapeutic potential.
  • 5-HT 2A receptors are expressed on smooth muscle of blood vessels and 5-HT secreted by activated platelets causes vasoconstriction as well as activation of additional platelets during clotting.
  • a 5-HT 2A inverse agonist will inhibit platelet aggregation and thus be a potential treatment as an antiplatelet therapy (see Satimura, K, et al., Clin Cardiol 2002 Jan. 25 (l):28-32; and Wilson, H.C et al., Thromb Haemost 1991 Sep 2;66(3):355-60).
  • 5-HT 2A inverse agonists can be used to treat, for example, claudication or peripheral artery disease as well as cardiovascular complications (see Br. Med. J. 298: 424 - 430, 1989), Arterial thrombosis (see, Pawlak, D. et al. Thrombosis Research 90: 259 - 270, 1998), atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23 - 31, 2003), vasoconstriction, caused by serotonin (see, Fujiwara, T. and Chiba, S.
  • 5-HT 2A inverse antagonists can increase circulating adiponectin in patients, suggesting that they would also be useful in protecting patients against indications that are linked to adiponectin, for example, myocardial ischemia reperfusion injury and artherosclerosis (see Nomura, Shosaku, et al. Blood Coagulation and Fibrinolysis 2005, 16, 423-428).
  • Agitation is a well-recognized behavioral syndrome with a range of symptoms, including hostility, extreme excitement, poor impulse control, tension and uncooperativeness (See Cohen-Mansfield J, and Billig, N., (1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J Am Geriatr Soc 34(10): 711-721). Agitation is often treated with antipsychotic medications such as haloperidol in nursing home and other assisted care settings.
  • Alzheimer's dementia there is emerging evidence that agents acting at the 5-HT 2A receptors in the brain have the effects of reducing agitation in patients, including Alzheimer's dementia (See Katz, I.R., et al., J Clin Psychiatry 1999 Feb., 60(2): 107-115; and Street, J.S., et al., Arch Gen Psychiatry 2000 Oct., 57(10):968-976).
  • Dysfunction of the 5-HT 2A receptor has also been linked with various sleep disorders, diabetic-related pathologies, glaucoma, progressive multifocal leukoencephalopathy (PML), hypertension, and pain. Accordingly, new compounds that act as 5-HT 2A receptor modulators are consistently needed to develop new drugs for the treatment of the above-mentioned and other diseases.
  • the compounds, compositions, and methods described herein are directed toward this end.
  • the present invention provides, inter alia, compounds of Formula I: I or pharmaceutically acceptable salts thereof, wherein constituent members are provided herein.
  • the present invention further provides compositions comprising at least one compound of Formula I, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods of preparing pharmaceutical compositions of the invention by admixing at least one compound of Formula I, or pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating the 5-HT 2A receptor by contacting the receptor with a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of treating a 5-HT 2A receptor related disease or disorder in a patient by administering to the patient a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating diseases and disorders in a patient related to, for example, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy, and the like, by administering to the patient a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the present invention provides, inter alia, compounds that modulate the 5-HT 2A receptor and have Formula I:
  • A is absent, O or NR 8 ;
  • D is absent, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, O, S, NR 9 , CO, COO,
  • CONR 9 SO, SO 2 , SONR 9 , OrNR 9 CONR 10 ;
  • Z is H, Ci -10 alkyl, NR'R", aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C] -6 haloalkyl, CN, NO 2 , OR a!
  • R 1 is H or Ci -6 alkyl
  • R 2 and R 3 are independently selected from H, halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • R 4 , R s , and R 6 are independently selected from H, halo, and C 1-4 alkyl;
  • R 7 , R 8 , R 9 , and R 10 are independently selected from H and C 1 ⁇ , alkyl;
  • R' and R" are independently selected from H, C(O)R" 1 , C(O)NR 01 R" 1 , C(O)OR 81 , C -6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C
  • R a , R al , and R 32 are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 OH, CN, amino, halo, Ci -6 alkyl, C )-6 alkoxy, Cj -6 haloalkyl, or C (
  • R b , R bl , and R b2 are independently selected from H, C,. 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 OH, CN, amino, halo, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl
  • R cl and R dl are independently selected from H, Ci -I0 alkyl, C )-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci -I0 alkyl, C !-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 OH, CN, amino, halo, Ci -6 alkoxy, Ci -6 haloalkyl, or Ci -6 haloalkoxy
  • A is absent. In some embodiments, A is O. In some embodiments, A is NR 8 . In some embodiments, A is NH.
  • Y is phenyl optionally substituted by Cy. In some embodiments, Y is phenyl optionally substituted by Cy 7 wherein said Cy is located at the meta or para position.
  • Y is Ci -I0 alkyl.
  • D is absent, Ci -4 alkylene, or COO.
  • D is absent.
  • D is alkylene. In some embodiments, D is COO.
  • Z is H, Ci -I0 alkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C,.
  • Z is H, Ci-io alkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C -6 haloalkyl, CN, NO 2 , OR al , SR al , C(O)R bl , C(O)NR 01 R" 1 , C(O)OR al , OC(O)R" 1 , OC(O)NR 01 R" 1 , NR ol R dl , NR 01 C(O)R" 1 , NR cl C(O)NR cl R dl , NR cl C(O)OR al ,
  • Z is H, Ci-io alkyl, or heterocycloalkyl.
  • Z is H. In some embodiments, Z is Ci. 10 alkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • -D-Z is, H, C(O)O-(Ci -I0 alkyl), COOH, or heterocycloalkyl-(Ci. ,o) alkyl.
  • R 1 is H or methyl. In some embodiments, R 1 is methyl.
  • R 2 and R 3 are independently selected from H and halo. In some embodiments, R 2 is H. In some embodiments, R 3 is H or halo.
  • R 3 is H. In some embodiments, R 3 is halo. In some embodiments, R 3 is Br. In some embodiments, R 4 , R 5 , and R 6 are each H. In some embodiments, R 7 is H.
  • the compounds have Formula II:
  • the compounds have Formula I ⁇ a, nib, or HIc: ma nib ⁇ ic.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci -6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n- pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkylene refers to a linking alkyl group.
  • alkenyl refers to an alkyl group having one or more double carbon- carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkenylene refers to a linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon- carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylene refers to a linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.
  • aryl groups have from 6 to about 20 carbon atoms.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, and alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 1, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • Ring-forming carbon atoms and ring- forming heteroatoms can also be substituted with one or two oxo or sulfide groups.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene and isoindolene groups.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • haloalkoxy refers to an -O-haloalkyl group.
  • arylalkyl refers to alkyl substituted by aryl and "cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • amino refers to NH 2 .
  • compound as used herein, is meant to encompass all stereoisomers, such as enantiomers and diastereomers, all geometric isomers, any tautomeric forms, any isotopic forms, any hydrated forms, and any solvated forms thereof, unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active forms, mixtures thereof, or racemic forms.
  • Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Isotopic forms include compounds containing various isotopes of the constituent atoms. Isotopes refer to those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Thus, deuterated and tritiated forms of the compounds described herein are encompassed as are other isotopic forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam — lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1 ,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Solvated or hydrated forms of the compounds refer to solid preparations of the compound that include water or solvent molecules.
  • the water or solvent molecules can often be present in a stoichiometric ratio with the compound, and may form part of a crystalline lattice if the compound is in a crystalline form.
  • substituted indicates that at least one hydrogen atom of a moiety is replaced by a non-hydrogen substituent or group.
  • a moiety herein it may have up to the full valance of substitution; for example, methyl can be substituted by 1, 2, or 3 substituents, methylene can be substituted by 1 or 2 substituents, phenyl can be substituted by 1, 2, 3, 4, or 5 substituents, naphthyl can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like, unless otherwise specified.
  • substituted with one or more substituents refers to the substitution with one substituent up to the total number of substituents physically allowed. Further, when a moiety is substituted with more than one substituent, the substituents can be identical or they can be different.
  • the compounds of the invention, or salts thereof are isolated.
  • isolated is meant that the compound is at least partially or substantially separated from the environment in which is was formed or discovered.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 90% by weight of the compound of the invention, or salt thereof.
  • Methods for isolating compounds and their salts are routine in the art and include, for example, chromatographic methods, distillation, crystallization, and the like.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • the compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Compounds of the invention can be synthesized according to routine methods by those skilled in the art and as shown in the below Schemes.
  • Scheme 1 depicts a general route to compounds of the invention.
  • amines 1-1 can be coupled with reactants of formula Y-A-CO-L (wherein Y and A are as defined herein, and L is a leaving group such as halo, etc.) to yield amide derivatives 1-2.
  • the N-atom of the amide group in 1-2 can then be alkylated by routine methods such as by reaction with an alkylating reagent (e.g., R 7 -L, wherein R 7 is an alkyl group and L is a leaving group) to give the compounds 1-3.
  • an alkylating reagent e.g., R 7 -L, wherein R 7 is an alkyl group and L is a leaving group
  • the amine compound 1-1 can be coupled with an isocyanate 1-4, an orthochloroformate 1-5, or acyl chloride 1-6 to yield their corresponding urea, carbamate, and amide products 1-7, 1-8, and 1-9, respectively.
  • Scheme 2 depicts the preparation of amine intermediates 2-2 which are useful in preparing compounds of the invention (see Scheme 1).
  • nitro compounds 2-1 can be converted to the corresponding amine 2-2 in the presence of a reducing agent such as iron powder in acetic acid/ethanol while heating.
  • a reducing agent such as iron powder in acetic acid/ethanol while heating.
  • Scheme 3 depicts a synthetic route to 5-(5-nitrobenzofuran-7-yl)-lH-pyrazoles 3-3 which are useful synthetic precursors as illustrated above in Scheme 2.
  • 7-bromo-5- nitrobenzofurans 3-1 can be reacted with pyrazolylboronic acids 3-2 under Suzuki coupling conditions to afford the desired product.
  • Scheme 4 illustrates example synthetic routes to pyrazole-substituted benzofurans.
  • carboxylic acids 4-1 can be esterified by reaction with alcohols ROH (where R is, for example, alkyl, cycloalkyl, etc.) optionally in the presence of a catalytic amount of acid or base.
  • ROH where R is, for example, alkyl, cycloalkyl, etc.
  • the resulting ester 4-2 can be transformed to product 4-3 via the routes of Schemes 1 and 2, or reduced with a suitable reducing agent such as DIBAL-H to give the hydroxymethyl compound 4-4.
  • Ester 4-3 can be treated with a reducing agent in a similar manner to also produce the corresponding hydroxymethyl product 4-5.
  • Scheme 5 illustrates an example synthetic route to further pyrazole-substituted benzofurans.
  • hydroxymethyl compound 5-1 can be converted to heterocycloalkyl- methyl compound 5-2 by first activation of the OH leaving group and then treatment with an amine (e.g., substituted or unsubstituted amine, alkylamine, dialkylamine, cyclic amine, pyrrolidine, piperidine, piperazine, morpholine, azepine, etc.).
  • an amine e.g., substituted or unsubstituted amine, alkylamine, dialkylamine, cyclic amine, pyrrolidine, piperidine, piperazine, morpholine, azepine, etc.
  • Such transformations can also be effected on various benzofuran precursors to the compounds of the invention, such as nitro compound 4-4 of Scheme 4 and its corresponding amine.
  • Scheme 6 illustrates an example method of preparing 4-bromopyrazole compounds 6-2.
  • pyrazole compounds 6-1 can be treated with a brominating agent such as NBS to afford the desired product.
  • a brominating agent such as NBS
  • other 4-halopyrazole compounds can be prepared by analogous methods with the use of a suitable halogenating agent.
  • Compounds of the invention can modulate activity of the 5-HT 2A receptor.
  • modulate is meant to refer to an ability to increase or decrease activity of the receptor.
  • compounds of the invention can be used in methods of modulating the 5-HT 2A receptor by contacting the receptor with any one or more of the compounds, salts thereof, or compositions thereof described herein.
  • compounds of the present invention can act as antagonists (i.e., inhibitors), agonists, or inverse agonists of the 5-HT 2A receptor.
  • the compounds disclosed herein can be useful in the treatment of various diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, these include conditions related to platelet aggregation, asthma, agitation, schizophrenia, sleep disorders, diabetic-related pathologies, glaucoma, progressive multifocal leukoencephalopathy (PML), hypertension, pain, and the like.
  • diseases and disorders include conditions related to platelet aggregation, asthma, agitation, schizophrenia, sleep disorders, diabetic-related pathologies, glaucoma, progressive multifocal leukoencephalopathy (PML), hypertension, pain, and the like.
  • PML progressive multifocal leukoencephalopathy
  • Antiplatelet agents are prescribed for a variety of conditions. For example, in coronary artery disease they are used to help prevent myocardial infarction or stroke in patients who are at risk of developing obstructive blood clots (e.g., coronary thrombosis).
  • obstructive blood clots e.g., coronary thrombosis
  • heart attack In a myocardial infarction (heart attack), the heart muscle does not receive enough oxygen- rich blood as a result of a blockage in the coronary blood vessels. If taken while an attack is in progress or immediately afterward (preferably within 30 minutes), antiplatelets can reduce the damage to the heart.
  • a transient ischemic attack (“TIA” or "mini-stroke”) is a brief interruption of oxygen flow to the brain due to decreased blood flow through arteries, usually due to an obstructing blood clot.
  • Antiplatelet drugs have been found to be effective in preventing TIAs.
  • Angina is a temporary and often recurring chest pain, pressure or discomfort caused by inadequate oxygen-rich blood flow (ischemia) to some parts of the heart.
  • ischemia inadequate oxygen-rich blood flow
  • antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.
  • Stroke is an event in which the brain does not receive enough oxygen-rich blood, usually due to blockage of a cerebral blood vessel by a blood clot.
  • Angioplasty is a catheter based technique used to open arteries obstructed by a blood clot. Whether or not stenting is performed immediately after this procedure to keep the artery open, antiplatelets can reduce the risk of forming additional blood clots following the procedure(s).
  • Coronary bypass surgery is a surgical procedure in which an artery or vein is taken from elsewhere in the body and grafted to a blocked coronary artery, rerouting blood around the blockage and through the newly attached vessel. After the procedure, antiplatelets can reduce the risk of secondary blood clots.
  • Atrial fibrillation is the most common type of sustained irregular heart rhythm (arrythmia). Atrial fibrillation affects about two million Americans every year. In atrial fibrillation, the atria (the heart's upper chambers) rapidly fire electrical signals that cause them to quiver rather than contract normally. The result is an abnormally fast and highly irregular heartbeat. When given after an episode of atrial fibrillation, antiplatelets can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism). 5-HT 2A receptors are expressed on smooth muscle of blood vessels and 5 -HT secreted by activated platelets causes vasoconstriction as well as activation of additional platelets during clotting.
  • 5-HT 2A inverse agonist will inhibit platelet aggregation and thus be a potential treatment as an antiplatelet therapy (see Satimura, K, et al., Clin Cardiol 2002 Jan. 25 (l):28-32; and Wilson, H.C et al., Thromb Haemost 1991 Sep 2;66(3):355-60).
  • 5-HT 2A inverse agonists can be used to treat, for example, claudication or peripheral artery disease as well as cardiovascular complications (see Br. Med. J. 298: 424 - 430, 1989), Arterial thrombosis (see, Pawlak, D. et al.
  • Thrombosis Research 90: 259 - 270, 1998) atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23 — 31, 2003), vasoconstriction, caused by serotonin (see, Fujiwara, T. and Chiba, S. Journal of Cardiovascular Pharmacology 26: 503 — 510, 1995), restenosis of arteries following angioplasty or stent placement (see, Fujita, M. et al. Am Heart J. 145 :el 6 2003). It can also be used alone or in combination with thrombolytic therapy, for example, tPA (see, Yamashita, T. et al.
  • the 5-HT 2A inverse agonists disclosed herein can provide beneficial improvement in microcirculation to patients in need of antiplatelet therapy by antagonizing the vasoconstrictive products of the aggregating platelets in, for example and not limited to the indications described above. Accordingly, in some embodiments, the present invention provides methods for reducing platelet aggregation in a patient in need thereof comprising administering to the patient a composition comprising a compound of the invention which is a 5-HT 2A inverse agonist.
  • the present invention provides methods for treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or a symptom of any of the foregoing in a patient in need of the treatment, comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist of the invention.
  • the present invention provides methods for reducing risk of blood clot formation in an angioplasty or coronary bypass surgery patient, or a patient suffering from atrial fibrillation, comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist disclosed herein at a time where such risk exists.
  • 5-HT (5-hydroxytryptamine) has been linked to the pathophysiology of acute asthma (see Cazzola, M. and Matera, M.G., TIPS, 2000, 21, 13; and De Bie, JJ. et al., British J. Pharm., 1998, 124, 857-864).
  • the compounds of the present invention disclosed herein are useful in the treatment of asthma, and the treatment of the symptoms thereof. Accordingly, in some embodiments, the present invention provides methods for treating asthma in a patient in need of the treatment, comprising administering to the patient a composition comprising a compound of the invention which is a 5-HT 2A inverse agonist. In further embodiments, methods are provided for treating a symptom of asthma in a patient in need of the treatment, comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • Alzheimer's disease is a common occurrence in the elderly and often associated with dementia such as those caused by Alzheimer's disease, Lewy Body, Parkinson's, and Huntington's, which are degenerative diseases of the nervous system and by diseases that affect blood vessels, such as stroke, or multi-infarct dementia, which is caused by multiple strokes in the brain can also induce dementia.
  • Alzheimer's disease accounts for approximately 50 to 70% of all dementias (See Koss E, et al., (1997), Assessing patterns of agitation in Alzheimer's disease patients with the Cohen- Mansfield Agitation Inventory. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1 l(suppl 2):S45-S50).
  • the present invention provides methods for treating agitation in a patient in need of such treatment comprising administering to the patient a composition comprising a compound of the invention which is 5-HT 2A inverse agonist.
  • the agitation is due to a psychiatric disorder other than dementia.
  • the present invention provides methods for treatment of agitation or a symptom thereof in a patient suffering from dementia comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • the dementia is due to a degenerative disease of the nervous system, for example and without limitation, Alzheimers disease, Lewy Body, Parkinson's disease, and Huntington's disease, or dementia due to diseases that affect blood vessels, including, without limitation, stroke and multi- infarct dementia.
  • methods are provided for treating agitation or a symptom thereof in a patient in need of such treatment, where the patient is a cognitively intact elderly patient, comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • Schizophrenia is a psychopathic disorder of unknown origin, which usually appears for the first time in early adulthood and is marked by a number of characteristics, psychotic symptoms, progression, phasic development and deterioration in social behavior and professional capability in the region below the highest level ever attained.
  • Characteristic psychotic symptoms are disorders of thought content (multiple, fragmentary, incoherent, implausible or simply delusional contents or ideas of doctrine) and of mentality (loss of association, flight of imagination, incoherence up to incomprehensibility), as well as disorders of perceptibility (hallucinations), of emotions (superficial or inadequate emotions), of self-perception, of intentions and impulses, of interhuman relationships, and finally psychomotors disorders (such as catatonia). Other symptoms are also associated with this disorder. ⁇ See, American Statistical and Diagnostic Handbook).
  • Haloperidol is a potent dopamine D 2 receptor antagonist. It is widely prescribed for acute schizophrenic symptoms, and is very effective for the positive symptoms of schizophrenia. However, Haldol is not effective for the negative symptoms of schizophrenia and may actually induce negative symptoms as well as cognitive dysfunction.
  • adding a 5-HT 2A inverse agonist concomitantly with Haldol can provide benefits including the ability to use a lower dose of Haldol without losing its effects on positive symptoms, while reducing or eliminating its inductive effects on negative symptoms, and prolonging relapse to the patient's next schizophrenic event.
  • Haloperidol is used for treatment of a variety of behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS). Further uses include in the treatment of infantile autism, huntington's chorea, and nausea and vomiting from chemotherapy and chemotherapeutic antibodies. Administration of compounds of the invention which are 5-HT 2A inverse agonists with haloperidol also will provide benefits in these indications.
  • the present invention provides methods for treating a behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS) comprising administering to the patient a dopamine D 2 receptor antagonist and a 5-HT 2A inverse agonist disclosed herein.
  • the present invention provides methods for treating a behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS) comprising administering to the patient haloperidol and a 5-HT 2A inverse agonist disclosed herein.
  • the present invention provides methods for treating infantile autism, huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to the patient a dopamine D 2 receptor antagonist and a 5-HT 2A inverse agonist disclosed herein.
  • the present invention provides methods for treating infantile autism, huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to the patient haloperidol and a 5-HT 2A inverse agonist disclosed herein.
  • the present invention provides methods for treating schizophrenia in a patient in need of the treatment comprising administering to the patient a dopamine D 2 receptor antagonist and a 5-HT 2A inverse agonist disclosed herein.
  • the dopamine D 2 receptor antagonist is haloperidol.
  • the administration of the dopamine D 2 receptor antagonist can be concomitant with administration of the 5-HT 2A inverse agonist, or they can be administered at different times.
  • haloperidol and the 5-HT 2A inverse agonist are administered in a single dosage form, and in other embodiments, they are administered in separate dosage forms.
  • the present invention further provides methods of alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to a patient suffering from schizophrenia, comprising administering to the patient a 5-HT 2A inverse agonist as disclosed herein.
  • A. DYSSOMNIAS a. Intrinsic Sleep Disorders: Psychophysiological insomnia, Sleep state misperception, Idiopathic insomnia, Obstructive sleep apnea syndrome, Central sleep apnea syndrome, Central alveolar hypoventilation syndrome, Periodic limb movement disorder, Restless leg syndrome and Intrinsic sleep disorder NOS. b. Extrinsic Sleep Disorders:
  • Time zone change (jet lag) syndrome Shift work sleep disorder, Irregular sleep-wake pattern, Delayed sleep phase syndrome, Advanced sleep phase syndrome, Non-24-hour sleep-wake disorder and Circadian rhythm sleep disorder NOS.
  • benzodiazepines The most common class of medications for the majority of sleep disorders are the benzodiazepines, but the adverse effect profile of benzodiazepines include daytime sedation, diminished motor coordination, and cognitive impairments. Furthermore, the National Institutes of Health Consensus conference on Sleeping Pills and Insomnia in 1984 have developed guidelines discouraging the use of such sedative-hypnotics beyond 4-6 weeks because of concerns raised over drug misuse, dependency, withdrawal and rebound insomnia. Therefore, it is desirable to have a pharmacological agent for the treatment of insomnia, which is more effective and/or has fewer side effects than those currently used. In addition, benzodiazepines are used to induce sleep, but have little to no effect on the maintenance of sleep, sleep consolidation or slow wave sleep. Therefore, sleep maintenance disorders are not currently well treated.
  • Some sleep disorders are sometimes found in conjunction with other conditions and accordingly those conditions are treatable by compounds of Formula I.
  • patients suffering from mood disorders typically suffer from a sleep disorder that can be treatable by compounds of Formula I.
  • Having one pharmacological agent which treats two or more existing or potential conditions, as does the present invention, is more cost effective, leads to better compliance and has fewer side effects than taking two or more agents.
  • the present invention provides a therapeutic agent for the use in treating Sleep Disorders.
  • the present invention provides one pharmaceutical agent, which can be useful in treating two or more conditions wherein one of the conditions is a sleep disorder.
  • compounds of the present invention described herein can be used alone or in combination with a mild sleep inducer (i.e. antihistamine).
  • NREM sleep comprises two physiological states: Non rapid eye movement (NREM) and rapid eye movement (REM) sleep.
  • NREM sleep consists of four stages, each of which is characterized by progressively slower brain wave patterns, with the slower patterns indicating deeper sleep. So called delta sleep, stages 3 and 4 of NREM sleep, is the deepest and most refreshing type of sleep. Many patients with sleep disorders are unable to adequately achieve the restorative sleep of stages 3 and 4. In clinical terms, patients' sleep patterns are described as fragmented, meaning the patient spends a lot of time alternating between stages 1 and 2 (semi-wakefulness) and being awake and very little time in deep sleep.
  • fragmented sleep architecture means an individual, such as a sleep disorder patient, spends the majority of their sleep time in NREM sleep stages 1 and 2, lighter periods of sleep from which the individual can be easily aroused to a Waking state by limited external stimuli. As a result, the individual cycles through frequent bouts of light sleep interrupted by frequent awakenings throughout the sleep period. Many sleep disorders are characterized by a fragmented sleep architecture. For example, many elderly patients with sleep complaints have difficulty achieving long bouts of deep refreshing sleep (NREM stages 3 and 4) and instead spend the majority of their sleep time in NREM sleep stages 1 and 2.
  • the term “sleep consolidation” means a state in which the number of NREM sleep bouts, particularly Stages 3 and 4, and the length of those sleep bouts are increased, while the number and length of waking bouts are decreased.
  • the architecture of the sleep disorder patient is consolidated to a sleeping state with increased periods of sleep and fewer awakenings during the night and more time is spent in slow wave sleep (Stages 3 and 4) with fewer oscillation Stage 1 and 2 sleep.
  • Compounds of the present invention can be effective in consolidating sleep patterns so that the patient with previously fragmented sleep can now achieve restorative, delta-wave sleep for longer, more consistent periods of time.
  • NREM sleep makes up about 75% of total sleep time; stage 1 accounting for 5-10% of total sleep time, stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%. About 90 minutes after sleep onset, NREM sleep gives way to the first REM sleep episode of the night. REM makes up approximately 25% of total sleep time. In contrast to NREM sleep, REM sleep is characterized by high pulse, respiration, and blood pressure, as well as other physiological patterns similar to those seen in the active waking stage. Hence, REM sleep is also known as "paradoxical sleep.” Sleep onset occurs during NREM sleep and takes 10-20 minutes in healthy young adults.
  • the four stages of NREM sleep together with a REM phase form one complete sleep cycle that is repeated throughout the duration of sleep, usually four or five times.
  • the cyclical nature of sleep is regular and reliable; a REM period occurs about every 90 minutes during the night.
  • the first REM period tends to be the shortest, often lasting less than 10 minutes, whereas the later REM periods may last up to 40 minutes.
  • the time between retiring and sleep onset increases and the total amount of night-time sleep decreases because of changes in sleep architecture that impair sleep maintenance as well as sleep quality. Both NREM (particularly stages 3 and 4) and REM sleep are reduced.
  • stage 1 NREM sleep which is the lightest sleep, increases with age.
  • delta power means a measure of the duration of EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and is thought to be a measure of deeper, more refreshing sleep. Delta power is hypothesized to be a measure of a theoretical process called
  • Process S and is thought to be inversely related to the amount of sleep an individual experiences during a given sleep period. Sleep is controlled by homeostatic mechanisms; therefore, the less one sleeps the greater the drive to sleep. It is believed that Process S builds throughout the wake period and is discharged most efficiently during delta power sleep. Delta power is a measure of the magnitude of Process S prior to the sleep period. The longer one stays awake, the greater Process S or drive to sleep and thus the greater the delta power during NREM sleep. However, individuals with sleep disorders have difficulty achieving and maintaining delta wave sleep, and thus have a large build-up of Process S with limited ability to discharge this buildup during sleep.
  • 5-HT 2A agonists tested preclinically and clinically mimic the effect of sleep deprivation on delta power, suggesting that subjects with sleep disorders treated with a 5-HT 2A inverse agonist or antagonist will be able to achieve deeper more refreshing sleep. These same effects have not been observed with currently marketed pharmacotherapies.
  • currently marketed pharmacotherapies for sleep have side effects such as hangover effects or addiction that are associated with the GABA receptor.
  • 5-HT 2A inverse agonists usually do not target the GABA receptor and so these side effects are not typically a concern.
  • onset, duration or quality of sleep e.g. non-restorative or restorative sleep
  • One method is a subjective determination of the patient, e.g., do they feel drowsy or rested upon waking.
  • Other methods involve the observation of the patient by another during sleep, e.g., how long it takes the patient to fall asleep, how many times does the patient wake up during the night, how restless is the patient during sleep, etc.
  • Another method is to objectively measure the stages of sleep using polysomnography.
  • Polysomnography is the monitoring of multiple electrophysiological parameters during sleep and generally includes measurement of EEG activity, electroculographic activity and electromyographic activity, as well as other measurements. These results, along with observations, can measure not only sleep latency (the amount of time required to fall asleep), but also sleep continuity (overall balance of sleep and wakefulness) and sleep consolidation (percent of sleeping time spent in delta-wave or restorative sleep) which may be an indication of the quality of sleep.
  • Stage 1 NREM sleep is a transition from wakefulness to sleep and occupies about 5% of time spent asleep in healthy adults.
  • Stage 2 NREM sleep which is characterized by specific EEG waveforms (sleep spindles and K complexes), occupies about 50% of time spent asleep.
  • Stages 3 and 4 NREM sleep (also known collectively as slow-wave sleep and delta-wave sleep) are the deepest levels of sleep and occupy about 10-20% of sleep time. REM sleep, during which the majority of vivid dreams occur, occupies about 20-25% of total sleep.
  • NREM stages 3 and 4 tend to occur in the first one-third to one-half of the night and increase in duration in response to sleep deprivation.
  • REM sleep occurs cyclically through the night. Alternating with NREM sleep about every 80-100 minutes. REM sleep periods increase in duration toward the morning. Human sleep also varies characteristically across the life span. After relative stability with large amounts of slow-wave sleep in childhood and early adolescence, sleep continuity and depth deteriorate across the adult age range. This deterioration is reflected by increased wakefulness and stage 1 sleep and decreased stages 3 and 4 sleep.
  • the compounds of the invention can be useful for the treatment of the sleep disorders characterized by excessive daytime sleepiness such as narcolepsy.
  • Inverse agonists at the serotonin 5-HT 2A receptor improve the quality of sleep at nightime which can decrease excessive daytime sleepiness.
  • Another aspect of the present invention relates to the therapeutic use of compounds of the present invention for the treatment of Sleep Disorders.
  • Compounds of the present invention are potent inverse agonists at the serotonin 5-HT 2A receptor and can be effective in the treatment of Sleep Disorders by promoting one or more of the following: reducing the sleep onset latency period (measure of sleep induction), reducing the number of nighttime awakenings, and prolonging the amount of time in delta-wave sleep (measure of sleep quality enhancement and sleep consolidation) without effecting REM sleep.
  • compounds of the present invention can be effective either as a monotherapy or in combination with sleep inducing agents, for example but not limited to, antihistamines.
  • DPN diabetic peripheral neuropathy
  • DN diabetic nephropathy
  • DR diabetic retinopathy
  • Serotonin is believed to play a role in vasospasm and increased platelet aggregability. Improving microvascular blood flow is able to benefit diabetic complications.
  • sarogrelate was evaluated for the prevention of the development or progression of diabetic nephropathy (Takahashi, T., et al., Diabetes Res CHn Pract. 2002 Nov; 58(2): 123-9).
  • sarpogrelate significantly reduced urinary albumin excretion level.
  • Topical ocular administration of 5-HT2 receptor antagonists result in a decrease in intra ocular pressure (IOP) in monkeys (Chang et al., 7. Ocul Pharmacol 1:137-147 (1985)) and humans (Mastropasqua et al., Acta Ophthalmol ScandSuppl 224:24-25 (1997)) indicating utility for similar compounds such as 5-HT 2A inverse agonists in the treatment of ocular hypertension associated with glaucoma.
  • the 5-HT2 receptor antagonist ketanserin (Mastropasqua supra) and sarpogrelate Takenaka et al., Investig Ophthalmol Vis Sd 36:S734 (1995) have been shown to significantly lower IOP in glaucoma patients.
  • Progressive multifocal leukoencephalopathy is a lethal demyelinating disease caused by an opportunistic viral infection of oligodendrocytes in immunocompromised patients.
  • the causative agent is JC virus, a ubiquitous papovavirus that infects the majority of the population before adulthood and establishes a latent infection in the kidney. Ln immunocompromised hosts, the virus can reactivate and productively infect oligodendrocytes. This previously rare condition, until 1984 reported primarily in persons with underlying lymphoproliferative disorders, is now more common because it occurs in 4% of patients with AIDS.
  • JC virus enters cells by receptor-mediated clathrin-dependent endocytosis. Binding of JC virus to human glial cells (e.g., oligodendrocytes) induces an intracellular signal that is critical for entry and infection by a ligand-inducible clathrin-dependent mechanism [Querbes et al., J Virology (2004) 78:250-256]. Recently, 5-HT 2A was shown to be the receptor on human glial cells mediating infectious entry of JC virus by clathrin-dependent endocytosis [Elphick et al., Science (2004) 306:1380-1383]. 5-HT 2A antagonists, including ketanserin and ritanserin, inhibited JC virus infection of human glial cells. Ketanserin and ritanserin have inverse agonist activity at 5- HT 2A .
  • 5-HT 2A antagonists including inverse agonists have been contemplated to be useful in the treatment of PML [Elphick et al., Science (2004) 306:1380-1383].
  • Prophylactic treatment of HIV-infected patients with 5-HT 2A antagonists is envisioned to prevent the spread of JC virus to the central nervous system and the development of PML.
  • Aggressive therapeutic treatment of patients with PML is envisioned to reduce viral spread within the central nervous system and prevent additional episodes of demyelination.
  • methods are provided for treating progressive multifocal leukoencephalopathy in a patient in need of such treatment, comprising administering to the patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • Serotonin has been observed to play an important role in the regulation of vascular tone, vasoconstriction, and pulmonary hypertension (see, Deuchar, G. et al. PuIm. Pharmacol. Ther.
  • Ketanserin a 5-HT 2A inverse agonist, has been demonstrated to protect against circulatory shocks, intracranial hypertension, and cerebral ischemia during heatstroke (see, Chang, C. et al. Shock 24(4): 336-
  • 5-HT 2A inverse agonists are also effective for the treatment of pain.
  • Sarpogrelate has been observed to provide a significant analgesic effect both on thermal induced pain in rats after intraperitoneal administration and on inflammatory pain in rats after either intrathecal or intraperitoneal administration (see, Nishiyama, T. Eur. J. Pharmacol. 516:18-22 2005).
  • This same 5-HT 2A inverse agonist in humans has been shown to be an effective treatment for lower back pain, leg pain and numbness associated with sciatica brought on by lumbar disc herniation
  • One aspect of the present invention encompasses methods for modulating the activity of a 5-HT 2A serotonin receptor by contacting the receptor with a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of platelet aggregation in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of an indication selected from coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of reducing the risk of blood clot formation in a patient undergoing an angioplasty or coronary bypass surgery comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of reducing the risk of blood clot formation in a patient suffering from atrial fibrillation, comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of asthma in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of a symptom of asthma in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One aspect of the present invention encompasses methods for the treatment of agitation or a symptom thereof in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the patient is a cognitively intact elderly patient.
  • One aspect of the present invention encompasses methods for the treatment of agitation or a symptom thereof in a patient suffering from dementia comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the dementia is due to a degenerative disease of the nervous system.
  • the dementia is Alzheimers disease, Lewy Body, Parkinson's disease or Huntington's disease.
  • the dementia is due to diseases that affect blood vessels.
  • the dementia is due to stroke or multi- infarct dementia.
  • One aspect of the present invention encompasses methods for the treatment of a patient suffering from at least one of the indications selected from behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia comprising administering to the individual in need thereof a therapeutically effective amount of a dopamine D 2 receptor antagonist and a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the dopamine D 2 receptor antagonist is haloperidol.
  • One aspect of the present invention encompasses methods for the treatment of a patient with infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to the individual in need thereof a therapeutically effective amount of a dopamine D 2 receptor antagonist and a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the dopamine D 2 receptor antagonist is haloperidol.
  • One aspect of the present invention encompasses methods for the treatment of schizophrenia in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a dopamine D 2 receptor antagonist and a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the dopamine D 2 receptor antagonist is haloperidol.
  • One aspect of the present invention encompasses methods for the treatment of alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to a patient suffering from the schizophrenia, comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms.
  • the haloperidol and the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition are administered in a single dosage form.
  • One aspect of the present invention encompasses methods for the treatment of a sleep disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the sleep disorder is a dyssomnia.
  • the dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-24-hour sleep- wake disorder.
  • psychophysiological insomnia sleep state misperception
  • idiopathic insomnia obstructive sleep apnea syndrome
  • central sleep apnea syndrome central alveolar hypoventilation syndrome
  • periodic limb movement disorder restless leg syndrome
  • the sleep disorder is a parasomnia.
  • the parasomnia is selected from the group consisting of confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps.
  • the sleep disorder is characterized by excessive daytime sleepiness such as narcolepsy.
  • the sleep disorder is associated with a medical or psychiatric disorder.
  • the medical or psychiatric disorder is selected from the group consisting of psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorder.
  • One aspect of the present invention encompasses methods for the treatment of a diabetic-related disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the diabetic-related disorder is diabetic peripheral neuropathy. In some embodiments, the diabetic-related disorder is diabetic nephropathy. In some embodiments, the diabetic-related disorder is diabetic retinopathy.
  • One aspect of the present invention encompasses methods for the treatment of glaucoma or other diseases of the eye with abnormal intraocular pressure.
  • One aspect of the present invention encompasses methods for the treatment of progressive multifocal leukoencephalopathy in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • the individual in need thereof has a lymphoproliferative disorder.
  • the lymphoproliferative disorder is leukemia or lymphoma.
  • the leukemia or lymphoma is chronic lymphocytic leukemia, Hodgkin's disease, or the like.
  • the patient in need thereof has a myeloproliferative disorder.
  • the patient in need thereof has carcinomatosis. In some embodiments, the patient in need thereof has a granulomatous or inflammatory disease. In some embodiments, the granulomatous or inflammatory disease is tuberculosis or sarcoidosis. In some embodiments, the patient in need thereof is immunocompromised. In some embodiments, the immunocompromised patient has impaired cellular immunity. In some embodiments, the impaired cellular immunity comprises impaired T-cell immunity.
  • the patient in need thereof is infected with HTV.
  • the HIV-infected patient has a CD4+ cell count of ⁇ 200/mm 3 .
  • the HIV-infected patient has AIDS.
  • the HIV-infected patient has AEDS-related complex (ARC).
  • ARC is defined as the presence of two successive CD4+ cell counts below 200/mm 3 and at least two of the following signs or symptoms: oral hairy leukoplakia, recurrent oral candidiasis, weight loss of at least 2.5 kg or 10% of body weight within last six months, multidermatomal herpes zoster, temperature above 38.5 0 C for more than 14 consecutive days or more than 15 days in a 30-day period, or diarrhea with more than three liquid stools per day for at least 30 days [see, e.g., Yamada et al., CHn. Diagn. Virol. (1993) 1:245-256].
  • the patient in need thereof is undergoing immunosuppressive therapy.
  • the immunosuppressive therapy comprises administering an immunosuppressive agent [see, e.g., Mueller, Ann Thorac Surg (2004) 77:354-362; and Krieger and Emre, Pediatr Transplantation (2004) 8:594-599].
  • the immunosuppressive therapy comprises administering an immunosuppressive agent selected from the group consisting of: corticosteroids (for example, prednisone and the like), calcineurin inhibitors (for example, cyclosporine, tacrolimus, and the like), antiproliferative agents (for example, azathioprine, mycophenolate mofetil, sirolimus, everolimus, and the like), T-cell depleting agents (for example, OKT ® 3 monoclonal antibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-IH (anti-CD52) mAb, anti-CD4 mAb, anti-T cell receptor mAb, and the like), anti-IL-2 receptor (CD25) mAb (for example, basiliximab, daclizumab, and the like), inhibitors of co-stimulation (for example, CTLA4-Ig, anti-CD 154 (CD40 ligand) mAb, and
  • the immunosuppressive agent and said compound or pharmaceutical composition are administered in separate doseage forms. In some embodiments, the immunosuppressive agent and said compound or pharmaceutical composition are administered in a single dosage form. In some embodiments, the patient in need thereof is undergoing immunosuppressive therapy after organ transplantation. In some embodiments, the organ is liver, kidney, lung, heart, or the like [see, e.g., Singh et al., Transplantation (2000) 69:467-472].
  • the patient in need thereof is undergoing treatment for a rheumatic disease.
  • the rheumatic disease is systemic lupus erythematosus or the like.
  • the compound or the pharmaceutical composition inhibits JC virus infection of human glial cells.
  • One aspect of the present invention encompasses processes for preparing a composition comprising admixing a compound according any embodiments described herein and pharmaceutically acceptable carrier.
  • One aspect of the present invention is the use of a compound of the invention, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for the production of a medicament for use in the treatment of a 5-HT 2A related disorder.
  • One aspect of the present invention is the use of a compound of the invention, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for the treatment of a 5-HT 2A related disorder.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting the 5-HT 2A receptor with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a 5-HT 2A receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the 5-HT 2A receptor.
  • an individual or patient such as a human
  • having a 5-HT 2A receptor as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the 5-HT 2A receptor.
  • the term "individual" or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "in need of treatment” or “in need thereof refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • a caregiver e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder;
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • agonist is meant to refer to a moiety that interacts with and activates the receptor, such as the 5-HT 2A receptor, and initiates a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
  • Antagonist is meant to refer to a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • inverse agonist refers to a moiety that binds the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decreases GTP binding to membranes.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • the compounds of the present invention can be administered as the sole active pharmaceutical agent (i.e., mono-therapy), they can also be used in combination with other pharmaceutical agents (i.e., combination-therapy) for the treatment of any one or more of the diseases/conditions/disorders described herein.
  • the present invention includes methods of treatment of 5-HT 2A serotonin receptor related disorders or diseases comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, in combination with one or more additional pharmaceutical agents as described herein.
  • Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include other antiplatelet, antithrombotic or anticoagulant drugs, antiarrhythmic agents, Cholesteryl ester transfer protein (CETP) inhibitors, Niacin or niacin analogs, Adenosine or adenosine analogs, Nitroglycerin or nitrates, prothrombolytic agents, and the like.
  • Other pharmaceutical agents including the agents set forth infra, are well known or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • the compounds of the present invention can also be used in combination with other antiplatelet, antithrombotic or anticoagulant drugs such as thrombin inhibitors, platelet aggregation inhibitors such as aspirin, clopidogrel (Plavix®), ticlopidine or CS-747 ⁇ i.e., acetic acid 5-[2-cyclopropyl-l -(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2- yl ester and its active metabolite ⁇ -99224, (Z)-2-[l-[2-cyclopropyl-l(-S)-(2-fluorophenyl)-2- oxoethyl]-4( ⁇ )-sulfanylpiperidin-3-ylidene]acetic acid ⁇ , abciximab (ReoPro®), eptif ⁇ batide (Integrilin®), tirofiban
  • antihypertensive agents such as angiotensin-converting enzyme inhibitors (e.g., captopril, lisinopril or fosinopril); angiotensin-II receptor antagonists (e.g., irbesartan, losartan or valsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat and gemopatrilat); ⁇ -blockers (such as propranolol, nadolol and carvedilol), PDE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, or clopidogrel (Plavix®) and the like.
  • angiotensin-converting enzyme inhibitors e.g., captopril, lisinopril or fosinopril
  • angiotensin-II receptor antagonists e.g., irbesartan, losartan or valsartan
  • the compounds of the present invention can also be used in combination with antiarrhythmic agents such as for atrial fibrillation, for example, amiodarone or dofetilide.
  • antiarrhythmic agents such as for atrial fibrillation, for example, amiodarone or dofetilide.
  • the compounds of the present invention can also be used in combination with
  • CTP Cholesteryl ester transfer protein
  • Niacin or niacin analogs for dislipidemia and atherosclerosis Niacin or niacin analogs for dislipidemia and atherosclerosis
  • Adenosine or adenosine analogs for vasodilation Nitroglycerin or nitrates for vasodilation.
  • the compounds of the present invention can be used in combination with • prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like.
  • tissue plasminogen activator natural or recombinant
  • streptokinase reteplase
  • activase lanoteplase
  • urokinase prourokinase
  • anisolated streptokinase plasminogen activator complex ASPAC
  • animal salivary gland plasminogen activators and the like.
  • the compounds of the present invention may also be used in combination with ⁇ - adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol; anticholinergics such as ipratropium bromide; anti-inflammatory cortiocosteroids such as beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; and anti -inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast and pranleukast.
  • ⁇ - adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol
  • anticholinergics such as ipra
  • Suitable pharmaceutical agents that can be used in combination with compounds of the present invention include antiretrovirals [see, e.g., Turpin, Expert Rev Anti Infect Ther (2003) 1 :97-128].
  • Some embodiments of the present invention include methods of treatment of progressive multifocal leukoencephalopathy as described herein comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention in combination with at least one pharmaceutical agent selected from the group consisting of: nucleoside reverse transcriptase inhibitors (for example, Retrovir ® , Epivir ® , Combivir ® , Hivid ® , Videx ® , Trizvir ® , Zerit ® , Ziagen ® , Vired ® , Emtricitabine, DAPD, and the like), non-nucleoside reverse transcriptase inhibitors (for example, Virammune ® , Rescriptor ® , Sustiva ® , GW68
  • a compound of the invention can be used in conjunction with highly active antiretroviral therapy (HAART).
  • HAART highly active antiretroviral therapy
  • the combination of a compound of the present invention and pharmaceutical agent can be prepared by mixing the respective active components either all together or independently with a pharmaceutically acceptable carrier, excipient, binder, diluent, etc., and administering the mixture or mixtures either orally or non-orally as a pharmaceutical composition(s).
  • a pharmaceutically acceptable carrier such as a pharmaceutically acceptable styrene, aminoethyl styrene, etc.
  • each can be formulated as separate pharmaceutical compositions given at the same time or at different times.
  • pharmaceutical compositions of the present invention comprise one or more compounds of the invention, or pharmaceutically acceptable salts thereof, and one or more further pharmaceutical agent(s) as a single pharmaceutical composition.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof can be administered in the form of a pharmaceutical composition which is a combination of at least one compound of the invention, or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition which is a combination of at least one compound of the invention, or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and p ⁇ o ⁇ ylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions of the present invention can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
  • Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the receptor in tissue samples, including human, and for identifying receptor ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes receptor assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 0, 18 F, 15 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.
  • a radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with the radio-labeled compound for binding to the EDO enzyme directly correlates to its binding affinity.
  • Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment of 5-HT 2A related diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.
  • Example compounds of the present invention are provided below in Table 1. These compounds were found to be inverse agonists of the 5-HT 2A receptor according to one or more of the assays provided herein.
  • Microwave irradiations were carried out using the Emrys Synthesizer (Personal Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 F 254 (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on a Buchi rotary evaporator. Celite 545® was used during palladium filtrations.
  • LCMS specs 1) PC: HPLC-pumps: LC-IOAD VP, Shimadzu Inc.; HPLC system controller: SCL-IOA VP, Shimadzu Die; UV-Detector: SPD-IOA VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, ABMDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller: SCL-IOA VP, Shimadzu Inc.
  • UV-Detector SPD-IOA VP, Shimadzu Inc; Autosampler: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex Software: Masschrom 1.5.2.
  • Example 1.1 Preparation of l-Methyl-5-(5-nitrobenzofuran-7-yl)-lH-pyrazoIe (Intermediate).
  • N-bromosuccinimide N-bromosuccinimide
  • Example 1.8 Preparation of l-[7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-benzofuran-5-yl]- 3-(3-chloro-phe ⁇ yl)-urea (Compound 13).
  • the title compound was prepared in a similar manner as described in Example 1.4 to give a white solid.
  • LCMS m/z (%) 445 (M+H 79 Br, 70), 447 (M+H 81 Br, 100).
  • Example 1.10 Preparation of l-[7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-bei ⁇ zofuran-5-yl]- 3-(3-methoxy-phenyI)-urea (Compound 3).
  • the title compound was prepared in a similar manner as described in Example 1.4 to give a white solid.
  • LCMS m/z (%) 441 (M+H 79 Br, 100), 443 (M+H 81 Br, 91).
  • Example 1.12 Preparation of l-[7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-benzofuran-5-yl]- 3-(4-isopropyI-phenyl)-urea (Compound 14).
  • Example 1.14 Preparation of Ethyl 7-Bromo-5-nitrobenzofuran-2-carboxylate (Intermediate). A solution of 7-bromo-5-nitrobenzofuran-2-carboxylic acid (3.38 g, 11.8 mmol) in
  • Example 1.16 Preparation of Ethyl 7-(4-Bromo-l-methyI-lH-pyrazol-5-yl)-5- nitrobenzofuran-2-carboxylate (Intermediate).
  • Example 1.17 Preparation of Ethyl 5-Amino-7-(4-bromo-l-methyl-lH-pyrazol-5- S yl)benzofuran-2-carboxylate (Intermediate).
  • Example 1.18 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-5-[3-(4-chloro- phenyl)-ureido]-benzofuran-2-carboxylic acid ethyl ester (Compound 22).
  • Example 1.20 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-5-[3-(2,4-difliioro- phenyl)-ureido]-benzofuran-2-carboxylic acid (Compound 15). 0 To a solution of 7-(4-bromo-2-methyl-2H-pyrazol-3-yl)-5-[3-(2,4-difluoro-phenyl)- ureido]-benzofuran-2-carboxylic acid ethyl ester (23.8 mg, 0.0458 mmol) in methanol (1 mL) and THF (5 mL) was added IM LiOH in water (1 mL).
  • Example 1.21 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-5-[3-(4-methoxy- phenyl)-ureido]-benzofuran-2-carboxylic acid ethyl ester (Compound 9).
  • Example 1.22 Preparation of 7-(4-Bromo-2-methyI-2H-pyrazol-3-yl)-5-[3-(4-methoxy- phenyl)-ureido]-benzofuran-2-carboxylic acid (Compound 4).
  • Example 1.23 Preparation of 7-(4-Bromo-2-methyI-2H-pyrazol-3-yl)-5- isobutoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester (Compound 2).
  • Example 1.24 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-5-[3-(4-fluoro- phenyl)-ureido]-benzofuran-2-carboxylic acid ethyl ester (Compound 16).
  • Example 1.25 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yI)-5-[3-(4- trifluoromethyl-phenyI)-ureido]-benzofuran-2-carboxylic acid ethyl ester (Compound 10).
  • Example 1.27 Preparation of 7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-5- isobutoxycarbonylainino-benzofura ⁇ -2-carboxylic acid (Compound 20).
  • Example 1.32 Preparation of 4-Bromo-l-methyl-5-(5-nitro-2-(pyrrolidin-l- ylmethyl)benzofura ⁇ -7-yl)-lH-pyrazole (Intermediate).
  • Example 1.33 Preparation of 4-Bromo-l-methyl-5-(5-amino-2-(pyrrolidin-l- ylmethyl)benzofuran-7-yI)-lH-pyrazole (Intermediate).
  • Example 1.34 Preparation of l-[7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-2-pyrrolidin-l- ylmethyl-benzofuran-5-yl]-3-(4-chloro-phenyl)-urea (Compound 11).
  • Example 1.35 Preparation of N-l7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-2-pyrrolidin-l- ylmethyl-benzofuran-5-yl]-3-trifluoromethyl-benzainide (Compound 5).
  • the vector utilized be pCMV.
  • This vector was deposited with the American Type Culture Collection (ATCC) on October 13, 1998 (10801 University Boulevard., Manassas, VA 20110-2209 USA) under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure. The DNA was tested by the ATCC and determined to be viable. The ATCC has assigned the following deposit number to pCMV: ATCC #203351.
  • DOI binding assay (hereinbelow) COS7 cells were transfected.
  • COS-7 cells were plated onto 24 well plates, usually 1x105 cells/well or 2x105 cells/well, respectively.
  • the cells were transfected by first mixing 0.25 ug cDNA in 50 ⁇ l serum-free DMEM/well and then 2 ⁇ L lipofectamine in 50 ⁇ L serum-free DMEM/well. The solutions ("transfection media") were gently mixed and incubated for 15-30 minutes at room temperature. The cells were washed with 0.5 mL PBS and then 400 ⁇ L of serum free media was mixed with the transfection media and added to the cells. The cells were then incubated for 3-4 hours at 37 0 C / 5% CO 2 .
  • transfection media was removed and replaced with 1 mL/well of regular growth media.
  • 13x106 293 cells per 150 mm plate were plated out.
  • 2 mL of serum Optimeml (Invitrogen Corporation) was added per plate followed by addition of 60 ⁇ L of lipofectamine and 16 ⁇ g of cDNA. Note that lipofectamine must be added to the Optimeml and mixed well before addition of cDNA. While complexes between lipofectamine and the cDNA are forming, media was carefully aspirated and cells were gently rinsed with 5 mL of Optimeml media followed by careful aspiration.
  • IP Inositol Phosphate
  • HEK293 cells are transiently transfected with a pCMV expression vector containing a human 5-HT 2A receptor (for the sequence of the receptor see U.S. Patent No. 6,541 ,209, sequence no. 24) as described in Example A.
  • An IP accumulation assay can be performed as described below.
  • Frozen plates are then thawed over the course of one hour, and the contents of the wells (approximately 220 ⁇ L) are placed over 400 ⁇ L of washed ion-exchange resin (AG 1-X8) contained in a MuI ti Screen Filtration plate and incubated for 10 minutes followed by filtration under vacuum pressure. Resin is then washed nine times with 200 ⁇ L of water and then tritiated inositol phosphates (IP, IP2, and IP3) are eluted into a collecting plate by the addition of 200 ⁇ L of IM ammonium formate and an additonal 10 minute incubation.
  • AG 1-X8 washed ion-exchange resin
  • IP tritiated inositol phosphates
  • the elutant is then transferred to 20 mL scintillation vials, 8 mL of SuperMix or Hi-Safe scintillation cocktails is added, and vials are counted for 0.5-1 minutes in a Wallac 1414 scintilation counter.
  • COS7 cells transfected with recombinant human 5-HT 2A receptors were cultured for 48 hr post transfection, collected, washed with ice-cold phosphate buffered saline, pH7.4 (PBS), and then centrifuged at 48,000Xg for 20 min at 4 0 C. The cell pellet was then resuspended in wash buffer containing 20 mM HEPES pH 7.4 and 0.1 mM EDTA, homogenized on ice using a Brinkman polytron, and recentrifuged at 48,000 X g for 20 min. at 4 0 C.
  • PBS ice-cold phosphate buffered saline
  • the resultant pellet was then resuspended in 20 mM HEPES, pH 7.4, homogenized on ice, and centrifuged (48,000Xg for 20 min at 4 0 C). Crude membrane pellets were stored at —80 0 C until used for radioligand binding assays.
  • Radioligand binding assays for human 5-HT 2A receptor was conducted using the 5-HT 2 agonist [ 125 I]DOI as radioligand. To define nonspecific binding, 10 ⁇ M DOI was used for all assays. For competitive binding studies, 0.5 nM [ 125 I]DOI was used and compounds were assayed over a range of 0.01 nM to 10 ⁇ M. Assays were conducted in a total volume of 200 ⁇ L in 96-weIl Perkin Elmer GF/C filter plates in assay buffer (50 mM Tris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl 2 , and 10 ⁇ M pargyline).
  • Compounds of the invention can be tested for their ability to aggregate human platelets.
  • Aggregation assays are performed using a Chrono-Log Optical aggregometer model 410.
  • Human blood ⁇ 100 mL
  • HRP Platelet rich plasma
  • PPP platelet poor plasma
  • Platelets are counted and their concentration is set to 250,000 cells/ ⁇ L by dilution with
  • DOI is a potent 5-HT 2A/2 c receptor agonist that crosses the blood-brain barrier.
  • the standard protocol used is described briefly below. Animals: '
  • Rats Male Sprague-Dawley rats weighing between 200-30Og are used for all tests. Rats are housed three to four per cage. These rats are na ⁇ ve to experimental testing and drug treatment. Rats are handled one to three days before testing to acclimate them to experimental manipulation. Rats are fasted overnight prior to testing.
  • (R)-DOI HCl (C I I H 16 INO 2 HCI) can be obtained from Sigma-Aldrich, and is dissolved in 0.9% saline.
  • Compounds of the invention are synthesized at Arena Pharmaceuticals Inc. and are dissolved in 100% PEG400. DOI is injected s.c. in a volume of 1 mL/kg, while compounds of the invention are administered p.o. in a volume of 2mL/kg.
  • the "Motor Monitor” (Hamilton-Kinder, Poway, CA) is used for all activity measurement. This apparatus recorded rears using infrared photobeams.
  • Locomotor activity testing is conducted during the light cycle (0630-1830) between 9:00 a.m. and 4:00 p.m. Animals are allowed 30 min acclimation to the testing room before testing began.
  • mice are first injected with vehicle or the compound of the invention (50 ⁇ mol/kg) in their home cages. Sixty minutes later, saline or DOI (0.3 mg/kg salt) is injected. 10 min after DOI administration, animals are placed into the activity apparatus and rearing activity is measured for 10 minutes.
  • Results (total rears over 10 minutes) are analyzed by t-test. P ⁇ 0.05 is considered significant.
  • LSD Displacement Protocol Lysergic acid diethylamide (LSD) is a potent 5-HT 2A receptor and dopamine D2 receptor ligand. An indication of the selectivity of compounds for either or both of these receptors involves displacement of radiolabeled-bound LSD from pre-treated brain sections. For these studies, radiolabeled 125 I-LSD (NEN Life Sciences, Boston, Mass., Catalogue number NEX-199) can be utilized; spiperone (RBI, Natick, Mass. Catalogue number s-128) a 5-HT 2A receptor and dopamine D2 receptor antagonist, can also utilized. Buffer consists of 50 nanomolar TRIS-HCl, pH 7.4.
  • Brain sections are incubated in (a) Buffer plus 1 nanomolar 125 I-LSD; (b) Buffer plus 1 nanomolar 125 I-LSD and 1 micromolar spiperone; or Buffer plus 1 nanomolar 125 I-LSD and 1 micromolar compound of interest for 30 minutes at room temperature. Sections are then washed 2 x 10 minutes at 4 0 C in Buffer, followed by 20 seconds in distilled H 2 O. Slides are then air- dried.
  • the 5-HT 2A receptor occupancy of a compound of the invention can be measured.
  • the study can be carried out in rhesus monkeys using PET and 18F-altanserin.
  • the PET radioligand used for the occupancy studies is 18 F-altanserin. Radiosynthesis of l8 F-altanserin is achieved in high specific activities and is suitable for radiolabeling 5-HT 2A receptors in vivo (see Staley et al., Nucl. Med. Biol., 28:271-279 (2001) and references cited within). Quality control issues (chemical and radiochemical purity, specific activity, stability etc) and appropriate binding of the radioligand are verified in rat brain slices prior to use in PET experiments.
  • Radiopharmaceutical is dissolved in sterile 0.9% saline, pH approx 6-7.
  • the compounds of the invention are dissolved in 60% PEG 400 - 40% sterile saline on the same day of the PET experiment.
  • the monkey is anesthetized by using ketamine (10 mg/kg) and is maintained using 0.7 to 1.25% isoflurane.
  • the monkey has two i.v. lines, one on each arm.
  • One i.v. line is used to administer the radioligand, while the other line is used to draw blood samples for pharmacokinetic data of the radioligand as well as the cold drugs.
  • rapid blood samples are taken as the radioligand is administered which then taper out by the end of the scan.
  • a volume of approximately 1 mL of blood is taken per time point, which is spun down, and a portion of the plasma is counted for radioactivity in the blood.
  • PET scans on the monkey are separated by at least two weeks.
  • Unlabeled Compound of the invention is administered intravenously, dissolved in 80% PEG 400:40% sterile saline.
  • PET data are analyzed by using cerebellum as the reference region and using the distribution volume region (DVR) method. This method has been applied for the analysis of 18F-altanserin PET data in nonhuman primate and human studies (Smith et al., Synapse, 30:380-392 (1998).
  • DVR distribution volume region
  • the effect of compounds of the invention on sleep and wake fullness can be compared to the reference drug Zolpidem. Drugs are administered during the middle of the light period (inactivity period).
  • compounds of the invention are tested for their effects on sleep parameters and are compared to Zolpidem (5.0 mg/kg, Sigma, St. Louis, MO) and vehicle control (80% Tween 80, Sigma, St. Louis, MO).
  • Zolpidem 5.0 mg/kg, Sigma, St. Louis, MO
  • vehicle control 80% Tween 80, Sigma, St. Louis, MO.
  • a repeated measures design is employed in which each rat is to receive seven separate dosings via oral gavage.
  • the first and seventh dosings are vehicle and the second through sixth are the test compounds and Zolpidem given in counter-balanced order. Since all dosings are administered while the rats are connected to the recording apparatus, 60% CO 2 /40% O 2 gas is employed for light sedation during the oral gavage process. Rats are fully recovered within 60 seconds following the procedure. A minimum of three days elapses between dosings.
  • dosing occurs during the middle of the rats' normal inactive period (6 hours following lights on). Dosing typically occurs between 13:15 and 13:45 using a 24 hour notation. All dosing solutions are made fresh on the day of dosing. Following each dosing, animals are continuously recorded until lights out the following day (-30 hours).
  • Animals are housed in a temperature controlled recording room under a 12/12 light/dark cycle (lights on at 7:00 am) and have food and water available ad libitum. Room temperature (24+2 0 C), humidity (50+20% relative humidity) and lighting conditions are monitored continuously via computer. Drugs are administered via oral gavage as described above, with a minimum of three days between dosings. Animals are inspected daily in accordance with NIH guidelines.
  • Wistar rats 300 + 25 g; Charles River, Wilmington, MA
  • EEG electroencephalograph
  • EMG electromyograph
  • isoflurane anesthesia 1-4%), the fur is shaved from the top of the skull and the skin was disinfected with Betadine and alcohol.
  • Betadine and alcohol A dorsal midline incision is made, the temporalis muscle retracted, and the skull cauterized and thoroughly cleaned with a 2% hydrogen peroxide solution.
  • Stainless steel screws (#000) are implanted into the skull and served as epidural electrodes.
  • EEG electrodes are positioned bilaterally at +2.0 mm AP from bregma and 2.0 mm ML and at -6.0 mm AP and 3.0 mm ML.
  • Multi-stranded twisted stainless steel wire electrodes are sutured bilaterally in the neck muscles for recording of the EMG.
  • EMG and EEG electrodes are soldered to a head plug connector that was affixed to the skull with dental acrylic. Incisions are closed with suture (silk 4-0) and antibiotics administered topically. Pain is relieved by a long-lasting analgesic (Buprenorphine) administered intramuscularly once post-operatively. Post-surgery, each animal is placed in a clean cage and observed until it is recovered. Animals are permitted a minimum of one week post-operative recovery before study.
  • mice are connected via a cable and a counter-balanced commutator to a Neurodata model 15 data collection system (Grass-Telefactor, West Warwick, RI).
  • the animals are allowed an acclimation period of at least 48 hours before the start of the experiment and are connected to the recording apparatus continuously throughout the experimental period except to replace damaged cables.
  • the amplified EEG and EMG signals are digitized and stored on a computer using SleepSign software (Kissei Comtec, Irvine CA).
  • EEG and EMG data are scored visually in 10 second epochs for waking (W), REMS, NREMS. Scored data are analyzed and expressed as time spent in each state per half hour. Sleep bout length and number of bouts for each state are calculated in hourly bins. A "bout" consists of a minimum of two consecutive epochs of a given state. EEG delta power (0.5-3.5 Hz) within NREMS is also analyzed in hourly bins. The EEG spectra during NREMS are obtained offline with a fast Fourier transform algorithm on all epochs without artifact. The delta power is normalized to the average delta power in NREMS between 23 :00 and 1 :00, a time when delta power is normally lowest.
  • Data are analyzed using repeated measures ANOVA. Light phase and dark phase data are analyzed separately. Both the treatment effect within each rat and the time by treatment effect within each rat is analyzed. Since two comparisons are made, a minimum value of P ⁇ 0.025 is required for post hoc analysis. When statistical significance is found from the ANOVAs, t-tests are performed comparing all compounds to vehicle and the test compounds to Zolpidem.
  • Glial Cells A compound of the invention can be shown to inhibit JC virus infection of human glial cells using the in vitro model of Elphick et al. [Science (2004) 306:1380-1383], essentially as described briefly here.
  • SVG human glial cell line
  • SVG is a human glial cell line established by transformation of human fetal glial cells by an origin defective SV40 mutant [Major et al., Proc. Natl. Acad. Sci. USA (1985) 82:1257-1261].
  • SVG cells are cultured in Eagle's minimum essential medium (Mediatech Inc., Hemdon, VA) supplemented with 10% heat-inactivated fetal bovine serum, and kept in a humidified 37°C 5% CO2 incubator.
  • the Mad-1/SVE ⁇ strain of JC virus [Vacante et al., Virology (1989) 170:353-361] is used for these experiments. While the host range of JC virus is typically limited to growth in human fetal glial cells, the host range of Mad-1/SVE ⁇ extends to human kidney and monkey cell types. Mad-1/SVE ⁇ is propagated in HEK cells. Virus titer is measured by hemagglutination of human type O erythrocytes.
  • SVG cells growing on coverslips are pre-incubated at 37 C C for 45 min with or without the compound of the invention diluted in media containing 2% FCS.
  • the compound of the invention is used at a concentration of about 1 nM to about 100 ⁇ M, at a concentration of about 10 nM to about 100 ⁇ M, at a concentration of about 1 nM to about 10 ⁇ M, or at a concentration of about 10 nM to about 10 ⁇ M.
  • JC virus (Mad-1/SVE ⁇ ) is then added at an MOI of 1.0 and the cells are incubated for 1 hr at 37 0 C in the continued presence of the compound of the invention.
  • V antigen positive cells are scored by indirect immunofluorescence (see below). Controls include the addition of the compound of the invention at 24 and 48 h postinfection. The percentage of infected cells in untreated cultures is set at 100%.
  • SVG cells growing on coverslips are fixed in ice cold acetone. To detect V antigen expression, the cells are then incubated for 30 min at 37 0 C with a 1 :10 dilution of hybridoma supernatant from PAB597.
  • the PAB597 hybridoma produces a monoclonal antibody against the SV40 capsid protein VPl which has been shown to cross-react with JC virus VPl .
  • the cells are then washed and incubated with goat anti-mouse Alexa Fluor 488 secondary antibody for an additional 30 min.
  • the cells are counterstained with 0.05% Evan's blue, mounted onto glass slides using 90% glycerol in PBS and visualized on Nikon E800 epi fluorescent scope. Images are captured using a Hamamatsu digital camera and analyzed using Improvision software.
  • Approximately 50 mL of blood is pooled from 3 male beagles.
  • the protocol for analyzing the effects of compounds on platelet aggregation are identical to those used for human platelets (see Example D, supra) except 5 ⁇ M ADP and 2 ⁇ M 5-HT are used to stimulate amplification of platelet aggregation.
  • Test compounds are administered to male rats (weighing 250-350 g) via PO injection at varying concentrations depending on compound potency ranging from 1 mpk-100 mpk. Animals are then anesthetized using Nembutal approximately 30 min post PO. Once the animal is fully anesthetized using approved surgical techniques the animal's right femoral artery is isolated in 2 different sections approximately 4-6 mm in length, one area for probe placement and one for Ferric Chloride patch positioning. The artery is then allowed to stabilize to allow recovery from the surgery.
  • a ventilator Harmonic Apparatus, Inc.
  • a micro arterial probe Transonic Systems, Inc
  • a small piece of filter paper soaked in 30% ferric chloride is placed on the area of the artery upstream of the probe for 10 min.
  • After 5 min of Ferric Choloride patch placement the last 3 mm of the rat's tail is removed.
  • the tail is then placed in a saline filled glass vial at 37 degree and the time it takes for bleeding to stop is recorded. After the Ferric chloride patch is removed the flow was recorded until the artery is occluded and time to occlusion is recorded.
  • Test compounds or reference compounds with acceptable levels of binding to rat 5-HT 2A receptors are evaluated for effects of thrombus formation, bleeding and platelet activity in a single model. This allows for the most accurate demonstration of separation of the test compound effects on platelet mediated thrombus formation from effects on bleeding.

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Abstract

L'invention concerne des dérivés du benzofuranne qui sont des modulateurs du récepteur sérotoninergique 5-HT2A et qui sont utilisés dans le traitement de diverses maladies et de divers troubles associés au récepteur 5-HT2A.
PCT/US2007/019084 2006-08-31 2007-08-30 Dérivés du benzofuranne utilisés comme modulateurs du récepteur 5-ht2a WO2008027483A1 (fr)

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Cited By (16)

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US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8785441B2 (en) 2004-11-19 2014-07-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8871797B2 (en) 2003-07-22 2014-10-28 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US9199940B2 (en) 2006-05-18 2015-12-01 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
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