[go: up one dir, main page]

WO2004028450A2 - Procede de fabrication de phenylpyrazoles utiles en tant que modulateurs selectifs de 5ht2a et leurs intermediaires - Google Patents

Procede de fabrication de phenylpyrazoles utiles en tant que modulateurs selectifs de 5ht2a et leurs intermediaires Download PDF

Info

Publication number
WO2004028450A2
WO2004028450A2 PCT/US2003/029736 US0329736W WO2004028450A2 WO 2004028450 A2 WO2004028450 A2 WO 2004028450A2 US 0329736 W US0329736 W US 0329736W WO 2004028450 A2 WO2004028450 A2 WO 2004028450A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
alkyl
solvent
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2003/029736
Other languages
English (en)
Other versions
WO2004028450A3 (fr
Inventor
Stefan Horns
Max Ray
Bradley Teegarden
Keith Drouet
Konrad Feichtinger
Katie Elwell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arena Pharmaceuticals Inc
Original Assignee
Arena Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arena Pharmaceuticals Inc filed Critical Arena Pharmaceuticals Inc
Priority to AU2003275093A priority Critical patent/AU2003275093A1/en
Publication of WO2004028450A2 publication Critical patent/WO2004028450A2/fr
Publication of WO2004028450A3 publication Critical patent/WO2004028450A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals

Definitions

  • the present invention concerns a process for making certain selective 5HT A modulators for the 5-HT A receptor.
  • the application concerns a process for making compounds of Formula (I), as disclosed herein below, which are useful in the prophylaxis or treatment of 5HT 2A mediated disorders.
  • G protein-coupled receptors share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The 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. Currently, 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.”
  • Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. Not surprisingly, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism, and neurodegenerative disorders.
  • Serotonin receptors are divided into seven subfamilies, referred to as 5-HT1 through 5-HT7, inclusive. These subfamilies are further divided into subtypes.
  • the 5- HT2 subfamily is divided into three receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C.
  • the human 5-HT2C receptor was first isolated and cloned in 1987, and the human 5-HT2A receptor was first isolated and cloned in 1990. These two receptors are thought to be the site of action of hallucinogenic drugs. Additionally, antagonists to the 5-HT2A and 5-HT2C 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-HT1C receptor (now known as the 5-HT2C receptor).
  • U.S. Patent Number 5,661,012 describes the isolation, characterization, and expression of a functional cDNA clone encoding the entire human 5- HT2A receptor.
  • Casey describes a mutation of the cysterne residue at position 322 of the rat 5-HT2A receptor to lysine (C322K), glutamine (C322Q), and arginine (C322R) which reportedly led to constitutive activation.
  • Herrick-Davis 2 describe mutations of the serine residue at position 312 of the rat 5-HT2C receptor to phenylalanine (S312F) and lysine (S312K), which reportedly led to constitutive activation.
  • the present invention provides a process for making compounds of Formula (I) useful in the prophylaxis or treatment of 5HT 2A mediated disorders, such as, 5HT 2A mediated platelet aggregation, asthma, agitation, degenerative diseases of the CNS, add-on therapy to Haloperidol for schizophrenia and other psychopathic disorders, as well as other diseases.
  • 5HT 2A mediated disorders such as, 5HT 2A mediated platelet aggregation, asthma, agitation, degenerative diseases of the CNS, add-on therapy to Haloperidol for schizophrenia and other psychopathic disorders, as well as other diseases.
  • Some embodiments of the invention relate to the process for making compounds of Formula (A5) that are useful as intermediates in making compounds of Formula (I): the process comprising hydrolyzing a compound of Formula (A4):
  • the hydrolyzing step is conducted between about 60°C to about 80°C.
  • the process for making a compound of Formula (A5) comprises the steps of halogenating a compound of Formula (A3):
  • halogenating reagent is N-bromosuccinimide or N- chlorosuccinimide.
  • the halogenating reagent is N- bromosuccinimide and the halogenating solvent is N,N-dimethylformamide and the halogenating step is conducted between about 20°C to about 60°C.
  • the alkali metal hydroxide is sodium hydroxide
  • the hydrolyzing solvent is aqueous ethanol
  • the hydrolyzing step is conducted between about 60°C to about 80°C.
  • the process for making a compound of Formula (A5) comprises the steps of cyclizing a compound of Formula (A2):
  • the cyclizing step is optionally conducted in a cyclizing solvent to yield the compound of
  • the process further comprises a cyclizing acid in the cyclizing step.
  • the cyclizing acid is hydrochloric acid.
  • the compound of Formula (B2) is methyl hydrazine.
  • the cyclizing solvent is methanol.
  • the halogenating reagent is N-bromosuccinimide or N-chlorosuccinimide
  • the halogenating solvent is N,N-dimethylformamide
  • the halogenating step is conducted between about 20°C to about 60°C.
  • the alkali metal hydroxide is sodium hydroxide
  • the hydrolyzing solvent is aqueous ethanol
  • the hydrolyzing step is conducted between about 60°C to about 80°C.
  • the process for making a compound of Formula (A5) comprises the steps of condensing a compound of Formula (Al):
  • the cyclizing step is optionally conducted in a cyclizing solvent to yield the compound of
  • the compound of Formula (BI) is N,N-dimethylformamide dimethyl acetal.
  • the condensing solvent is ethanol and the condensing step is conducted at a temperature of about 25°C to about 95°C. hi some embodiments the condensing step is conducted at a temperature of about 70°C to about 80°C.
  • the process further comprises a cyclizing acid in the cyclizing step and the cyclizing acid is hydrochloric acid.
  • the compound of Formula (B2) is methyl hydrazine and the cyclizing solvent is methanol.
  • the halogenating reagent is ⁇ -bromosuccinimide or ⁇ -chlorosuccinimide
  • the halogenating solvent is ⁇ , ⁇ - dimethylformamide
  • the halogenating step is conducted between about 20°C to about 60°C.
  • the alkali metal hydroxide is sodium hydroxide
  • the hydrolyzing solvent is aqueous ethanol
  • the hydrolyzing step is conducted between about 60°C to about 80°C.
  • Some embodiments of the invention include a process for making a compound of Formula (A4):
  • the halogenating reagent is N-bromosuccinimide or N-chlorosuccinimide.
  • the halogenating reagent is N-bromosuccinimide and the halogenating solvent is N,N-dimethylformamide.
  • the halogenating step is conducted between about 20°C to about 60°C.
  • Some embodiments of the invention include a process for making a compound of Formula (A3):
  • the cyclizing step is optionally conducted in a cyclizing solvent to yield the compound of Formula (A3); wherein K ⁇ is C ⁇ _ alkyl; R 10 is C 1-6 alkyl; and R ⁇ is C 1-3 alkyl.
  • the process further comprises a cyclizing acid in the cyclizing step.
  • the cyclizing acid is hydrochloric acid.
  • the compound of Formula (B2) is methyl hydrazine.
  • the cyclizing solvent is methanol.
  • the condensing step is optionally conducted in an condensing solvent to yield a compound of Formula (A2); wherein R 10 is C 1-6 alkyl; R ⁇ is C 1-3 alkyl; and R 1 is C 1-6 alkyl or alkylaryl; or both R 12 groups together form a 5 or 6 membered heterocyclic ring.
  • the compound of Formula (BI) is N,N-dimethylformamide dimethyl acetal.
  • the condensing solvent is ethanol and the condensing step is conducted at a temperature of about 25°C to about 95°C.
  • R 6 and R 7 are each independently selected from H, halogen, or haloalkyl; provided that at least one R 3 , R , R 5 , Rg and R 7 is not H; R 0 is a CI, Br, I, mesylate or tosylate; and R 1 is a -Cs alkyl;.
  • the organic base is pyridine.
  • the non-reactive solvent is methylene chloride.
  • the intermediate has the Formula (C2):
  • some embodiments of the invention relate to a process for making a compound of Formula (I):
  • R 1 and R 2 have the same meaning as described above; to yield the compound of Formula (I); wherein R ⁇ is C 1-2 alkyl; R 2 is CI or Br; R 3 , R 4 , R 5 , R and R are each independently selected from H, halogen, or haloalkyl; provided that at least one R 3 , ⁇ , R 5 , Re and R is not H; R 20 is a CI, Br, I, mesylate or tosylate; and R 21 is a -Cs alkyl.
  • the organic base is pyridine.
  • the non-reactive solvent is methylene chloride.
  • the intermediate is Formula (C4):
  • Some embodiments of the invention include a compound of Formula (A4):
  • R 1 is C 1-2 alkyl
  • R 2 is CI or Br
  • R 10 is C 1-6 alkyl. hi some embodiments R 1 and R 10 are both CH 3 , and R 2 is Br.
  • Some embodiments of the invention include a compound of Formula (A3):
  • R 1 is C 1- alkyl; and R 10 is C 1-6 alkyl. hi some embodiments R ⁇ and R 10 are both CH 3 .
  • Some embodiments of the invention include a compound of Formula (A2):
  • R 10 is C 1-6 alkyl; and R ⁇ is C 1-3 alkyl. In some embodiments R 10 and R ⁇ are both CH 3 .
  • Some embodiments of the invention include a compound of Formula (C2): wherein Ri is C 1- alkyl; R is CI or Br; and R 21 is Ci-C 8 alkyl.
  • a compound of Formula (C2) are when R t is CH 3 ; R is Br; and R 1 is CH 3 .
  • Some embodiments of the invention include a compound of Formula (C4):
  • R 3 , R 4 , R , R and R 7 are each independently selected from H, halogen, or haloalkyl; provided that at least one is not H; and R 21 is -Cs alkyl.
  • compounds of Formula (C3) are when R 3 , Rj, R 5 , R 6 and R are each independently selected from H, F or CI; and R 21 is CH 3 .
  • the invention encompasses a process for making compounds of
  • Ri is C 1-2 alkyl; R 2 is Cl or Br; R , Ri, R 5 , R ⁇ and R 7 are each independently selected from H, halogen, or haloalkyl; provided that at least one is not H; comprising the steps of:
  • Rn 2 N-CH(OR 12 ) 2 (BI) wherein R ⁇ is C 1-3 alkyl; and R 12 is C 1-6 alkyl or alkylaryl; or both
  • R 12 groups together form a 5 or 6 membered heterocyclic ring; the condensing step is optionally conducted in a condensing solvent to yield a compound Formula (A2).
  • a compound of Formula (A2) is also referred to as an enaminone and is of the formula:
  • a variety of groups for R 10 may be utilized provided that the resulting acyl group bearing the R 10 group can be removed as described in step (iv).
  • R 10 may be selected from, but not limited to, the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, pentyl, neopentyl and hexyl.
  • R 10 is methyl.
  • R ⁇ may be selected from, but not limited to, the group consisting of methyl, ethyl, propyl and iso-propyl.
  • R ⁇ is methyl.
  • R 12 may be selected from, but not limited to, the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, tert-butyl and neopentyl.
  • R 12 is methyl.
  • Examples of NN-dialkylformamide acetals of Formula (BI) when R 1 is alkyl include for example, NN-dimethylformamide dimethyl acetal, NN-dimethylformamide diethyl acetal, NN- dimethylformamide dipropyl acetal, NN-dimethylformamide diisopropyl acetal, NN- dimethylformamide dibutyl acetal, NN-dimethylformamide di-tert-butyl acetal and NN- dimethylformamide dineopentyl acetal.
  • R 12 is cycloalkyl
  • R 12 may be selected from, but not limited to, the group consisting of cyclopentyl or cyclohexyl.
  • R 12 is cycloalkyl
  • R 1 is selected from, but not limited to, the group consisting of benzyl, 1-phenylethyl and 2-phenylethyl.
  • NN-dialkylformamide acetal of the Formula (BI) when R 1 is C 1-2 alkylaryl includes, NN-dimethylformamide dibenzyl acetal.
  • the NN-dialkylformamide acetal of Formula (BI) may be selected from, but not limited to, the group consisting of NN- dimethylformamide ethylene acetal and NN 5,5-tetramethyl-l ,3-dioxan-2-amine and are represented by the following structure:
  • NN-dimethylformamide N,N, 5 , 5 -tetr amethyl- ethylene acetal l,3-dioxan-2-amine.
  • R ⁇ and R 12 are both methyl and the compound is represented by the following structure:
  • the condensing solvent may optionally be present or absent, hi the instance that the condensing solvent is absent then the N,N-diallkylformamide dialkylacetal of
  • Formula (BI) serves both as a reactant in condensation step (i) and as the solvent.
  • the solvent is selected from, but not limited to, the group consisting of methanol, ethanol, butanol, pentanol, 1-propanol and 2-propanol.
  • the condensing solvent is present and preferably the solvent is ethanol.
  • the condensing step is conducted at a temperature between about 25°C to about 95°C.
  • the condensing step is conducted at a temperature between about 50°C to about 85°C and most preferably between about 70°C to about 80°C.
  • the molar ratio of an acetophenone of Formula (Al) to an NN- dialkylformamide dialkyl acetal of Formula (BI) is such that the NN-dialkylformamide dialkyl acetal is used in excess.
  • the molar ratio of the acetophenone to the N,N-dialkylformamide dialkyl acetal is in a ratio of 1 to at least about 1.
  • the NN- dialkylformamide dialkyl acetal is present in at least about 1 molar equivalent compared to the acetophenone.
  • any amount of NN-dialkylformamide dialkyl acetal in excess of this about 1 molar equivalent may serve the role of a solvent or some other function, such as, to increase the rate of the reaction, improve mechanical manipulation (i.e., stirring, mixing) and the like.
  • the molar ratio of an acetophenone of Formula (Al) to a NN-dialkylformamide dialkyl acetal of Formula (BI) is typically about 1 : 1 to about 1:3, and preferably the ratio is between about 1 : 1.1 to about 1:2.
  • the presence of the NN-dialkylformamide dialkyl acetal outside these ranges in excess may be determined by methods known in the art.
  • the alkylhydrazine is methyl hydrazine and Ri is methyl.
  • the cyclizing solvent may optionally be present or absent. In the instance that the cyclizing solvent is absent then the alkylhydrazine of Formula (B2) serves both as a reactant in the cychzation step (ii) and as the solvent.
  • the solvent is selected from, but not limited to, the group consisting of methanol, ethanol, butanol, pentanol, 1-propanol and 2-propanol.
  • the cyclizing solvent is present and preferably the solvent is methanol.
  • the cyclizing step (ii) further comprises the addition of a cyclizing acid, selected from, but not limited to, the group consisting of hydrochloric acid, hydrobromic acid, acetic acid and trifluoroacetic acid; the cyclizing acid is preferably hydrochloric acid, hi some embodiments the molar ratio of the alkylhydrazine and cyclizing acid is typically between the range of about 1:0.1 to about 1:20; in another embodiment the molar ratio of the alkylhydrazine and cyclizing acid is between about 1 :05 to about 1:12 and preferably the range is between about 1 :1 to about 1:8.
  • a cyclizing acid selected from, but not limited to, the group consisting of hydrochloric acid, hydrobromic acid, acetic acid and trifluoroacetic acid
  • the cyclizing acid is preferably hydrochloric acid, hi some embodiments the molar ratio of the alkylhydrazine and cyclizing acid is typically between the range of about 1:
  • the molar ratio of the enaminone of Formula (A2) to alkylhydrazine of Formula (B2) is such that the alkylhydrazine is present in excess.
  • the molar ratio of the enaminone of Formula (A2) to the compound of Formula (B2) is in a ratio of 1 to at least 1.
  • the alkylhydrazine is present in at least about 1 molar equivalent compared to the enaminone of Formula (A2).
  • any amount of alkylhydrazine in excess of this about 1 molar equivalent serves as the role of a solvent or some other function, such as, to increase the rate of the reaction, improve mechanical manipulation (i.e., stirring, mixing) and the like.
  • the cychzation solvent is present, in general the molar ratio of the enaminone to alkylhydrazine is between about 1 : 1 to about 1:3; another range is typically between about 1 : 1 to about 1:1.5; and preferably the range is between about 1 : 1 to about 1:1.2.
  • the cyclizing step is conducted at a temperature between about -25°C to about 60°C, preferably the cyclizing step is conducted at a temperature between about -10°C to about 25°C.
  • Some embodiments of the invention show a high degree of regiospecificity in the cychzation; TABLE 1 illustrates the ratio of 2-methylpyrazole to 1-methylpyrazole.
  • the halogenating reagent may be selected from the available reagents known in the art, such as, for example, N-bromosuccinimide (i.e., NBS), l,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide (pyrHBr 3 ) and the like; preferably, N-bromosuccinimide is the halogenating reagent for when R 2 is Br.
  • This step is superior to the use of bromine (i.e., Br 2 ) in the bromination step.
  • bromine i.e., Br 2
  • the use of bromine in CH 2 C1 2 required large stoichiometric excess of bromine and excessive reaction times. Even under these conditions the reaction gave selectivity difficulties as observed by the presence of significant amounts of unconverted starting material and dibrominated by products.
  • bromine CH 2 C1 2 gave heterogeneous reaction mixtures and reaction monitoring difficulties.
  • the halogenating reagent is preferably N-chlorosuccinimide (i.e., NCS) for when R 2 is CI.
  • NCS N-chlorosuccinimide
  • the molar ratio of a compound of Formula (A3) to halogenating reagent is typically in the range varying between a ratio of about 1 :0.9 to about 1:1.1; preferably the range is between about 1 :0.95 to about 1 : 1.05.
  • the use of excess halogenating reagent may lead to the incorporation of multiple bromines into the product.
  • the halogenating solvent is a suitable polar solvent such as NN-dimethylformamide (i.e., DMF), methylsulfoxide, acetonitrile, ethyl acetate, methylene chloride and the like; preferably the solvent is DMF.
  • NN-dimethylformamide i.e., DMF
  • methylsulfoxide acetonitrile
  • ethyl acetate methylene chloride and the like
  • methylene chloride preferably the solvent is DMF.
  • DMF NN-dimethylformamide
  • acetonitrile ethyl acetate
  • methylene chloride methylene chloride
  • the halogentating step is conducted at a temperature between about 10°C to about 80°C, preferably the halogenating step is conducted at a temperature between about 20°C to about 60°C.
  • Suitable bases for this step include, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • alkali metal hydroxide is sodium hydroxide.
  • the molar ratio of a compound of Formula (A4) to alkali metal hydroxide is typically in the range varying between a ratio of about 1:1 to about 1:10; another range is typically between about 1 :3 to about 1:8; preferably the range is between about 1 :4 to about 1 :6.
  • the aqueous hydrolyzing solvent is a mixture of water with a suitable polar solvent selected from the group consisting of tetrahydrofuran (THF), methanol, ethanol, 1-propanol, 2-propanol, butanol and pentanol; included are mixtures thereof.
  • a suitable polar solvent selected from the group consisting of tetrahydrofuran (THF), methanol, ethanol, 1-propanol, 2-propanol, butanol and pentanol; included are mixtures thereof.
  • the polar solvent is ethanol.
  • the amount of water present is typically determined by the amount necessary to dissolve the corresponding alkali metal hydroxide.
  • the hydrolyzing step is conducted at a temperature between about 20°C to about 100°C.
  • the condensing step is conducted at a temperature between about 50°C to about 85°C and most preferably between about 60°C to about 80°C.
  • Step (v) may use a commercially available aryl isocyanate or one that can be prepared by known methods and coupled with the aniline of Formula (A5) to yield a compound of Formula (I).
  • An analogous two-part step is described in Steps (vi) and (vii) in which the isocyanate is prepared (i.e., Step (vi)) from the aniline of
  • Step (viii) is yet another urea forming step.
  • an aniline of Formula (A5) may be reacted with a substituted alkyl chloroformate in the presence of an orgamc base to give in intermediate that is subsequently coupled with an aniline of Formula (A8).
  • This step may be modified, as illustrated in Step (ix) to give yet another urea forming step, namely, aniline of Formula (A8) may be reacted with a substituted alkyl chloroformate to give an intermediate that is reacted with an aniline of Formula (A5).
  • aniline of Formula (A8) may be reacted with a substituted alkyl chloroformate to give an intermediate that is reacted with an aniline of Formula (A5).
  • Step (v) Coupling a compound of Formula (A5) with a compound of Formula (A6):
  • Isocyanates and isocyanate equivalents are well known in the art; many isocyanates are commercially available. For those isocyanates that are not commercially available, they may be readily prepared utilizing the corresponding anilines, for example, the use of phosgene (i.e., C ⁇ C ⁇ O) or triphosgene [i.e., bis-trichloromethyl carbonate,
  • isocyanate equivalents may also be used and prepared from the corresponding aniline by the sequential action of carbonyl dumidazole and methyl iodide in THF and acetonitrile respectively as described by Batey et al. in Tetrahedron Lett. 1998, 39, 6267-6270. This procedure may give rise to useful isocyanate equivalents as illustrated in the reaction scheme below:
  • the molar ratio of a compound of Formula (A5) to a compound of Formula (A6) is typically in the range of varying between about 1 : 1 to about 1:1.5; preferably about 1:1 to about 1:1.2.
  • the coupling solvent is a suitable non-reactive solvent such as N,N-dimethylformamide (i.e., DMF), methylsulfoxide, acetonitrile, ethyl acetate, methylene chloride and the like; preferably the solvent is methylene chloride.
  • the coupling step (v) is typically conducted at a temperature between about 0°C to about 60°C; preferably the temperature is between about 10°C to about 45°C.
  • step (v) comprises a compound of Formula (A5) that may be converted into a compound bearing an isocyanate or isocyanate equivalent in a manner described above.
  • This alternative embodiment comprises two steps identified as steps (vi) and (vii); these steps are specifically described, infra.
  • J is an isocyanate or isocyanate equivalent
  • An isocyanate generating reagent is also defined as forming a chemical species that reacts in a manner comparable to an isocyanate, such as the chemical species shown in brackets in Scheme 3 below:
  • the molar ratio of a compound of Formula (A5) to an isocyanate generating reagent is typically in the range varying between about 1:1 to about 1:2; preferably about 1:1 to about 1:1.2.
  • the isocyanate generating solvent is a suitable non- reactive solvent such as NN-dimethylformamide (i.e., DMF), methylsulfoxide, acetonitrile, tetrahydrofuran (i.e., THF), ethyl acetate, methylene chloride, toluene and the like; preferably the solvent is methylene chloride, acetonitrile, THF or toluene; and most preferably, the solvent is substantially free of water.
  • NN-dimethylformamide i.e., DMF
  • THF tetrahydrofuran
  • ethyl acetate methylene chloride, toluene and the like
  • the solvent is methylene chloride, acetonitrile, THF
  • the coupling step (vi) is typically conducted at a temperature between about -10°C to about 60°C; preferably the temperature is between about 10°C to about 50°C. It is generally understood in the art that although the isocyanate or isocyanate equivalent may be isolated it may not always be necessary to do so and that this fact would be recognized by the artesian. Therefore, in certain instances the isocyanate or isocyanate equivalent may be generated in situ and reacted directly with the appropriate aniline without isolation. Step (vii)
  • Formula (A8) is typically in the range varying between about 1 : 1 to about 1:1.5; preferably about 1:1 to about 1:1.2.
  • the coupling solvent is a suitable non-reactive solvent such as NN-dimethylformamide (i.e., DMF), methylsulfoxide, acetonitrile, ethyl acetate, methylene chloride and the like; preferably the solvent is methylene chloride.
  • the coupling step (vii) is typically conducted at a temperature between about 0°C to about 60°C; preferably the temperature is between about 10°C to about 50°C.
  • Step (viii) is yet another urea forming step.
  • This is an alternative process step to that of step (v), supra, to yield compounds of the inventions.
  • This alternative embodiment comprises a compound of Formula (A5) that may be converted into a compound bearing an isocyanate or isocyanate equivalent in a analogous manner as described above.
  • This alternative embodiment comprises the making of an intermediate that may be isolated or directly coupled with a compound Formula (A6); this particular step is identified as step (viii) and is specifically described infra.
  • Some embodiments of the invention relate to a process for making a compound of Formula (I):
  • R ⁇ is C ⁇ - 2 alkyl
  • R2 is CI or Br
  • R 3 , j, R 5 , Re and R are each independently selected from H, halogen, or haloalkyl; provided that at least one is not H.
  • This process comprises the step of: reacting a compound of Formula (A5):
  • R 20 is a leaving group, such as, CI, Br, I, mesylate, tosylate, and the like; and R 21 is a -Cs alkyl; such as, methyl, ethyl, propyl, butyl, pentyl, isopropyl, nenopentyl, hexyl, octyl and the like; in the presence of an organic base; such as, pyridine, dimethylaminopyridine, piperidine, morpholine and the like. In some embodiments the organic base is pyridine. This step is conducted in a non-reactive solvent to give an intermediate.
  • the non-reactive solvent is a suitable polar solvent, such as NN- dimethylformamide (i.e., DMF), methylsulfoxide, acetonitrile, ethyl acetate, tetrahydrofuran (i.e., THF), methylene chloride and the like; preferably the solvent is methylene chloride.
  • NN- dimethylformamide i.e., DMF
  • methylsulfoxide acetonitrile
  • ethyl acetate tetrahydrofuran
  • THF tetrahydrofuran
  • methylene chloride methylene chloride
  • the intermediate formed may be isolated or subsequently used in a coupling reaction with a compound of Formula (A8):
  • Intermediate (CI) may result from the addition of a compound of Formula (A5) to the substituted alkyl chloroformate.
  • Another intermediate may have the structure of Formula (C2):
  • R 20 by the organic base of the intermediate (CI).
  • an additional organic base such as one described supra for this step, may be used in reacting the intermediate with an aniline of Formula (A5).
  • the molar ratio of a compound of Formula (A5) to a substituted alkyl chloroformate of Formula (B6) is typically in the range varying between about 1 : 1 to about 1:2; preferably about 1:1 to about 1:1.5.
  • Step (vii) maybe conducted at a temperature between about 0°C to about 60°C; preferably the temperature is between about 10°C to about 45°C.
  • step (ix) i an alternative but analogous manner to step (viii), step (ix) may be conducted using the aniline of Formula (A8) and treating it with a substituted alkyl chloroformate of Formula (B6) to generate an intermediate, which in turn may be coupled with a compound of Formula (A5) to yield a compound of Formula (I). Additional details of Step (ix) are specifically described infra.
  • This process comprises the step of reacting a compound of Formula (A8):
  • R 3 , R 4 , R 5 , R and R 7 are each independently selected from H, halogen, or haloalkyl; provided that at least one is not H; with a substituted alkyl chloroformate of Formula (B6):
  • R 20 is a CI, Br, I, mesylate or tosylate, and the like; and R 21 is a -Cs alkyl, such as those examples described supra.
  • This reaction is conducted in the presence of an organic base, such as, pyridine, dimethylaminopyridine, piperidine, morpholine and the like; in a non-reactive solvent to give an intermediate.
  • the organic base is pyridine.
  • the non-reactive solvent can be one of the solvents described in step (viii).
  • the solvent is methylene chloride.
  • Intermediate (C4) may arise from displacement of the R 20 leaving group by the organic base (i.e., pyridine) and subsequent addition of a compound of Formula (A8); or from the displacement of the R 20 by the organic base of intermediate (C3).
  • organic base i.e., pyridine
  • an additional organic base such as one described supra for this step, maybe used in reacting the intermediate with an aniline of Formula (A5).
  • the molar ratio of a compound of Formula (A8) to a substituted alkyl chloroformate Formula (B6) is typically in the range varying between about 1:1 to about 1 :2; preferably about 1 : 1 to about 1:1.5.
  • This step may be conducted at a temperature between about 0°C to about 60°C; preferably the temperature is between about 10°C to about 45°C.
  • the invention encompasses a process for making compounds that are useful as intermediates in the process for making compounds of Formula (I).
  • One embodiment is a process for making a compound of Formula (A5):
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of the following structure:
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of Formula (A4):
  • Rt is C 1-2 alkyl; R 2 is CI or Br; and R 10 is C 1-6 alkyl, preferably R ⁇ and R 10 are both CHs, and R 2 is Br.
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of Formula (A3):
  • R ⁇ is C 1 - 2 alkyl; and R 10 is C 1-6 alkyl, preferably R ⁇ and R 10 are both CH 3 .
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of Formula (A2):
  • R 10 is C 1-6 alkyl; and R ⁇ is C 1-3 alkyl, preferably R 10 and R ⁇ are both CH 3 .
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of Formula (C2):
  • R t is C 1-2 alkyl; R 2 is CI or Br; and R 21 is -Cs alkyl.
  • R ⁇ is CH 3 ; R 2 is Br; and R 21 is CH 3 .
  • the invention encompasses a useful intermediate in the making of compounds of Formula (I) wherein the intermediate is of Formula (C4):
  • R 3 , i, R 5 , R and R 7 are each independently selected from H, halogen, or haloalkyl; provided that at least one is not H; and R 21 is -Cs alkyl.
  • R 3 , j, R 5 , Re and R 7 are each independently selected from H, F or CI; provided that at least one is not H; and R 21 is CH 3 .
  • AGONISTS shall mean moieties that activate the intracellular response when they bind to the receptor, or enhance GTP binding to membranes.
  • PARTIAL AGONISTS shall mean moieties which activate the intracellular response when they bind to the receptor to a lesser degree/extent than do agonists, or enhance GTP binding to membranes to a lesser degree/extent than do agonists.
  • ANTAGONIST shall mean moieties that competitively bind to the receptor at the same site as the agonists but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agomsts or partial agonists. ANTAGONISTS do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • CANDIDATE COMPOUND shall mean a molecule (for example, and not limitation, a chemical compound) which is amenable to a screening technique.
  • COMPOSITION shall mean a material comprising at least two compounds or two components; for example, and not limitation, a Pharmaceutical Composition is a Composition.
  • COMPOUND EFFICACY shall mean a measurement of the ability of a compound to inhibit or stimulate receptor functionality, as opposed to receptor binding affinity.
  • INHD3IT or INHIBITING in relationship to the term “response” shall mean that a response is decreased or prevented in the presence of a compound as opposed to in the absence of the compound.
  • INVERSE AGONISTS shall mean moieties that bind the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit 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 decrease 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.
  • Antiplatelet therapies (5HT2a mediated platelet aggregation) : Antiplatelet agents (antiplatelets) 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).
  • heart attack hi 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.
  • TLA transient ischemic attack
  • mini-stroke A transient ischemic attack
  • 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, hi patients with angina, 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. In high-risk patients, taking antiplatelets regularly has been found to prevent the formation blood clots that cause first or second strokes.
  • 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).
  • 5HT2a receptors are expressed on smooth muscle of blood vessels and 5HT secreted by activated platelets causes vasoconstriction as well as activation of additional platelets during clotting.
  • 5HT2a 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.
  • the 5HT2A inverse agonists disclosed herein 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 limitation, the indications described above.
  • 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 ll(suppl 2):S45-S50).
  • Agitated behaviors can also be manifested in cognitively intact elderly people and by those with psychiatric disorders other than dementia
  • 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 psychomotoric disorders (such as catatonia). Other symptoms are also associated with this disorder. (See, American Statistical and Diagnostic Handbook).
  • Haloperidol is a potent dopamine D2 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. In accordance with some methods of the invention, adding a 5HT2a inverse agonist concomitantly with Haldol will 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 la Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS). Further uses include in the prophylaxis or treatment of infantile autism, huntington's chorea, and nausea and vomiting from chemotherapy and chemotherapeutic antibodies. Administration of 5HT2a inverse agonists disclosed herein with haloperidol also will provide benefits in these indications.
  • compounds of Formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound of the invention is effective in the prophylaxis or treatment of humans.
  • compositions for treating 5-HT2A mediated diseases as defined may optionally include one or more ingredients as listed above.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy- propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily ' suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile inj ectable aqueous or oleagenous suspension. This suspension may be formulated according to methods known in the art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile inj ectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula (I) may also be administered in the form of a suppositories for rectal administration of the drug.
  • compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the "primary" screen designed to directly identify human 5HT 2A /5HT 2 C receptor inverse agonists consisted of a membrane-based GTP ⁇ S binding assay utilizing membranes prepared from COS7 cells transiently transfected with the constitutively active human 5-HT 2 c receptor.
  • Candidate compounds (lO ⁇ M final assay concentration) directly identified as inhibiting ligand-independent receptor-mediated increases in GTP ⁇ S binding by greater than 50-75% (arbitrary cut-off value) were considered active "hits”.
  • Primary assay hits were then re-tested in the same assay to reconfirm their inverse agonist activity.
  • directed libraries could be created, i.e., additional candidate compounds were synthesized based upon the structures of the reconfirmed hits (geared towards, e.g., improvement in the characteristics of the compounds) whereby the directed library compounds were then evaluated for the ability to compete for radioligand binding to both mutant human 5HT 2 c (AP-1) and native 5-HT 2 c receptors and radioligand binding to mutant and endogenous
  • 5HT 2 A receptors 5HT 2 A receptors. Because these directed library candidate compounds were based upon the structures of compounds that were directly identified from the membrane-based GTP ⁇ S binding assay, the directed library compounds were not re-tested in the membrane-based GTP ⁇ S binding assay but rather were then confirmed via the radioligand binding analyses.
  • the radioligand binding analysis tests were initially performed at 1 O ⁇ M test compound in triplicate and if the compound inhibited radiolabeled binding by 50% or more, the analysis was followed by an eight concentration radioligand competitive binding evaluation (triplicate determinations at each test compound concentration) to determine Ki values.
  • test compounds were capable of inhibiting ligand- independent mutant 5-HT 2A (AP-3) receptor-mediated accumulation of inositol phosphates (e.g., IP, JJP 2 , IP 3 ).
  • AP-3 ligand- independent mutant 5-HT 2A
  • This evaluation involved initial testing of compound at lO ⁇ M in triplicate and if compound inhibited inositol phosphate accumulation by 50% or more, this analysis was followed by an eight concentration (triplicate determinations at each test compound concentration) IC 50 determination.
  • This final assay confirms that the directly identified compounds retained inverse agonist properties.
  • COS7 cells transiently transfected with human mutated 5HT2C receptor (AP-1) were used to directly identify inverse agonists in screening libraries (Tripos, ie).
  • Candidate compound screens were performed in a total assay volume of 200 ⁇ l using scintillant- coated Wallac ScintistripTM plates.
  • the primary assay was comprised of the following chemicals (at indicated final assay concentrations): 20 mM HEPES, pH 7.4, 100 mM
  • a total of sixteen wells of each plate were dedicated for an eight-concentration clozapine (a confirmed 5HT2C/2A inverse agonist) dose response curve (duplicate determinations at each concentration). Finally, a total of five assay wells of each plate were dedicated to define the negative control (AP-1 receptor expressing membranes without addition of candidate compounds) and three wells from each plate to define the positive control (membranes without AP-1 receptor). Reconfirmation experiments involve re-testing candidate compounds in the same assay described above, except that candidate compounds were evaluated in triplicate, thus allowing evaluation of 24 compounds per 96-well assay plate. Similar to the primary assay plates, an eight-concentration clozapine dose response curve (duplicate determinations at each concentration) and the same negative and positive control wells were also included within each 96-well plate.
  • Radioligand binding competition experiments were performed in a total assay volume of 200 ⁇ l using standard 96-well microtiter plates.
  • the final assay ingredients consisted of assay buffer (20 mM HEPES and 10 mM MgCk), InM ( 3 H)mesulergine, and 50 ⁇ g of membranes (COS7 with AP-1 as defined above).
  • Nonspecific ( 3 H)mesulergine binding was defined in the presence of 100 ⁇ M mianserin.
  • Incubations were performed for 1 hour at 37°C.
  • Receptor bound radioligand was resolved from free radioligand by rapid filtration of the assay mixture over a Wallac FiltermatTM Type B filter, followed by washing with ice-cold assay buffer using a SkatronTM cell harvester.
  • Radioactivity was counted using a Wallac 1205 BetaPlateTM counter.
  • Each assay plate contained five negative control wells (membranes expressing receptor and no candidate compound addition) and three positive control wells (each containing 100 ⁇ M mianserin).
  • candidate compounds were diluted into assay buffer and screened at a final concentration of 10 ⁇ M, in triplicate.
  • candidate compounds were diluted in assay buffer and eight different concentrations were evaluated, in triplicate. A total of 16 wells were designated for an eight-concentration mianserin dose response curve evaluation for both assays.
  • the same assay conditions were also used to evaluate competition of test compound for radioligand binding to membranes expressing native 5-HT 2 c receptor.
  • Radioligand binding competition experiments were performed in a total assay volume of 200 ⁇ l using standard 96-well microtiter plates.
  • the final assay ingredients comprised assay buffer (20 mM HEPES and lOmM MgCl 2 ), InM ( 3 H)LSD, and 50 ⁇ g of the above- defined membranes (COS7 with AP-1).
  • Nonspecific ( 3 H)LSD binding was defined in the presence of 100 ⁇ M serotonin.
  • Incubations were performed for 1 hour at 37° C.
  • Receptor bound radioligand was resolved from free radioligand by rapid filtration of the assay mixture over a Wallac FiltermatTM Type B filter, followed by washing with ice-cold assay buffer using a SkatronTM cell harvester.
  • Radioactivity was counted using a Wallac 1205 BetaPlateTM counter.
  • Each assay plate contained five negative control wells (membranes expressing receptor and no candidate compound addition) and three positive control wells (containing 100 ⁇ M mianserin).
  • candidate compounds were diluted into assay buffer and screened at a final concentration of 10 ⁇ M in triplicate.
  • candidate compounds were diluted in assay buffer and eight different concentrations were evaluated in triplicate. A total of 16 wells were designated for an eight-concentration serotonin dose response curve evaluation for both assays.
  • the same assay conditions were also used to evaluate competition of test compound for radioligand binding to membranes expressing native 5-HT 2A receptor.
  • HPLC-method A Column: Luna C8, 150 x 4.6 mm, 3 ⁇ m SLC-56, with pre-column; Detection: 260 nm; Temperature: 30 °C; Flow rate: 1.5 ml / min; Run time: 21 min; Post time: 8 min; Injection volume: 5 ⁇ l; Solvents: A: 5 mmol NH 4 -acetate in water, B: 5 mmol NH 4 - acetate in water / acetonitrile 2 : 8 (v/v); and
  • GC-method A used specifically for Compounds (4), (5), (7), (8), Column: HP-5 (crosslinked Ph Me-siloxane); Initial temp.: 50 °C; Initial time: 2 min; Heating rate: 10 °C / min; Final temp.: 250 °C; and Final time: 10 min.
  • the reactor was charged with methanol (12404 g) followed by methylhydrazine (1427 g, 31.0 mol, 1.16 equivalents). After cooling to 0 - 5 °C internal temp. 37 % aqueous HCI (8380 g, 85.0 mol, 3.2 equivalents) were added within 30 to 60 min. at an internal temp, of ⁇ 10 °C. After cooling to - 10 to 0 °C a suspension of 3-
  • the reactor was charged with 5 -(3 -acetamidophenyl)-l -methylpyrazole (1135 g, 5.27 moles) that was suspended in N,N-dimethylformamide (2855 g).
  • Diisopropyl ether 1446 g was added and after stirring for 30 to 60 min. at an internal temp, of 55 to 60 °C the phases were separated. The organic layer was cooled down to 0 - 5 °C with stirring within 1 to 2 h and seeded at 44 °C. It was stirred for further 30 to 60 min. at 0 to 5 °C and filtered. The product was dried in vacuum at 40 to 50 °C, yielding 96.8 g (61 %) of 5-(3-aminophenyl)-4-bromo-l-methylpyrazole, purity 98.1 % ( ⁇ PLC- method A). By evaporation of the mother liquor a second crop of product (55 g, 35 %) could by isolated.
  • the reaction was conducted as follows: a mixture of 5-(3- acetamidophenyl)-4-bromo-l -methylpyrazole (4) as the hydrobromide (1.50 g, 4.0 mmoles), cone HCI (0.80 g, 8 mmoles) in ethanol (3.1 g) and water (1.4 g) was heated to reflux. Samples were taken at various time points and analyzed by HPLC. TABLE 3
  • the reactor was charged with 5-(3'-acetaminophenyl)-4-bromo-l-methyl-iH- pyrazole 4 (1189 g, 4.04 mol), followed by ethanol (2980 g) and aqueous NaO ⁇ solution (30% by weight) (2685 g, 20.1 mol, 5 equivalents). It was heated to reflux whereupon an emulsion was formed. After 16 h ⁇ PLC-analysis revealed consumption of starting material. It was cooled to an internal temp, of 40 to 50 °C and ethanol was evaporated under reduced pressure until 1420 g of reaction mixture were left.
  • the reactor was charged with 5-(3 '-acetaminophenyl)-4-chloro-l-methyl-iH- pyrazole 7 (397 g, 1.59 mol) followed by ethanol (995 g) and aqueous NaO ⁇ solution (30% by weight) (1056 g, 7.92 mol, 5 equivalents). It was heated to reflux whereupon a yellowish emulsion was formed. After 5.2 h of reflux ⁇ PLC analysis showed consumption ( ⁇ 0.5 % left) of starting material. It was cooled to an internal temp, of 50 to 70 °C and ethanol was evaporated at a pressure of 90 to 130 mbar until 1462 g of reaction mixture were left.
  • Diisopropyl ether (684 g) was added with efficient stirring , after separation of phases the aqueous layer was retransferred into the reactor and again extracted with diisopropyl ether (150 g). Both organic layers were combined and seeded followed by cooling of the suspension to - 8 to -12 °C of internal temp, within 1 to 2 h. It was stirred over night at this temperature. The product was filtered an dried over night in vacuum at 40 to 50 °C, yielding 168.4 g (51 %) of the amine 8.
  • Pyridinium salt (2) from Example 12, was dissolved in anhydrous CH C1 2 (3 mL). The solution was stirred and treated with pyridine (118 ⁇ L, 1.46 mmol). The solution was stirred at room temperature for five minutes. Then the solution was heated to 39°C and isopropylamine (45.5 ⁇ L, 0.53mmol) was added drop by drop. After two hours the reaction was complete. The reaction mixture was quenched with 5 mL IN HCI and the organic layer was extracted with EtOAc.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à un procédé de fabrication de certains modulateurs sélectifs du récepteur 5HT2a de formule (I) dans laquelle R1-R7 sont tels que définis dans la description ainsi que leurs intermédiaires. Les composés de formule (I) sont utiles dans la prophylaxie et le traitement de maladies, telles que l'agrégation plaquetttaire, l'asthme, l'agitation, les maladies dégénératives du système nerveux central et analogues provoquées par le récepteur 5HT2A.
PCT/US2003/029736 2002-09-24 2003-09-22 Procede de fabrication de phenylpyrazoles utiles en tant que modulateurs selectifs de 5ht2a et leurs intermediaires Ceased WO2004028450A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003275093A AU2003275093A1 (en) 2002-09-24 2003-09-22 Process of making phenylpyrazoles useful as selective 5ht2a modulators and intermediates thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41329902P 2002-09-24 2002-09-24
US60/413,299 2002-09-24

Publications (2)

Publication Number Publication Date
WO2004028450A2 true WO2004028450A2 (fr) 2004-04-08
WO2004028450A3 WO2004028450A3 (fr) 2004-10-07

Family

ID=32043230

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/029736 Ceased WO2004028450A2 (fr) 2002-09-24 2003-09-22 Procede de fabrication de phenylpyrazoles utiles en tant que modulateurs selectifs de 5ht2a et leurs intermediaires

Country Status (2)

Country Link
AU (1) AU2003275093A1 (fr)
WO (1) WO2004028450A2 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006081335A3 (fr) * 2005-01-26 2007-05-24 Arena Pharm Inc Procedes permettant de preparer des urees de phenylpyrazole substituees
WO2010062321A1 (fr) * 2008-10-28 2010-06-03 Arena Pharmaceuticals, Inc. Procédés utiles pour la préparation de 1-[3-(4-bromo-2-méthyl-2h-pyrazol-3-yl)-4-méthoxy-phényl]-3-(2,4-difluoro‑phényl)-urée, et formes cristallines associées
US7812176B2 (en) 2004-03-23 2010-10-12 Arena Pharmaceuticals, Inc. Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof
US7884101B2 (en) 2004-11-19 2011-02-08 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives 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
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
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8754238B2 (en) 2003-07-22 2014-06-17 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
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
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
WO2024122617A1 (fr) 2022-12-08 2024-06-13 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine et dérivé carbocyclique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2682379B1 (fr) * 1991-10-09 1994-02-11 Rhone Poulenc Agrochimie Nouveaux phenylpyrazoles fongicides.

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8754238B2 (en) 2003-07-22 2014-06-17 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
US9775829B2 (en) 2003-07-22 2017-10-03 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
US9273035B2 (en) 2003-07-22 2016-03-01 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
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
US7812176B2 (en) 2004-03-23 2010-10-12 Arena Pharmaceuticals, Inc. Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof
US10781180B2 (en) 2004-11-19 2020-09-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US7884101B2 (en) 2004-11-19 2011-02-08 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives 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
WO2006081335A3 (fr) * 2005-01-26 2007-05-24 Arena Pharm Inc Procedes permettant de preparer des urees de phenylpyrazole substituees
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
US8680119B2 (en) 2006-05-18 2014-03-25 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
US8664258B2 (en) 2006-05-18 2014-03-04 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
USRE45337E1 (en) 2006-05-18 2015-01-13 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
USRE45336E1 (en) 2006-05-18 2015-01-13 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10450276B2 (en) 2006-05-18 2019-10-22 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
US9987252B2 (en) 2006-05-18 2018-06-05 Arena Pharmaceuticals, Inc. Primary amines and derivitves thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9783502B2 (en) 2006-05-18 2017-10-10 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
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
US9221755B2 (en) 2006-05-18 2015-12-29 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
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US9328107B2 (en) 2006-05-18 2016-05-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
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
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
US9732039B2 (en) 2006-10-03 2017-08-15 Arena Pharmeceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10351531B2 (en) 2006-10-03 2019-07-16 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10058549B2 (en) 2007-08-15 2018-08-28 Arena Pharmaceuticals, Inc. Imidazo[1,2-α]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
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
US10787437B2 (en) 2008-04-02 2020-09-29 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
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
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
US9745270B2 (en) 2008-10-28 2017-08-29 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
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
WO2010062321A1 (fr) * 2008-10-28 2010-06-03 Arena Pharmaceuticals, Inc. Procédés utiles pour la préparation de 1-[3-(4-bromo-2-méthyl-2h-pyrazol-3-yl)-4-méthoxy-phényl]-3-(2,4-difluoro‑phényl)-urée, et formes cristallines associées
US9801856B2 (en) 2008-10-28 2017-10-31 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10071075B2 (en) 2008-10-28 2018-09-11 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
US10117851B2 (en) 2008-10-28 2018-11-06 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
CN109438352A (zh) * 2008-10-28 2019-03-08 艾尼纳制药公司 治疗5-ht2a5-羟色胺受体相关障碍的5-ht2a5-羟色胺受体调节剂组合物
US9353064B2 (en) 2008-10-28 2016-05-31 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
US10583122B2 (en) 2008-10-28 2020-03-10 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10543193B2 (en) 2008-10-28 2020-01-28 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
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
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US11304932B2 (en) 2015-07-15 2022-04-19 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
WO2024122617A1 (fr) 2022-12-08 2024-06-13 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine et dérivé carbocyclique
EP4631938A1 (fr) 2022-12-08 2025-10-15 Shionogi & Co., Ltd Hétérocycle contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine et dérivé carbocyclique

Also Published As

Publication number Publication date
AU2003275093A1 (en) 2004-04-19
AU2003275093A8 (en) 2004-04-19
WO2004028450A3 (fr) 2004-10-07

Similar Documents

Publication Publication Date Title
US20230277505A1 (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
WO2004028450A2 (fr) Procede de fabrication de phenylpyrazoles utiles en tant que modulateurs selectifs de 5ht2a et leurs intermediaires
AU764766B2 (en) Non-endogenous, constitutively activated human serotonin receptors and small molecule modulators thereof
US6150393A (en) Small molecule modulators of non-endogenous, constitutively activated human serotonin receptors
EP2018371B1 (fr) Amines primaires et dérivés de celles-ci utilisés en tant que modulateurs du récepteur de la sérotonine 5-ht2a utiles pour traiter des troubles associés à ce récepteur
US7754866B2 (en) Non-endogenous, constitutively activated human serotonin receptors and small molecule modulators thereof
CA2753061C (fr) Nouveaux analogues heteropyrroles agissant sur les recepteurs cannabinoides
WO2003062206A2 (fr) Modulateurs a petites molecules du recepteur de serotonine 5-ht2a utiles pour la prophylaxie et le traitement de troubles associes
US6541209B1 (en) Non-endogenous, constitutively activated human serotonin receptors and small molecule modulators thereof
KR20160138098A (ko) 아미드 화합물
JPH039114B2 (fr)
JPH07503727A (ja) ベンゾジアゼピン受容体結合剤として有用な４−オキソ−および４Ｈ−イミダゾ（５，１−ｃ）（１，４）ベンゾオキサジン類
ZA200600596B (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US20030224442A1 (en) Non-endogeneous, constitutively activated human serotonin receptors and small molecule modualtors thereof
AU2003257531A1 (en) Non-endogenous,. constitutively activated human serotonin receptors and small molecule modulators thereof
HK1072943B (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
HK1094205A (en) Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
CN101448792A (zh) 增强ampa受体的化合物及其在医药中的用途
JPH05178836A (ja) アンジオテンシンｉｉ拮抗性ピリジン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP