US20040248883A1 - Novel heteroaryl derivatives, their preparation and use - Google Patents

Novel heteroaryl derivatives, their preparation and use Download PDF

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US20040248883A1
US20040248883A1 US10/482,764 US48276404A US2004248883A1 US 20040248883 A1 US20040248883 A1 US 20040248883A1 US 48276404 A US48276404 A US 48276404A US 2004248883 A1 US2004248883 A1 US 2004248883A1
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piperazin
dioxin
dihydrobenzo
ethylsulfanyl
chloro
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Mario Rottlander
Ejner Moltzen
Ivan Mikkelsen
Thomas Ruhland
Kim Andersen
Christian Krog-Jensen
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H Lundbeck AS
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Assigned to H. LUNDBECK A/S reassignment H. LUNDBECK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROTTLANDER, MARIO, MOLTZEN, EJNER KNUD, RUHLAND, THOMAS, JENSEN, CHRISTIAN KROG, MIKKELSEN, IVAN, ANDERSEN, KIM
Publication of US20040248883A1 publication Critical patent/US20040248883A1/en
Priority to US11/758,511 priority Critical patent/US7393845B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • 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
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heteroaryl derivatives potently binding to the 5-HT 1A receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention have also potent serotonin reuptake inhibition activity and are thus considered particularly useful for the treatment of depression.
  • 5-HT 1A agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.
  • 5-HT 1A ligands may be useful in the treatment of ischaemia
  • 5-HT 1A antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer's disease, and in combination with SSR1 antidepressants also to be useful in the treatment of depression.
  • 5-HT reuptake inhibitors are well-known antidepressant drugs and useful for the treatment of panic disorders and social phobia
  • Dopamine D 4 receptors belong to the family of dopamine D 2 -like receptors which is considered to be responsible for the antipsychotic effects of neuroleptics. Doparine D 4 receptors are primarily located in areas of the brain other than striatum, suggesting that dopamine D 4 receptor ligands have antipsychotic effect and are devoid of extrapyramidal activity.
  • dopamine D 4 receptor ligands are potential drugs for the treatment of psychosis and positive symptoms of schizophrenia and compounds with combined effects at dopamine D 4 , and serotonergic receptors may have the further benefit of improved effect on negative symptoms of schizophrenia, such as anxiety and depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep.
  • Dopamine D 3 receptors also belong to the family of dopamine D 2 like receptors. D 3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
  • agents acting on the 5-HT 1A receptor are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired.
  • antagonists at the same time having potent serotonin reuptake inhibition activity and/or D 4 and/or D 3 activity may be particularly useful for the treatment of various psychiatric and neurological diseases.
  • X represents O, NR 16 , S or CR 4 R 5 .
  • Y is —CR 6 R 7 —, —CR 6 R 7 —CR 8 R 9 —, —CR 6 ⁇ CR 7 — or CO—CR 6 R 7 ; or
  • X and Y together form a group —CR 4 ⁇ CR 5 — or —CR 4 ⁇ CR 5 —CR 6 R 7 —;
  • Z represents O or S
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • m is 2 or 3:
  • A is O or S
  • W is N, C or CH
  • Q is N, C or CH
  • R 1 -R 9 are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, hydroxy, formyl, acyl, amino, C 1-6 -alkylamino, di(C 1-6 -alkyl)amino, acylamino, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylamiocarbonylamino and di(C 1-6 -alkyl)aminocarbonylamino; and
  • R 16 is selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1-6 -alyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloallyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl-C 1-6 -alkyl, formyl, acyl; and
  • R 10 and R 11 are each independently selected from hydrogen and C 1-6 -alkyl or may together form a bridge consisting of two or three methylene groups;
  • R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylsulphonyl, hydroxy, formyl, acyl, amino, acylamino, aminocarbonyl, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylaminocarbonylamino, di(C 1-6 -alkyl)aminocarbonylamino, SO 2 NR 20 R 21 and NR 20 R 21 wherein R 20 and R 21 independently represent hydrogen,
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin uptake and antagonism of 5-HT 1A receptors.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the combined effect of 5-HT 1A receptors and dopamine D 4 receptors.
  • the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders; other psychiatric disorders such as psychosis and neurological disorders.
  • affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders
  • other psychiatric disorders such as psychosis and neurological disorders.
  • the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin uptake and antagonism of 5-HT 1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
  • the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the effect of 5-HT 1A and D 4 receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof.
  • the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression.
  • the compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
  • the compounds of the invention have high affinity for the 5-HT 1A and D 4 receptors. Accordingly, the compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders; other psychiatric disorders such as psychosis and neurological disorders.
  • affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders
  • other psychiatric disorders such as psychosis and neurological disorders.
  • Z is O.
  • Y is —CH 2 CH 2 — or —CH 2 CO—.
  • X is O or NH.
  • W is N.
  • n is 2.
  • n is 2, 3 or 4.
  • n is 2.
  • R 1 , R 2 and R 3 independently represent hydrogen, halogen or CN.
  • R 12 , R 13 , R 14 , R 15 and R 16 are independently selected from a group consisting of hydrogen, heteroaryl, trifluoromethyl, cyano, C 1-6 -alkyl, halogen, NR 20 R 21 , SO 2 NR 20 R 21 , aryl, C 1-6 -alkylsulfonyl and carbonylamino.
  • R 12 , R 13 , R 14 , R 15 and R 16 are independently selected from hydrogen, thiophen, trifluoromethyl, cyano, methyl, ethyl, cyclopropyl, chloro, bromo, fluoro, piperazine, 1-piperazine-4-methyl, 1-piperidine, 1-piperidinyl-sulfonyl, methanesulfonyl, methylsulfid, phenyl and carbonylamino.
  • Specific compounds of the invention are compounds selected from:
  • C 1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
  • C 2-6 alkenyl and C 2-6 alkynyl designate such groups having from two to six carbon atoms inclusive.
  • Halogen means fluoro, chloro, bromo or iodo.
  • C 3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C 1-6 alkoxy, C 1 alkylthio and C 1-6 alkylsulphonyl designate such groups in which the alkyl group is C 1-6 alkyl as defined above.
  • aryl designates an aromatic hydrocarbon such as phenyl or naphtyl.
  • heteroaryl refers to a mono- or bicyclic heterocyclic aromatic group containing at least one N, S or O atom, such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrimidyl, tetraaolyl, benzofuranyl, benzothienyl, benzimidazolyl, indolyl.
  • Preferred heteroaryls are monocyclic aryls. Especially preferred are thienyl and piperidinyl.
  • Acyl means —CO-alkyl wherein the alkyl group is C 1-6 alkyl as defined above.
  • Amino means NH 2 .
  • C 1-6 alkylamino means —NH-alkyl and di(C 1-6 -alkyl)amino means —N-(alkyl) 2 where the alkyl group is C 1-6 alkyl as defined above.
  • Acylamino means —NH-acyl wherein acyl is as defined above.
  • C 1-6 alkoxycarbonylamino means alkyl-O—CO—NH— wherein the alkyl group is C 1-6 alkyl as defined above.
  • C 1-6 alkylaminocarbonylamino means alkyl-NH—CO—NH— wherein the alkyl group is C 1-6 alkyl as defined above.
  • di(C 1-6 -alkyl)aminocarbonylamino means (alkyl) 2 —N—CO—NH— wherein the alkyl group is C 1-6 alkyl as defined above.
  • a phenyl group which may be substituted means a phenyl group which may be substituted one or more times with a substituent selected form halogen, trifluoromethyl, cyano, nitro, amino, C 1-6 -ylamino, di(C 1-6 -alkyl)amino, C 1-6 -alkyl, C 1-6 -alkoxy and hydroxy.
  • organic acid addition salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
  • the acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomers).
  • the invention includes all such isomers and any mixtures thereof including racemic mixtures.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystalfisation of d- or 1-(tartrates, mandelates or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
  • Optically active compounds can also be prepared from optically active starting materials.
  • the compounds of the invention can be prepared by one of the following methods comprising
  • n, m, R 1 -R 3 , R 10 , R 11 , R 12 -R 15 , W, X, Y, Z, A and the dotted line are as defined above;
  • L is a suitable leaving group such as e.g. chloro and n, m, R 1 -R 3 , R 10 , R 11 , R 12 R 15 , Q, W, X, Y, Z, A and the dotted line are as defined above;
  • the reductive amination according to method a) is preferably carried out in an inert organic solvent such as dimethylformamide or tetrahydrofuran in the presence of a reducing agent, eg triacetoxyborohydride, at room temperature.
  • a reducing agent eg triacetoxyborohydride
  • the arylation according to method b) is conveniently performed in an inert organic solvent such as dimethylformamide in the presence of a base (eg potassium tert-butoxide) at a temperature in the range of 40-100° C., preferably in the range of 40-80° C., and most preffered around 50° C.
  • a base eg potassium tert-butoxide
  • Arylpiperazine derivatives of formula (II) are either commercially available or conveniently prepared from the corresponding arylamine according to the method described by Martin et al. J. Med. Chem. 1989, 32, 1052, or the method described by Kruse et al. Rec. Trav. Chim. Pays - Bas 1988, 107, 303.
  • the starting arylamines are either commercially available or are well-described in the literature.
  • Aryltetrahydropyridine derivatives of formula (II) are known from literature, cf. U.S. Pat. No. 2,891,066; McElvain et al. J. Amer. Chem. Soc. 1959, 72, 3134.
  • the corresponding arylbromide is lithiated with BuLi followed by addition of 1-benzyl-4-piperidone.
  • Subsequent treatment with acid gives the N-benzyl-aryltetrahydropyridine.
  • the benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to give the corresponding ethyl carbamate followed by acidic or alkaline hydrolysis.
  • the starting arylbromides are either commercially available or well-described in the literature.
  • Aldehydes of formula (IL) are prepared as described in the Examples below.
  • the starting chloropyridines are commercially available or made by methods well-described in the literature
  • Mass spectra were obtained by an alternating scan method to give molecular weight information.
  • the molecular ion, MH+ was obtained at low orifice voltage (5-20V) and fragmentation at high orifice voltage (100V).
  • NMR signals corresponding to acidic protons are generally omitted. Content of water in crystalline compounds was determined by Karl Fischer titration.
  • Standard workup procedures refer to extraction with the indicated organic solvent from proper aqueous solutions, drying of combined organic extracts (anhydrous MgSO 4 or Na 2 SO 4 ), filtering and evaporation of the solvent in vacuo.
  • silica gel of type Kieselgel 60, 230400 mesh ASTM was used.
  • ion-exchange chromatography SCX 1 g, Varian Mega Bond Elut®, Chrompack cat. no. 220776. Prior use the SCX-columns were preconditioned with 10% solution of acetic acid in methanol (3 mL).
  • the affinity of the compounds of the invention to 5-HT 1A receptors was determined by measuring the inhibition of binding of a radioactive ligand at 5-HT 1A receptors as described in the following test:
  • the 5-HT 1A antagonistic activity of some of the compounds of the invention has been estimated in vitro at cloned 5-HT 1A receptors stably expressed in transfected HeLa cells (HA7).
  • 5-HT 1A antagonistic activity is estimated by measuring the ability of the compounds to antagonize the 5-HT induced inhibition of forskolin induced cAMP accumulation.
  • the assay was performed as a modification of the method described by Pauwels, P. J. et al. Biochem. Pharmacol. 1993, 45, 375.
  • Compounds 1a, 1b, 1e and 1v were tested and showed IC 50 values of less than 7000 nM.
  • the compounds of the present invention possess valuable activity as serotonin re-uptake inhibitors and have antagonistic effect at 5-HT 1A receptors.
  • the compounds of the invention are therefore considered useful for the treatment of diseases and disorders responsive to the inhibition of serotonin re-uptake and antagonistic activity at 5-HT 1A receptors.
  • Diseases responsive to the inhibition of serotonin re-uptake are well-known in the art and include affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, etc.
  • the antagonistic activity at 5-HT 1A receptors of the compounds of the invention will counteract the negative feed back mechanism induced by the inhibition of serotonin reuptake and is thereby expected to improve the effect of the serotonin reuptake inhibiting activity of the compounds of the invention.
  • the compounds as claimed herein are therefore considered to be particularly useful as fast onset of action medicaments for the treatment of depression.
  • the compounds may also be useful for the treatment of depressions which are non-responsive to currently available SSRIs.
  • the compounds of the invention show affinity for the 5-HT 1A receptors, inhibitory activity at serotonin reuptake sites, and affinity for dopamine D 3 and D 4 receptors. Accordingly, the compounds are considered useful for the treatment of psychiatric and neurological disorders as mentioned previously.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
  • compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
  • suitable route for example orally in the form of tablets, capsules, powders, syrups, etc.
  • parenterally in the form of solutions for injection.
  • methods well-known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
  • the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 1000 mg.
  • the total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.

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US20060004023A1 (en) * 2001-07-20 2006-01-05 Daniela Brunner Treatment for attention-deficit hyperactivity disorder
US20060258678A1 (en) * 2001-06-29 2006-11-16 Rottlaender Mario Novel indole derivatives

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US7262293B2 (en) * 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof
US7160888B2 (en) 2003-08-22 2007-01-09 Warner Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
WO2006056600A1 (en) 2004-11-26 2006-06-01 Janssen Pharmaceutica N.V. Isoxazoline-indole derivatives with an improved antipsychotic and anxiolytic a ivity
WO2011080341A1 (en) 2010-01-04 2011-07-07 Enantia, S.L. Process for the preparation of rivaroxaban and intermediates thereof
KR101384384B1 (ko) 2010-04-12 2014-04-10 롯데케미칼 주식회사 올레핀 중합용 촉매 조성물 및 이를 사용한 폴리올레핀의 제조방법
KR100986301B1 (ko) * 2010-04-12 2010-10-07 아주대학교산학협력단 테트라하이드로퀴놀린 유도체로부터 유래한 티오펜-축합고리 싸이클로펜타디에닐 4족 금속 화합물 및 이를 이용한 올레핀 중합
ES2596719T3 (es) 2010-04-12 2017-01-11 Lotte Chemical Corporation Procedimiento de preparación de un copolímero de olefin-dieno usando un compuesto de metal de transición que incluye un ligando de ciclopentadienilo de anillo condensado con tiofeno
EP2559711B1 (en) 2010-04-12 2017-06-14 Lotte Chemical Corporation Supported catalyst for polymerizing olefin and method for preparing polyolefin using same
KR101384450B1 (ko) 2010-04-12 2014-04-25 롯데케미칼 주식회사 티오펜-축합고리 사이클로펜타디에닐 리간드를 포함하는 전이금속 화합물을 사용한 올레핀-디엔 공중합체의 제조방법

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Cited By (5)

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US20060258678A1 (en) * 2001-06-29 2006-11-16 Rottlaender Mario Novel indole derivatives
US7342015B2 (en) 2001-06-29 2008-03-11 H. Lundbeck A/S Indole derivatives
US20060004023A1 (en) * 2001-07-20 2006-01-05 Daniela Brunner Treatment for attention-deficit hyperactivity disorder
US7504395B2 (en) 2001-07-20 2009-03-17 Psychogenics, Inc. Treatment for attention-deficit hyperactivity disorder
US7557109B2 (en) 2001-07-20 2009-07-07 Psychogenics, Inc. Treatment for attention-deficit hyperactivity disorder

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NZ529460A (en) 2005-09-30
MXPA03011769A (es) 2004-04-02
UA75407C2 (en) 2006-04-17
PL365249A1 (en) 2004-12-27
ATE312094T1 (de) 2005-12-15
JP2004535449A (ja) 2004-11-25
CN1310909C (zh) 2007-04-18
BG108531A (bg) 2004-08-31
DE60207857D1 (de) 2006-01-12
EA006203B1 (ru) 2005-10-27
US7393845B2 (en) 2008-07-01
SK652004A3 (en) 2004-09-08
CA2451228A1 (en) 2003-01-09
BR0210401A (pt) 2004-08-17
CZ2004156A3 (cs) 2004-05-12
NO326514B1 (no) 2008-12-22
NO20035673D0 (no) 2003-12-18
EP1399438B1 (en) 2005-12-07
WO2003002556A1 (en) 2003-01-09
DE60207857T2 (de) 2006-07-20
EP1399438A1 (en) 2004-03-24
AU2002344949B2 (en) 2007-05-24
DK1399438T3 (da) 2006-04-18
HUP0400344A2 (hu) 2004-09-28
IL158828A0 (en) 2004-05-12
IS7021A (is) 2003-11-10
KR20040019026A (ko) 2004-03-04
EA200400102A1 (ru) 2004-04-29
HK1068622A1 (en) 2005-04-29
ES2252471T3 (es) 2006-05-16
IS2425B (is) 2008-10-15
NO20035673L (no) 2003-12-18

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