WO2001043740A1 - Antipsychotic heterocycle compounds - Google Patents
Antipsychotic heterocycle compounds Download PDFInfo
- Publication number
- WO2001043740A1 WO2001043740A1 PCT/US2000/033617 US0033617W WO0143740A1 WO 2001043740 A1 WO2001043740 A1 WO 2001043740A1 US 0033617 W US0033617 W US 0033617W WO 0143740 A1 WO0143740 A1 WO 0143740A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methylbenzothiazole
- tetrahydropyrid
- propoxy
- piperidinyl
- butoxy
- Prior art date
Links
- 0 C*(C*)CC(C1)[C@]1(C1=C*(*)c2ccccc12)N Chemical compound C*(C*)CC(C1)[C@]1(C1=C*(*)c2ccccc12)N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention pertains to cyclic amino derivatives having psychotropic and bio-affecting properties and to their preparation and use in treating patients suffering from or susceptible to psychosis, acute mania, mild anxiety states, or depression in combination with psychotic episodes by the administration of these cyclic amino derivatives. More specifically, the invention is concerned with the medicinal use of compounds having benzene or benzothiazole rings linked by sidechains to the nitrogen atom of 4- substituted-1 ,2,5,6-tetrahydropyridine and -piperidine moieties. These compounds possess unique dopaminergic and serotonergic profiles that make them useful in the treatment of psychosis and other mental illnesses caused by disorders of the dopaminergic and serotonergic systems.
- Y O, S, or a bond
- R 1 is naphthyl, phenyl, substituted phenyl, halo, alkyl, alkylthio, alkoxy, benzyloxy, OH, CONH 2 .
- Ar is aryl or a selected group of heteroaryl moieties not including benzothiazole.
- a series of nitrogen-containing heterocycles linked by oxygen to alkanamines comprising, inter alia, compounds of formula 6, were disclosed and claimed for the treatment of conditions related to the reuptake of serotonin and by the 5-HT ⁇ a receptor (US Patent 5,741 ,789, April 21 , 1998, and US Patent 5,627,196, May 6, 1997).
- D represents a nitrogen-containing residue that completes
- Z can be with R 2 being absent when a double bond is intended or being hydrogen or a substituent, including a benzyl group.
- R 3 is a non-hydrogen substituent that can be indole.
- the invention is concerned with the use of certain benzene or benzothiazole compounds linked by sidechains to indolyl- 1 ,2,5,6-tetrahydropyridines and -piperidines or substituted 4- benzylpiperidines.
- These compounds possess a unique dopaminergic and serotonergic profile useful for treating CNS disorders such as psychosis and depression and they conform to Formula I:
- Ar is selected from
- Z is II or III
- Y is sulfur or oxygen
- R 1 and R 4 are independently selected from H and lower alkyl
- R 2 , R 3 , R 6 and R 7 are independently selected from H, halogen, and lower alkoxy;
- R 5 is selected from H, halogen, lower alkoxy and cyano; m is an integer from 2-6;
- n is zero or the integer 1 or 2;
- a dotted line represents an optional double bond.
- Halo or "halogen” refers to fluoride, chloride, bromide or iodide substituents with fluoride, chloride and bromide preferred.
- “Lower” refers to an alkyl or alkoxy group having from one to four carbon atoms.
- compounds of Formula I also encompass all pharmaceutically acceptable acid addition salts and/or solvates thereof.
- the present invention is also considered to include stereoisomers including geometric as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diasteromers, which arise as a consequence or structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
- Preferred compounds are those wherein m is 3, n is 1 and Y is oxygen.
- the pharmaceutically acceptable acid addition salts of the invention are those in which the counter ion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of the bases of Formula I. They are generally preferred for medical usage. In some instances, they have physical properties which makes them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes.
- the salts are routinely made by admixture of a Formula I base with the selected acid, preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the anion of one salt of the substance of the Formula I is replaced by another anion under conditions which allow for separation of the desired species such as by precipitation from solution or extraction into a solvent, or elution from or retention on an ion exchange resin.
- Pharmaceutically acceptable acids for the purposes of salt formation of the substances of Formula I include sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, fumaric, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and others.
- Intermediates of Formulas IV and VII are conveniently made by alkylating (Reactions 4, 5) appropriate benzothiazoles or benzenes with dihaloalkanes in solvents such as acetone, acetonitrile, DMSO, DMF, or the like, and in the presence of suitable bases, such as trialkyl amines or sodium, potassium, or cesium carbonate, or the like, under standard alkylation conditions.
- the tetrahydropyridine intermediates (VIII) can be reduced using using hydrogen and a suitable catalyst such as platinum, palladium, or ruthenium catalysts, in solvents such as ethanol, ethyl acetate, or the like, to give the piperidine intermediates (IX).
- a suitable catalyst such as platinum, palladium, or ruthenium catalysts, in solvents such as ethanol, ethyl acetate, or the like.
- the N-protecting group can then be cleaved using methods known to those skilled in the art to give the piperidine intermediates of Formula Vb.
- the piperidine intermediates of Formula VI are conveniently prepared by condensation of an N-protected-4-piperidone with reagents such as benzyl phosphonate esters using bases such as NaH, LDA, sodium or potassium alkoxides, or the like, in solvents such as THF, diethyl ether, or the like, to provide the benzylidene intermediate, XI. Subsequent reduction of the benzylidene group using hydrogen and platinum, palladium, or ruthenium catalysts, in solvents such as ethanol, ethyl acetate, or the like, provides the piperidine intermediate, X. The N-protecting group is then cleaved using methods known to those skilled in the art to give the piperidine intermediates of Formula II as depicted in Reaction 7.
- the compounds of Formula I bind potently to the human 5-HT transporter and inhibit the re-uptake of endogenous serotonin.
- Selective serotonin reuptake inhibitors are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain (see: R.W. Fuller, Pharmacologic Modification of Serotonergic Function: Drugs for the Study and Treatment of Psychiatric and Other Disorders," J. Clin. Psychiatry. 47:4 (Suppl.) April 1986, pp. 4-8).
- Compounds of the present invention are also envisioned to be useful for treating psychosis, acute mania, mild anxiety states or depression with secondary psychotic episodes.
- the present compounds are also envisioned to be useful in treating obsessive-compulsive disorders, feeding disorders, anxiety disorders and panic disorders.
- the compounds of Formula I also are antagonists at the human D 2 L receptor as determined by [ 3 H]-spiperone binding studies using human D 2 ⁇ _ receptors stably expressed in HEK-293 cells.
- Clinical studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) augment the efficacy of traditional neuroleptic antipsychotic agents in improving negative symptoms in schizophrenic patients (Silver, et al., 1998, J. Clin. Psvchopharmacol. 18:208; Goff, et al., 1994, Psychopharmacoloqy 117:417). Therefore, the compounds of Formula I possess a unique serotonergic and dopaminergic profile, making the compounds of the present invention useful for treating psychosis, and in particular, the negative symptoms in schizophrenic patients.
- SSRIs selective serotonin reuptake inhibitors
- Another aspect of the instant invention provides a method for treating a mammal afflicted with psychosis, depression, or chronic pain which comprises administering systemically to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.
- the administration and dosage regimen of compounds of Formula I are considered to be done in the same manner as for the reference compound fluoxetine, cf: Schatzberg, et al., J. Clin. Psychopharmacoloqy 7/6 Suppl. (1987) pp. 4451 -4495, and references therein.
- the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgement and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.05 to about 10 mg/kg, preferably 0.1 to 2 mg/kg, when administered parenterally and from about 1 to about 50 mg/kg, preferably about 5 to 20 mg/kg, when administered orally.
- Systemic administration refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous). Generally, it will be found that when a compound of the present invention is administered orally, a larger quantity of the active agent is required to produce the same effect as a similar quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective antidepressant effects without causing any harmful or untoward side effects.
- the compounds of the present invention may be administered for antipsychotic and antidepressant purposes either as individual therapeutic agents or as mixtures with other therapeutic agents.
- they are generally given as pharmaceutical compositions comprised of an antidepressant amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- Pharmaceutical compositions which provide from about 1 to 500 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions.
- oral compositions may be in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate).
- binding agents e.g. starch
- wetting agents e.g. sodium lauryl sulfate
- Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.
- Example 12 5- ⁇ 3-[4-(5-cyanoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]propoxy ⁇ -2-methylbenzothiazole
- Example 13 5- ⁇ 4-[4-(4-fluoroindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yl]butoxy ⁇ -2- methylbenzothiazole;
- Example 14 5- ⁇ 5-[4-(4-fluoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1-yl]pentoxy ⁇ - 2-methylbenzothiazole;
- Example 15 5- ⁇ 4-[4-(5-fluoroindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yl]butoxy ⁇ -2- methylbenzothiazole;
- Example 16 5- ⁇ 5-[4-(5-fiuoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yljpentoxy ⁇ - 2-methylbenzothiazole;
- Example 17 5- ⁇ 3-[4-(7-fluoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yljpropoxy ⁇ - 2-methylbenzothiazole;
- Example 18 5- ⁇ 4-[4-(7-fluoroindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yl]butoxy ⁇ -2- methylbenzothiazole;
- Example 19 5- ⁇ 5-[4-(7-fluoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yl]pentoxy ⁇ - 2-methylbenzothiazole;
- Example 20 5- ⁇ 4-[4-(5-chloroindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yljbutoxy ⁇ - 2-methylbenzothiazole;
- Example 21 5- ⁇ 5-[4-(5-chloroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]pentoxy ⁇ -2-methylbenzothiazole;
- Example 22 5- ⁇ 3-[4-(6-chloroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]propoxy ⁇ -2-methylbenzothiazole;
- Example 23 5- ⁇ 4-[4-(6-chloroindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yljbutoxy ⁇ - 2-methylbenzothiazole;
- Example 24 5- ⁇ 5-[4-(6-chloroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]pentoxy ⁇ -2-methylbenzothiazole;
- Example 25 5- ⁇ 3-[4-(6-bromoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1- yl]propoxy ⁇ -2-methylbenzothiazole;
- Example 26 5- ⁇ 4-[4-(6-bromoindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yljbutoxy ⁇ - 2-methylbenzothiazole;
- Example 27 5- ⁇ 5-[4-(6-bromoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1- yl]pentoxy ⁇ -2-methylbenzothiazole;
- Example 28 5- ⁇ 3-[4-(7-bromoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]propoxy ⁇ -2-methylbenzothiazole;
- Example 29 5- ⁇ 4-[4-(7-bromoindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 -yljbutoxy ⁇ - 2-methylbenzothiazole;
- Example 30 5- ⁇ 5-[4-(7-bromoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]pentoxy ⁇ -2-methylbenzothiazole;
- Example 31 5- ⁇ 3-[4-(5-methoxyindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]propoxy ⁇ -2-methylbenzothiazole;
- Example 32 5- ⁇ 4-[4-(5-methoxyindol-3-yl)1 ,2,5,6-tetrahydropyrid-1 - yljbutoxy ⁇ -2-methylbenzothiazole;
- Example 33 5- ⁇ 5-[4-(5-methoxyindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yl]pentoxy ⁇ -2-methylbenzothiazole;
- Example 34 5- ⁇ 3-[4-(5-fluoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yljpropoxy ⁇ - 2-methylbenzothiazole;
- Example 36 5- ⁇ 3-[4-(5-bromoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 - yljpropoxy ⁇ -2-methylbenzothiazole;
- Example 37 5- ⁇ 3-[4-(5-cyanoindol-3-yl)piperidinyl]propoxy ⁇ -2- methylbenzothiazole;
- Example 38 5- ⁇ 4-[4-(5-cyanoindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yljbutoxy ⁇ - 2-methylbenzothiazole;
- Example 40 2-methyl-5-[3-[4-(2-bromo-5-fluorobenzyl)-piperidinyl]-propoxyl]- benzothiazole.
- Example 41 5- ⁇ 3-[4-(2H-benzo[d]1 ,3-dioxolan-4- ylmethyl)piperidinyl]propoxy ⁇ -2-methylbenzothiazole;
- Example 46 5-(3- ⁇ 4-[(3-methoxyphenyl)methyl]piperidinyl ⁇ propoxy)-2- methylbenzothiazole;
- Example 48 5-(3- ⁇ 4-[(2,5-dichlorophenyl)methyl]piperidinyl ⁇ propoxy)-2- methylbenzothiazole.
- HEK-293 cells that stably express recombinant human dopamine D 2L receptors were grown at 37 °C in 5% C0 2 as a monolayer in medium consisting of EMEM supplemented with 10% fetal bovine serum and G418 sulfate (500 yg/ml).
- EMEM fetal bovine serum
- G418 sulfate 500 yg/ml
- membranes for radioligand binding experiments cells were rinsed twice with phosphate-buffered saline (138 mM NaCI, 4.1 mM KCI, 5.1 mM Na 2 P0 4 , 1.5 mM KH 2 P0 2 11.1 mM glucose, pH 7.4), and incubated for 5-10 min.
- hypotonic lysis buffer consisting of 10 mM Tris (pH 7.4) and 5 mM EDTA.
- Cells were transferred from plates to polypropylene tubes (16 x 100 mm), homogenized and centrifuged at 32,000 x g for 20 min. Following centrifugation, pellets were resuspended by homogenization in buffer consisting of 50 mM Tris (pH 7.7 at 25 °C) and 1 mM EDTA. Homogenates were stored at -80 °C until needed. On the day of an experiment, homogenates were thawed then centrifuged at 32,000 x g for 20 min.
- Test data IC 5 o values lower than 250 nM are considered to reflect affinity for dopamine D 2 L receptors.
- Compounds with IC 5 o values lower than 100 nM comprise preferred compounds.
- HEK-293 cells that stably express human serotonin transporters were grown at 37 °C in 5% C0 2 as a monolayer in medium consisting of EMEM supplemented with 10% fetal bovine serum and G418 sulfate (500 ⁇ g/ml).
- EMEM fetal bovine serum
- G418 sulfate 500 ⁇ g/ml.
- membranes for radioligand binding experiments cells were rinsed twice with phosphate-buffered saline (138 mM NaCI, 4.1 mM KCI, 5.1 mM Na 2 P0 4 , 1.5 mM KH 2 0 4 , 11.1 mM glucose, pH 7.4).
- Cells were transferred from plates to polypropylene tubes (16 x 100 mm), centrifuged at 1 ,200 x g for 5 min and were frozen at -80 °C until assay. Following centrifugation, pellets were resuspended by homogenization in buffer consisting of 50 mM Tris (pH 7.7 at 25 °C), 120 mM NaCI and 5 mM KCI and then centrifuged at 32,000 x g for 10 min. Following centrifugation, supernatants were discarded and pellets were resuspended in buffer consisting of 50 mM Tris (pH 7.4 at 25 °C), 150 mM NaCI and 5 mM KCI.
- the assay buffer consisted of 50 mM Tris (pH 7.4 at 25 °C), 120 mM NaCI and 5 mM KCI (pH 7.4 with cone. HCI). Plates were incubated for 1 hour at 25 °C, then filtered through 0.5% PEI treated Whatman GF/B filters using a Brandel cell harvester. Filters were washed three times with 3 ml of ice-cold tris wash buffer.
- Non-specific binding was defined with 10 ⁇ M fluoxetine. Amount of radioligand bound in the presence and absence of competitor was analyzed by plotting (-)log drug concentration versus the amount of radioligand specifically bound. The midpoint of the displacement curve (IC 50 , nM), signifies the potency. Ki values were calculated using the method of Cheng and Prusoff (1973).
- Test data IC 5 o values lower than 250 nM are considered to reflect activity as an inhibitor of serotonin re-uptake.
- Compounds with IC 50 values lower than 100 nM comprise preferred compounds.
- the following compounds of Formula I inhibit the re-uptake of serotonin with Ki lower than 100 nM, and are dopamine D ⁇ _ ligands with Ki lower than 100 nM: 5- ⁇ 3-[4-(5-fluoroindol-3-yl)-1 ,2,5,6-tetrahydropyrid-1 -yl]propoxy ⁇ -2- methylbenzothiazole;
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00992008A EP1242072A4 (en) | 1999-12-17 | 2000-12-12 | Antipsychotic heterocycle compounds |
AU37899/01A AU3789901A (en) | 1999-12-17 | 2000-12-12 | Antipsychotic heterocycle compounds |
CA002394548A CA2394548A1 (en) | 1999-12-17 | 2000-12-12 | Antipsychotic heterocycle compounds |
JP2001544878A JP2003517481A (en) | 1999-12-17 | 2000-12-12 | Antipsychotic heterocyclic compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17220099P | 1999-12-17 | 1999-12-17 | |
US60/172,200 | 1999-12-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001043740A1 true WO2001043740A1 (en) | 2001-06-21 |
Family
ID=22626741
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/033617 WO2001043740A1 (en) | 1999-12-17 | 2000-12-12 | Antipsychotic heterocycle compounds |
Country Status (6)
Country | Link |
---|---|
US (1) | US6476051B2 (en) |
EP (1) | EP1242072A4 (en) |
JP (1) | JP2003517481A (en) |
AU (1) | AU3789901A (en) |
CA (1) | CA2394548A1 (en) |
WO (1) | WO2001043740A1 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002048105A2 (en) * | 2000-11-16 | 2002-06-20 | Wyeth | Aryloxy piperidinyl derivatives for the treatment of depression |
EP1304324A1 (en) * | 2000-07-18 | 2003-04-23 | Sumitomo Pharmaceuticals Company, Limited | Serotonin reuptake inhibitors |
WO2003068236A1 (en) * | 2002-02-18 | 2003-08-21 | Glaxo Group Limited | Piperidine and piperazine derivatives possessing affinity at 5ht-1 type receptors |
WO2005049559A2 (en) | 2003-11-17 | 2005-06-02 | Boehringer Ingelheim International Gmbh | Novel piperidine-substituted indoles- or hetero-derivatives thereof and their use as modulators of chemokine receptor (ccr-3) |
WO2005077924A1 (en) * | 2004-02-11 | 2005-08-25 | Grünenthal GmbH | Substituted 4,5,6,7-tetrahydro-benzothiazol-2-ylamine compounds |
US7002025B2 (en) | 2000-03-07 | 2006-02-21 | Resolution Chemicals Limited | Process for the preparation of citalopram |
WO2006117314A2 (en) | 2005-04-30 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel piperidin- substituted indoles and their use as ccr-3 modulators |
WO2008049874A1 (en) | 2006-10-27 | 2008-05-02 | Boehringer Ingelheim International Gmbh | Piperidyl-propane-thiol ccr3 modulators |
US7368470B2 (en) | 2003-08-13 | 2008-05-06 | Gruenenthal Gmbh | Substituted 3-pyrrolidine-indole derivatives |
US7829705B2 (en) | 2000-12-18 | 2010-11-09 | Biota Scientific Management Pty. Ltd. | Antiviral agents |
US8063223B2 (en) | 2008-02-05 | 2011-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Benzylpiperizine compound |
RU2468025C2 (en) * | 2007-04-04 | 2012-11-27 | Мерк Шарп Энд Домэ Корп. | Therapeutic agents |
US8778970B2 (en) | 2009-08-04 | 2014-07-15 | Dainippon Sumitomo Pharma Co., Ltd | Benzyl piperidine compound |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060122177A1 (en) * | 2004-12-07 | 2006-06-08 | Solvay Pharmaceuticals B.V. | Phenylpiperazines with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4530932A (en) * | 1982-10-05 | 1985-07-23 | Roussel Uclaf | 4-(1H-indol-3-yl)-α-methyl-piperidine-1-ethanol derivatives |
US5521197A (en) * | 1994-12-01 | 1996-05-28 | Eli Lilly And Company | 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5741789A (en) | 1995-01-17 | 1998-04-21 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5627196A (en) | 1995-01-17 | 1997-05-06 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
ZA9610736B (en) * | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
US5962473A (en) | 1996-08-16 | 1999-10-05 | Eli Lilly And Company | Methods of treating or ameliorating the symptoms of common cold or allergic rhinitis with serotonin 5-HT1F |
WO1998011895A1 (en) | 1996-09-18 | 1998-03-26 | Eli Lilly And Company | A method for the prevention of migraine |
ZA977967B (en) | 1996-09-23 | 1999-03-04 | Lilly Co Eli | Combination therapy for treatment of psychoses |
ZA9711376B (en) | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
EP1070715A4 (en) * | 1998-03-19 | 2002-10-17 | Nihon Nohyaku Co Ltd | Arylpiperidine derivatives and use thereof |
-
2000
- 2000-12-12 AU AU37899/01A patent/AU3789901A/en not_active Abandoned
- 2000-12-12 CA CA002394548A patent/CA2394548A1/en not_active Abandoned
- 2000-12-12 EP EP00992008A patent/EP1242072A4/en not_active Withdrawn
- 2000-12-12 JP JP2001544878A patent/JP2003517481A/en active Pending
- 2000-12-12 US US09/735,384 patent/US6476051B2/en not_active Expired - Lifetime
- 2000-12-12 WO PCT/US2000/033617 patent/WO2001043740A1/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4530932A (en) * | 1982-10-05 | 1985-07-23 | Roussel Uclaf | 4-(1H-indol-3-yl)-α-methyl-piperidine-1-ethanol derivatives |
US5521197A (en) * | 1994-12-01 | 1996-05-28 | Eli Lilly And Company | 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists |
Non-Patent Citations (1)
Title |
---|
See also references of EP1242072A4 * |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7002025B2 (en) | 2000-03-07 | 2006-02-21 | Resolution Chemicals Limited | Process for the preparation of citalopram |
EP1304324A4 (en) * | 2000-07-18 | 2004-03-10 | Sumitomo Pharma | Serotonin reuptake inhibitors |
EP1304324A1 (en) * | 2000-07-18 | 2003-04-23 | Sumitomo Pharmaceuticals Company, Limited | Serotonin reuptake inhibitors |
US6787560B2 (en) | 2000-07-18 | 2004-09-07 | Sumitomo Pharmaceuticals Company Limited | Serotonin reuptake inhibitor |
WO2002048105A2 (en) * | 2000-11-16 | 2002-06-20 | Wyeth | Aryloxy piperidinyl derivatives for the treatment of depression |
US6610712B2 (en) | 2000-11-16 | 2003-08-26 | Wyeth | Aryloxy piperidinyl derivatives for the treatment of depression |
WO2002048105A3 (en) * | 2000-11-16 | 2002-10-31 | Wyeth Corp | Aryloxy piperidinyl derivatives for the treatment of depression |
US7829705B2 (en) | 2000-12-18 | 2010-11-09 | Biota Scientific Management Pty. Ltd. | Antiviral agents |
US8624025B2 (en) | 2000-12-18 | 2014-01-07 | Biota Scientific Management Pty Ltd | Antiviral agents |
US7951955B2 (en) | 2000-12-18 | 2011-05-31 | Biota Scientific Management Pty Ltd | Antiviral agents |
US8217171B2 (en) | 2000-12-18 | 2012-07-10 | Biota Scientific Management Pty. Ltd. | Antiviral agents |
WO2003068236A1 (en) * | 2002-02-18 | 2003-08-21 | Glaxo Group Limited | Piperidine and piperazine derivatives possessing affinity at 5ht-1 type receptors |
US7368470B2 (en) | 2003-08-13 | 2008-05-06 | Gruenenthal Gmbh | Substituted 3-pyrrolidine-indole derivatives |
WO2005049559A2 (en) | 2003-11-17 | 2005-06-02 | Boehringer Ingelheim International Gmbh | Novel piperidine-substituted indoles- or hetero-derivatives thereof and their use as modulators of chemokine receptor (ccr-3) |
US7544806B2 (en) | 2003-11-17 | 2009-06-09 | Boehringer Ingelheim International Gmbh | Piperidine-substituted indoles-or heteroderivatives thereof |
WO2005077924A1 (en) * | 2004-02-11 | 2005-08-25 | Grünenthal GmbH | Substituted 4,5,6,7-tetrahydro-benzothiazol-2-ylamine compounds |
US7348347B2 (en) | 2004-02-11 | 2008-03-25 | Gruenenthal Gmbh | Substituted 4,5,6,7-tetrahydrobenzthiazol-2-ylamine compounds |
US7759365B2 (en) | 2005-04-30 | 2010-07-20 | Boehringer Ingelheim International Gmbh | Piperidine-substituted indoles |
WO2006117314A2 (en) | 2005-04-30 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel piperidin- substituted indoles and their use as ccr-3 modulators |
WO2008049874A1 (en) | 2006-10-27 | 2008-05-02 | Boehringer Ingelheim International Gmbh | Piperidyl-propane-thiol ccr3 modulators |
RU2468025C2 (en) * | 2007-04-04 | 2012-11-27 | Мерк Шарп Энд Домэ Корп. | Therapeutic agents |
US8232405B2 (en) | 2008-02-05 | 2012-07-31 | Dainippon Sumitomo Pharma Co., Ltd. | Benzylpiperizine compound |
US8557998B2 (en) | 2008-02-05 | 2013-10-15 | Dainippon Sumitomo Pharma Co., Ltd | Benzylpiperizine compound |
US8063223B2 (en) | 2008-02-05 | 2011-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Benzylpiperizine compound |
US8778970B2 (en) | 2009-08-04 | 2014-07-15 | Dainippon Sumitomo Pharma Co., Ltd | Benzyl piperidine compound |
Also Published As
Publication number | Publication date |
---|---|
US6476051B2 (en) | 2002-11-05 |
EP1242072A1 (en) | 2002-09-25 |
EP1242072A4 (en) | 2004-02-04 |
CA2394548A1 (en) | 2001-06-21 |
US20020072611A1 (en) | 2002-06-13 |
JP2003517481A (en) | 2003-05-27 |
AU3789901A (en) | 2001-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6476051B2 (en) | Antipsychotic heterocycle compounds | |
ES2286444T3 (en) | DERIVATIVES OF N-PHENYL (PIPERIDIN-2-IL) METHYLBENZAMIDE, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS. | |
KR100667645B1 (en) | Cyclic amine ccr3 antagonists | |
JP4597386B2 (en) | Piperidine-indole compounds having 5-HT6 affinity | |
JP3157839B2 (en) | Fused tropane derivatives, their production and use | |
HU218907B (en) | Process for producing pharmaceutical compositions containing tetrahydrocarbazole derivatives as active components and process for producing a group of the active ingredients | |
JP2000512296A (en) | Serotonin reuptake inhibition | |
EP0666258A1 (en) | Indolylcycloaklanylamin- und Indolylcycloalkenylamine derivatives, their preparation and their use as anti-migraine agents | |
WO2004037817A1 (en) | N-oxide compounds | |
JP2005537293A (en) | N- [phenyl (piperidin-2-yl) methyl] benzamide derivative, process for producing the same, and therapeutic use thereof | |
US6716837B1 (en) | Heterocyclic compounds for the treatment of migraine | |
HUT74096A (en) | 3-indolylpiperidine derivatives | |
TW201018467A (en) | Novel compounds as calcium channel blockers | |
US20090029979A1 (en) | 5-htx modulators | |
US20050148583A1 (en) | Phenoxyalkylamine derivatives useful as opioid delta receptor ligands | |
HU227799B1 (en) | N-acyl-2-substituted -4-(benzimidazolyl- or imidazopyridinyl-substituted residues)-piperidines as tachykinin antagonosts | |
US6225324B1 (en) | Antidepressant heterocyclic compounds | |
SK141998A3 (en) | Piperidines and pyrrolidines | |
JPH09500124A (en) | N- (piperidinyl-1-alkyl) -substituted cyclohexanecarboxylic acid amides as 5-HT1A receptor antagonists | |
CA2175498C (en) | Phenylindole compounds | |
JPH11116572A (en) | Fluoroindole compound useful for treating central nervous system disorder | |
EP1250336B1 (en) | Piperidine derivatives and their use as serotonin receptor antagonists | |
JPH09504272A (en) | Imidazolone and oxazolone derivatives as dopamine antagonists | |
JP2005082508A (en) | 2-alkoxy-6-amino-5-halogeno-n-(1-substituted-4-piperidinyl)pyridine-3-carboxamide derivative and pharmaceutical composition containing the same | |
EP1598068A1 (en) | Antipsychotic heterocycle compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ 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 NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN 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) | ||
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 544878 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 37899/01 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2394548 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000992008 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2000992008 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000992008 Country of ref document: EP |