WO2008055933A1 - 1,2,3-triazole derivatives as sigma receptor inhibitors - Google Patents
1,2,3-triazole derivatives as sigma receptor inhibitors Download PDFInfo
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- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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Definitions
- the present invention relates to compounds having pharmacological activity towards the sigma receptor, and more particularly to some 1,2,3-triazole derivatives, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and prophylaxis of a disease mediated by sigma receptor.
- sigma receptor a cell surface receptor of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids.
- CNS central nervous system
- sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355).
- the sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs.
- SKF 10047 has nanomolar affinity for the sigma 1 ( ⁇ -1) site, and has micromolar affinity for the sigma ( ⁇ -2) site.
- Haloperidol has similar affinities for both subtypes.
- Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them.
- Possible sigma- site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. ScL, 1992, 13:85-86).
- sigma binding sites are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. ScL, 1996, 93:8072-8077). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
- 1,2,3-triazole ring system has been the subject of considerable research mainly due to the pharmacological properties shown by some of its derivatives and also because of its usefulness in synthetic organic chemistry.
- 1,2,3-triazoles as antimicrobial agents, as potassium channel activators (Calderone, V. et al. Eur. J. Med. Chem., 2005, 40, 521-528).
- 1,2,3-Triazole derivatives of glycosyl and galactoside have been respectively described as glycosidase (Rossi, L. L. et al., Bioorg. Med. Chem.
- 1,2,3-triazole moiety has been identified as an effective replacement for a peptide group in HIV-I protease inhibitors (Brik, J. et al, Chembiochem, 2005, 6, 1167-1169). Concerning synthetic issues, 1,2,3- triazoles can be considered the ideal representatives of "click chemistry" (KoIb, C. et al., Angew. Chem. Int. Edit., 2001, 40, 2004-2021), and recently, 1,2,3-triazole has been used as a safer and practical alternative to cyanide in Bruylants reaction (Prashad M. et al., Tetrahedron Lett., 2005, 46, 5455-5458).
- the compounds present a 1,2,3-triazole group which are characterized by the substitution in the 2 position by an alkyl chain which ends in an amine type substituent.
- the invention is directed to a compound of the formula I:
- Ri is selected from hydrogen, Ci-C 6 alkyl and substituted or unsubstituted aryl
- R 2 and R 3 are independently selected from hydrogen and halogen;
- R 4 and R5 are independently selected from hydrogen, Ci-C 6 alkyl and cycloalkyl, or form, together with the nitrogen to which they are attached, a substituted or unsubstituted heterocyclyl group; with the proviso that R 4 and R 5 are not both hydrogen, n in an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, or a pharmaceutically acceptable salt, stereoisomer, prodrug or solvate thereof.
- Ri is hydrogen, Ci-C 3 alkyl, unsubstituted phenyl or a phenyl substituted by a C1-C3 alkyl, more preferably hydrogen, methyl, phenyl or 4-methyl-phenyl.
- R 2 and R 3 are independently selected from hydrogen and halogen, more preferably hydrogen and chloride. In another preferred embodiment one of R 2 and R3 is in the para position of the phenyl group.
- R 4 and R 5 form, together with the nitrogen to which they are attached, a substituted or unsubstituted heterocyclyl group, preferably selected from piperidine, piperazine, imidazole, pyrrolidine, morpholine and azepane.
- n is preferably 2, 3, 4, 5 or 6.
- the invention is directed to a process for the preparation of a compound of formula I or a salt, isomer, prodrug or solvate thereof.
- the invention is directed to a pharmaceutical composition which comprises a compound as defined above or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
- a pharmaceutical composition which comprises a compound as defined above or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
- the invention is directed to the compound of formula I as defined above for its use as a medicament.
- Another aspect of the invention is the use of a compound of formula I as defined above in the manufacture of a medicament for the treatment or prophylaxis of a sigma-1 receptor mediated disease or condition.
- the compound of formula I is used in the manufacture of a medicament for the treatment of diarrhoea, lipoprotein disorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including ***e, amphetamine, ethanol and nicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia; inflammation or autoimmune diseases.
- the medicament is for the treatment of pain, especially neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.
- the present invention refers to a compound of formula (I) as defined above for its use in the treatment of the diseases mentioned above.
- the invention relates to the use of a compound of formula (I) as defined above as pharmacological tool, as anxiolytic or as immunosuppressant.
- Ci-C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- Heterocyclyl refers to a substituted or unsubstituted stable 3-to 8-membered ring radical which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 4-to 7-membered ring with one or more heteroatoms, more preferably a 5, 6 or 7-membered ring with one or more heteroatoms. It may be partially of fully saturated or aromatic. Additionally, the heterocycle may be also monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized.
- heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, morpholine, pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
- the heterocyclyl group may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl such as benzyl.
- an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
- Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consists solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
- Aryl refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical.
- the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
- Halo refers to bromo, chloro, iodo or fluoro.
- Ri is hydrogen, C 1 -C 3 alkyl, unsubstituted phenyl or a phenyl substituted in para position by a C1-C3 alkyl, more preferably hydrogen, methyl, phenyl or 4-methyl-phenyl.
- R 2 and R 3 are independently selected from hydrogen and halogen, more preferably hydrogen and chloride. In another preferred embodiment one of R 2 and R3 is in the para position of the phenyl group.
- R 4 and R 5 form, together with the nitrogen to which they are attached, a substituted or unsubstituted heterocyclyl group, preferably selected from piperidine, piperazine, imidazole, pirrolidine, morpholine and azepane.
- n is 2, 3, 4, 5 or 6.
- Preferred compounds of formula I are the following: - l- ⁇ 3-[4-(4-chloro-phenyl)-5-phenyl-[l, 2, 3]triazol-2-yl]-propyl ⁇ -piperidine; - l-[3-[4-(p-chlorophenyl)-5-phenyl-([l,2,3]triazol-2-yl)propyl]-imidazole;
- Preferred salts of the compounds of formula I are the following:
- the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
- salts of compounds provided herein are synthesized from the parent compound which contains a basic moiety by conventional chemical methods.
- such salts are, for example, prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent or in a mixture of the two.
- nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
- acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
- mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
- organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
- Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
- prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides.
- the compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention.
- Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
- the compounds of formula I, their salts, isomers, prodrugs or solvates are preferably in pharmaceutically acceptable or substantially pure form.
- pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
- Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula I, or of its salts, isomers, solvates or prodrugs.
- the compounds of the present invention represented by the above described formula (I) may include enantiomers depending on the presence of quiral centres.
- the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
- a process to prepare the compounds of formula (I) or a salt, isomer, prodrug or solvate thereof comprises the alkylation reaction of a compound NHR 4 R 5 with a compound of formula (IV):
- Ri is selected from hydrogen, Ci-C 6 alkyl and substituted or unsubstituted aryl;
- R 2 and R 3 are independently selected from hydrogen and halogen
- R 4 and R 5 are independently selected from hydrogen, lower alkyl and cycloalkyl, or form, together with the nitrogen to which they are attached, a substituted or unsubstituted heterocyclyl group; and n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, with the proviso that R 4 and R 5 are not both hydrogen.
- This reaction takes place under basic conditions, for example in the presence of hydroxides such as potassium hydroxide, using a phase transfer catalyst, for example Bu 4 NBr.
- hydroxides such as potassium hydroxide
- a phase transfer catalyst for example Bu 4 NBr.
- M/-l,2,3-triazoles of formula (III) can be obtained by cycloaddition of tri-n- butyltin azide with mono- or disubstituted alkynes of formula (II):
- the mono- or di-substituted alkynes (II) used in this synthesis may be obtained from commercial sources or may be prepared from the corresponding iodobenzene and monosubstituted alkyne (J. F. Nguefack, V. Bolitt, D. Sinou, Tetrahedron Lett. 1996,
- One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
- the additional ionic and solvent moieties must also be non-toxic.
- the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
- Another aspect of this invention relates to a method of treating or preventing a sigma-1 receptor mediated disease which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
- sigma-1 mediated diseases that can be treated or prevented are diarrhoea, lipoprotein disorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including ***e, amphetamine, ethanol and nicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia; inflammation, autoimmune diseases, especially neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.
- the compounds of the invention can also be
- the present invention further provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
- pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
- the pharmaceutical compositions are in oral form, either solid or liquid.
- Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tab letting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
- binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
- fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol
- the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
- the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
- compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form.
- Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
- Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
- an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
- active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
- Step A A mixture of tri-w-butyltin azide (0.86 mL, 3.15 mmol) with the 4- chlorophenylethynylbenzene (3 mmol) was heated at 150 0 C for 70 h in a sealed glass bottle. The resulting solution was purified by column chromatography (eye lohexane/ AcOEt, 5:1) and recrystallized from (cyclohexane/ AcOEt) to give 4-(p- chlorophenyl)-5-phenyl-lH(2H)-[l,2,3]triazole as a white solid (413 mg, 54% yield); m.p. 124-126 0 C.
- Step B To a solution of 4-(/>chlorophenyl)-5-phenyl-lH(2H)-[l,2,3]triazole (0.16 mmol) in acetonitrile (3 mL) was added K 2 CO 3 (26 mg, 0.19 mmol) and Bu 4 NBr (5 mg, 0.02 mmol). The mixture was stirred for 1 h at reflux temperature. Then 1,3- dibromopropane (38 mg, 0.19 mmol) was added and the mixture was stirred at reflux for 10 min. The resulting solution was filtered and the remaining solid material was washed with Et 2 O (20 mL). Evaporation of the combined solutions afforded an oil residue.
- Step C 41-[3-[4-(p-chlorophenyl)-5-phenyl-(-[l,2,3]triazol-2-yl)]-3-bromopropane (26 mg, 0.07 mmol) and piperidine (9 mg, 0.10 mmol) were refluxed in ethanol for 1 h in presence of dry sodium carbonate ( 11 mg, 0.10 mmol). The reaction mixture was then filtrated.
- Example 16 l-[3-[4-(p-chlorophenyl)-5-phenyl-([l,2,3]triazol-2-yl)propyl]-(4- phenyl)piperidine (compound 16).
- Example 20 l-[3-[4-phenyl-([l,2,3]triazol-2-yl)propyl]-piperidine (compound 20).
- Example 24 l-[4-(4-phenyl-2H-[l,2,3]triazol-2-yl)-buty]-azepane (compound 24).
- Example 25 l-[3-(4-phenyl-2H-[l,2,3]triazol-2-yl)-propyl]-azepane (
- Example 26 4-[3-(4-phenyl-2H-l,2,3-triazol-2-yl)-propyl]-morpholine (compound 26).
- Example 28 l-[2-(4-phenyl-2H-[l,2,3]triazol-2-yl)-ethyl]-azepanium oxalate (compound 28). l-[2-(4-Phenyl-[l,2,3]triazol-2-yl)-ethyl]azepane (compound 22) (0.25 mmol) was dissolved in ether (0.5 mL) and mixed with a solution of oxalic acid (0.25 mmol) in AcOEt (0.1 mL) to give l-[2-(4-Phenyl-[l,2,3]triazol-2-yl)-ethyl]azepanium oxalate as a white precipitate which was filtered off and dried in vacuum.
- Example 29 cyclohexyl-[3-(4-phenyl-2H-l,2,3]triazol-2-yl)propyl]-ammonium oxalate (compound 29).
- Example 30 l-[4-(4-phenyl-2H-[l,2,3]triazol-2-yl)-butyl]-azepanium oxalate (compound 30).
- Example 31 l-[3-(4-phenyl-2H-[l,2,3]triazol-2-yl)-propyl]-azepanium oxalate (compound 31).
- Ci 9 H 26 N 4 O 4 x 2 H 2 O x 1 Z 2 C 2 H 2 O 4 (455.4): caldc. C 54.91, H 6.68, N 12.81; found C
- Example 32 4-[3-(4-phenyl-2H-[l,2,3]triazol-2-yl)-propyl]-morpholin-4-ium oxalate (compound 32).
- Brain membrane preparation and binding assays for the ⁇ l -receptor were performed as described (DeHaven-Hudkins et al., 1992) with some modifications.
- guinea pig brains were homogenized in 10 vols. (w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4, with a Kinematica Polytron PT 3000 at 15000 r.p.m. for 30 s.
- the homogenate was centrifuged at lOOOg for 10 min at 4 0 C and the supernatants collected and centrifuged again at 4800Og for 15 min at 4 0 C.
- the pellet was resuspended in 10 volumes of Tris-HCl buffer (50 mM, pH 7.4), incubated at 37 0 C for 30 min, and centrifuged at 4800Og for 20 min at 4 0 C. Following this, the pellet was resuspended in fresh Tris-HCl buffer (50 mM, pH 7.4) and stored on ice until use.
- Each assay tube contained 10 ⁇ L of [ 3 H](+)-pentazocine (final concentration of 0.5 nM), 900 ⁇ L of the tissue suspension to a final assay volume of 1 mL and a final tissue concentration of approximately 30 mg tissue net weight/mL.
- Non-specific binding was defined by addition of a final concentration of 1 ⁇ M haloperidol.
- All tubes were incubated at 37 0 C for 150 min before termination of the reaction by rapid filtration over Schleicher & Schuell GF 3362 glass fibre filters [previously soaked in a solution of 0,5% polyethylenimine for at least 1 h]. Filters were then washed with four times with 4 mL of cold Tris-HCl buffer (50 mM, pH 7.4).
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BRPI0718586-3A2A BRPI0718586A2 (en) | 2006-11-10 | 2007-11-07 | COMPOUND, PROCESS FOR PREPARATION, PHARMACEUTICAL COMPOSITION CONTAINING THEREOF, USES OF THIS AND METHOD OF TREATMENT OR PREVENTION OF DISEASES |
EP07822321A EP2097392B1 (en) | 2006-11-10 | 2007-11-07 | 1,2,3-triazole derivatives as sigma receptor inhibitors |
CA002668996A CA2668996A1 (en) | 2006-11-10 | 2007-11-07 | 1,2,3-triazole derivatives as sigma receptor inhibitors |
MX2009004745A MX2009004745A (en) | 2006-11-10 | 2007-11-07 | 1,2,3-triazole derivatives as sigma receptor inhibitors. |
JP2009535724A JP2010509281A (en) | 2006-11-10 | 2007-11-07 | 1,2,3-triazole derivatives as sigma receptor inhibitors |
US12/514,213 US8193223B2 (en) | 2006-11-10 | 2007-11-07 | 1,2,3-triazole derivatives as sigma receptor inhibitors |
ES07822321T ES2413559T3 (en) | 2006-11-10 | 2007-11-07 | 1,2,3-Triazole derivatives as sigma receptor inhibitors |
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EP2752411A1 (en) | 2013-01-07 | 2014-07-09 | Laboratorios Del Dr. Esteve, S.A. | 1,2,3-triazole-4-amine derivatives for the treatment of sigma receptor related diseases and disorders |
WO2014173903A1 (en) | 2013-04-23 | 2014-10-30 | Laboratorios Del Dr. Esteve, S.A. | PYRAZINO[1,2-a]INDOLE COMPOUNDS, THEIR PREPARATION AND USE IN MEDICAMENTS |
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US9963453B2 (en) | 2013-04-23 | 2018-05-08 | Laboratorios Del Dr. Esteve S.A. | Substituted pyrazino[1,2-a]indoles as sigma receptor activity modulators |
EP3893892A4 (en) * | 2018-12-12 | 2022-09-14 | Rutgers, the State University of New Jersey | Organic compounds |
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CN107406420B (en) | 2015-01-30 | 2020-11-06 | 纽罗克里生物科学有限公司 | Substituted triazoles and methods related thereto |
CN106866555B (en) * | 2017-02-08 | 2019-04-30 | 东南大学 | 1- benzhydryl -4- methyl piperazine class compound preparation method and application |
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WO2002036119A1 (en) * | 2000-11-02 | 2002-05-10 | K And K Biosciences, Inc. | Δ2,-1,2,3-triazoline anticonvulsants and their active metabolite analogues, the aminoalkylpyridines, are excitatory amino acid antagonists and antiischemic agents, useful in the treatment of cerebral ischemia resulting from stroke |
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WO1991009594A1 (en) | 1989-12-28 | 1991-07-11 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
AU2006311786A1 (en) * | 2005-11-04 | 2007-05-18 | Merck Sharp & Dohme Corp. | Diphenylmethane derivatives as inhibitors of leukotriene biosynthesis |
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- 2006-11-10 EP EP06380289A patent/EP1921071A1/en not_active Withdrawn
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Patent Citations (2)
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WO2002036119A1 (en) * | 2000-11-02 | 2002-05-10 | K And K Biosciences, Inc. | Δ2,-1,2,3-triazoline anticonvulsants and their active metabolite analogues, the aminoalkylpyridines, are excitatory amino acid antagonists and antiischemic agents, useful in the treatment of cerebral ischemia resulting from stroke |
US6638954B2 (en) * | 2000-11-02 | 2003-10-28 | K And K Biosciences, Inc. | Δ2-1,2,3-triazoline anticonvulsants and their active metabolite analogues, the aminoalkylpyridines, are excitatory amino acid antagonists and antiischemic agents, useful in the treatment of cerebral ischemia resulting from stroke |
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EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2752411A1 (en) | 2013-01-07 | 2014-07-09 | Laboratorios Del Dr. Esteve, S.A. | 1,2,3-triazole-4-amine derivatives for the treatment of sigma receptor related diseases and disorders |
WO2014106622A1 (en) | 2013-01-07 | 2014-07-10 | Laboratorios Del Dr. Esteve, S.A. | 1,2,3-triazole-4-amine derivatives for the treatment of sigma receptor related diseases and disorders |
WO2014173903A1 (en) | 2013-04-23 | 2014-10-30 | Laboratorios Del Dr. Esteve, S.A. | PYRAZINO[1,2-a]INDOLE COMPOUNDS, THEIR PREPARATION AND USE IN MEDICAMENTS |
US9879015B2 (en) | 2013-04-23 | 2018-01-30 | Laboratorios Del Dr. Esteve S.A. | Pyrazino[1,2-a]indole compounds, their preparation and use in medicaments |
US9963453B2 (en) | 2013-04-23 | 2018-05-08 | Laboratorios Del Dr. Esteve S.A. | Substituted pyrazino[1,2-a]indoles as sigma receptor activity modulators |
EP2832720A1 (en) | 2013-07-30 | 2015-02-04 | Laboratorios Del. Dr. Esteve, S.A. | 1,2-disubstituted cyclobutyl compounds |
US9464069B2 (en) | 2013-07-30 | 2016-10-11 | Laboratorios Del Dr. Esteve S.A. | 1,2-disubstituted cyclobutyl compounds |
EP3893892A4 (en) * | 2018-12-12 | 2022-09-14 | Rutgers, the State University of New Jersey | Organic compounds |
CN116178286A (en) * | 2021-11-26 | 2023-05-30 | 华东师范大学 | High-selectivity N 2 Alkyl substituted triazole derivative and synthetic method and application thereof |
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KR20090087032A (en) | 2009-08-14 |
ES2413559T3 (en) | 2013-07-16 |
MX2009004745A (en) | 2009-05-22 |
EP2097392B1 (en) | 2013-03-13 |
RU2009122198A (en) | 2010-12-20 |
US8193223B2 (en) | 2012-06-05 |
AU2007316606A1 (en) | 2008-05-15 |
US20100004265A1 (en) | 2010-01-07 |
BRPI0718586A2 (en) | 2014-03-11 |
EP2097392A1 (en) | 2009-09-09 |
JP2010509281A (en) | 2010-03-25 |
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CA2668996A1 (en) | 2008-05-15 |
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