WO2007014843A1 - 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor - Google Patents
2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor Download PDFInfo
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Definitions
- the present invention relates to compounds of formula I:
- R 1 is H, hydroxy, C 1-6 - alkoxy or NR a R b , wherein R a and R b are independently H or C 1- 6 -alkyl;
- R 2 is H, hydroxy or F; or R 1 and R 2 are together -O- or -NH- thereby forming a 5-membered heterocyclic ring with the carbon atoms to which they are attached; R 3 is t-butyl, 1,1-dimethylpropyl or aryl; R 4 is H;
- R 5 is C 1-6 - alkyl or C 1-6 -haloalkyl
- R 6 is H, hydroxy or C 1-6 - alkyl; as well as optical isomers and pharmaceutically acceptable salts thereof, except for (RS)-
- the compounds of formula I and their salts are distinguished by valuable therapeutic properties. It has been found that the compounds are active on the GABA B receptor.
- GABA ⁇ -Aminobutyric acid
- GABA the most abundant inhibitory neurotransmitter, activates both ionotropic GABA A/C and metabotropic GABA B receptors (Hill and Bowery, Nature, 290, 149-152, 1981).
- GABA B receptors that are present in most regions of the mammalian brain on presynaptic terminals and postsynaptic neurons are involved in the fine-tuning of inhibitory synaptic transmission. Presynaptic GABA B receptors through modulation of high- voltage activated Ca 2+ channels (P/Q- and N- type) inhibit the release of many neurotransmitters.
- GABA B receptor activates G-protein coupled inwardly rectifying K+ (GIRK) channel and regulates adenylyl cyclase (Billinton et ah, Trends Neuros ⁇ ., 24, 277-282, 2001; Bowery et al, Pharmacol. Rev,. 54, 247-264, 2002). Because the GABA B receptors are strategically located to modulate the activity of various neurotransmitter systems, GABA B receptor ligands hence could have potential therapeutics in the treatment of anxiety, depression, epilepsy, schizophrenia and cognitive disorders (Vacher and Bettler, Curr. Drug Target, CNS Neurol. Disord. 2, 248- 259, 2003; Bettler et al, Physiol Rev.
- GABA B receptor ligands might also have potential therapeutic application in the peripheral nervous system.
- GABA B receptors are heteromeric structures composed of two types of subunits, GABA B RI and GABA B R2 subunits (Kaupmann et al, Nature, 386, 239-246, 1997; Nature, 396, 683-687, 1998).
- the structures of GABA B RI and R2 show that they belong to a family of G-protein coupled receptors (GPCRs) called family 3.
- GPCRs G-protein coupled receptors
- Other members of the family 3 GPCRs include the metabotropic glutamate (mGlul-8), calcium- sen sing, vomeronasal, pheromone and putative taste receptors (Pin et al, Pharmaco.. Ther. 98, 325-354, 2003).
- the family 3 receptors are characterized by two distinctly separated topological domains: an exceptionally long extracellular amino -terminal domain (ATD, 500-600 amino acids), which contains a venus flytrap module for the agonist binding (orthosteric site) (Galvez et al, J. Biol. Chem., 275, 41166-41174, 2000) and the 7TM helical segments plus intracellular carboxyl- terminal domain that is involved in receptor activation and G-protein coupling.
- ATD extracellular amino -terminal domain
- 6 venus flytrap module for the agonist binding (orthosteric site)
- 7TM helical segments plus intracellular carboxyl- terminal domain that is involved in receptor activation and G-protein coupling.
- the mechanism of receptor activation by agonist in GABA B R1R2 heterodimer is unique among the GPCRs.
- GABA B RI subunit binds to GABA, while the GABA B R2 is responsible for coupling and activation of G-protein (Havlickova et al, MoI Pharmacol. 62, 343-350, 2002; Kniazator al,J. Neuros ⁇ ., 22, 7352-7361, 2002).
- GABA B RI KO mice were more anxious in two anxiety paradigm, namely the light-dark box (decreased time in light) and staircase tests (decreased rears and steps climbed). They showed a clear impairment of passive avoidance performance model indicating impaired memory processes.
- the GABA B RI KO also displayed increased hyperlocomotion and hyperactivity in new environment. Gassmann et al, JNeurosci. 24, 6086-6097, 2004 has shown that GABA ⁇ R2KO mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity and severe memory impairment, comparable to GABA B RIKO mice.
- GABA ⁇ R2KO mice Moreover, altered anxiety and depression behavior was observed in GABA ⁇ R2KO mice (Mombereau et al, Neuroreport, 16, 307-310, 2005) Therefore, heteromeric GABA B R1R2 receptors are responsible for these phenotypes.
- the GABA B RI gene is mapped to chromosome 6p21.3, which is within the HLA class I, a region with linkage for schizophrenia, epilepsy and dyslexia (Peters et al, Neurogenetics, 2, 47-54, 1998).
- SNPs Five single nucleotide polymorphisms (SNPs); the A-7265G (promoter region), C10497G (intron 9), Ser-491-Ser (T to C, exon 12), Phe-659-Phe (A to G, exon 16) and A33795G (3'-UTR) have been found in the GABA B RI gene.
- the association of A-7265G polymorphism of GABA B RI gene with schizophrenia Zai et al, Eur Neuropsychopharmacol 15, 347-52, 2005
- OCD Obsessive-compulsive disorder
- Psychiatry 146, 353-356, 1989.
- baclofen was found to be an effective and well-tolerated treatment. It resulted in significant improvements in the overall symptoms of PTSD, most notably the avoidance, emotional numbing and hyperarousal symptoms and also in reduced accompanying anxiety and depression (Drake et al, Ann. Pharmacother. 37, 1177-1181, 2003).
- baclofen was able to reverse the reduction in prepulse inhibition (PPI) of the acoustic startle response induced by dizocilpine, but not by apomorphine in rat PPI model of psychosis (Bortolato et al, Psychopharmacology, 171, 322-330, 2004). Therefore, GABA B - A - receptor agonist has a potential in the pharmacological therapy of psychotic disorders.
- PPI prepulse inhibition
- GABA B receptor agonist for bladder dysfunction, intestinal and pulmonary disorders such as overactive bladder (bladder function is under tonic GABA B control), gastroesophageal reflux disease and heartburn, cough and asthma (Bolser et al, Br J Pharmacol, 113, 1344-1348, 1994; Dicpinigaitis et al, J Clin Pharmacol, 38, 364-367, 1998; Dicpinigaitis et al, Arch Phys Med Rehabil, 81, 921-923, 2000; Cange et al, Aliment Pharmacol Ther, 16, 869-873, 2002; Lehmann et al, Eur J Pharmacol, 448, 67-70, 2002;Pehrson et al, J Urol, 168, 2700-2705, 2002; Sanger et al, Auton Autacoid Pharmacol, 22, 147-154, 2002; Symond
- GABA B receptor ligands called positive allosteric modulators, CGP7930 [2,6-di-tert- butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] and its aldehyde analogue CGP13501.
- CGP7930 2,6-di-tert- butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol
- CGP13501 aldehyde analogue
- GABA B enhancers have no effect on receptor activity in the absence of GABA, but do enhance allosterically the affinity of the GABA B receptor for the endogenous GABA, it is expected that these ligands should have an improved side effect profile as compared to baclofen. Indeed, GS39783 at 0.1-200 mg/kg, PO had no effect on spontaneous locomotor activity, rotarod, body temperature and traction test in comparison to baclofen, which showed these side effects at 2.5-15 mg/kg, PO. GS39783 did not have any effect on cognition performance as assessed by passive avoidance behavioral test in mice and rats.
- GS39783 exhibited anxiolytic- like effects in the elevated plus maze (rat), elevated zero maze (mice and rats), and the stress- induced hyperthermia (mice) test paradigms. Therefore, GS39783 represents a novel anxiolytic without side-effects associated with baclofen or benzodiazepines ⁇ Cry an et al, J Pharmacol Exp Then, 310, 952-963, 2004). The preclinical investigation with the CGP7930 and GS39783 has shown that both compounds were effective at decreasing cocaine self- administration in rats ⁇ Smith et al, Psychopharmacology, 173, 105-111, 2004).
- CGP7930 has also been preclinically studied for the treatment of Gastro- Esophageal Reflux Disease (GERD) and was found to be effective (WO 03/090731, use of GABA B receptor positive modulators in gastro-intestinal disorders).
- GABA B receptor positive modulators in gastro-intestinal disorders.
- mGlu2 receptor [LY487379, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2- trifluoroethylsulfonyl)-pyrid-3-ylmethylamine and its analogs] (WO 01/56990, Potentiators of glutamate receptors) and mGlu5 receptor (CPPHA, N- ⁇ 4-chloro-2-[(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl] phenyl ⁇ -2-hydroxybenzamide) (O'Brien et al, J. Pharmaco. Exp.
- Dyachenko, V. I et al. in Steric effects of ortho substituents in reactions of phenols and phenolates with polyfluoro ketones, Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1989), (4), 923-8 already disclosed (RS)-5,l-O ⁇ -tert-hu ⁇ .y ⁇ -?>-hy ⁇ xoxy-?>- trifluoromethyl-3H-benzofuran-2-one. Nevertheless Dyachenko, V. I et al. belongs to pure chemistry literature and neither teach nor suggests that said compound may have an activity at the GABA- B receptor.
- Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable acid addition salts thereof.
- a further object of the invention is the use of the compound of formula I or of (i?5)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one and acceptable acid addition salts thereof for the manufacture of such medicaments useful in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, such as anxiety, depression, epilepsy, schizophrenia, cognitive disorders, spasticity and skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, neuropathic pain and craving associated with cocaine and nicotine, psychosis, panic disorder, posttraumatic stress disorders, for bladder dysfunction, intestinal and pulmonary disorders such as overactive bladder, gastroesophageal reflux disease and heartburn, cough and asthma.
- illnesses and disorders of the kind referred to earlier such as anxiety, depression, epilepsy, schizophrenia, cognitive disorders, spasticity and skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral
- aryl means a monovalent cyclic aromatic hydrocarbon moiety selected from optionally substituted phenyl or naphthyl. Substituents for aryl include but are not limited to halo, hydroxy, Ci- ⁇ -alkyl, Q- ⁇ -alkoxy, Q- ⁇ -haloalkyl, C 1-7 - haloalkoxy as well as those groups specifically illustrated by the examples herein below with the examples.
- Ci- ⁇ -alkyl denotes a straight- or branched-carbon chain group containing from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of such groups are are methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl as well as those specifically illustrated by the examples herein below.
- Ci- ⁇ -haloalkyl denotes a C 1-6 - alkyl group as defined above which is substituted by one or more halogen.
- Q- ⁇ -haloalkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as well as those groups specifically illustrated by the examples herein below.
- Preferred Ci- ⁇ -haloalkyl are difluoro- or trifluoro- methyl or ethyl.
- Ci-o-alkoxy denotes a group wherein the alkyl group is as defined above and the alkyl group is connected via an oxygen atom.
- Preferred Q- ⁇ -alkoxy are MeO- and Et-O as well as those groups specifically illustrated by the examples herein below.
- Hydrox denotes one, two or three -OH group(s).
- R 1 and R 2 are together -O- or -NH- thereby forming a 5- membered heterocyclic ring with the carbon atoms to which they are attached" means either one of the groups of the following formula:
- pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, which include but are not limited to hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid.
- the compounds according to the invention are those compounds of formula I wherein: R 1 is H, hydroxy, Q- ⁇ -alkoxy or NR a R b , wherein R a and R b are independently H or C 1- 6 - alkyl;
- R 2 is H, hydroxy or F
- R 3 is t-butyl, 1,1-dimethylpropyl or aryl
- R 4 is H;
- R 5 is C 1-6 - alkyl or C 1-6 -haloalkyl;
- R 6 is H, hydroxy or C 1-6 - alkyl; as well as optical isomers and pharmaceutically acceptable salts thereof, for example the following compounds:
- R 3 is tt--1butyl, 1,1-dimethylpropyl or aryl
- R 4 is H
- R is Ci- 6 - alkyl or Ci- ⁇ -haloalkyl
- R 6 is H, hydroxy or C 1-6 - alkyl; as well as optical isomers and pharmaceutically acceptable salts thereof, except for (RS)- 5,7-Di-ter?-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one, for example the following compounds:
- R 3 is tt--1butyl, 1,1-dimethylpropyl or aryl
- R 4 is ⁇
- R is C 1 - O - alkyl or Ci- ⁇ -haloalkyl; R 6 is H, hydroxy or Ci- ⁇ -alkyl; as well as optical isomers and pharmaceutically acceptable salts thereof, for example
- the invention also encompasses processes for the preparation of the compounds of the invention as follows:
- the process of the invention for preparing compounds of formula I comprises the step of reacting a compound of formula II
- the process of the invention for preparing compounds of formula I comprises the step of reacting a compound of formula III
- the process of the invention for preparing compounds of formula I-a comprises the cyclization reaction of a compound of formula I:
- R 1 is Q- ⁇ -alkoxy and R 2 is OH, into a compound of formula I- a, wherein R 2 to R 6 are as defined hereinabove.
- the process of the invention for preparing compounds of formula I comprises the step of hydrolyzing the R 1 moiety which is a Q- ⁇ -alkoxy in a compound of formula I:
- the invention also encompasses a compound of formula I, I-a or I-b, whenever it is prepared according to the above-mentioned process.
- the ester was readily hydrolyzed with aqueous 1 N NaOH in dioxane at ambient temperature.
- the compounds of formula I, I-a and I-b and their pharmaceutically acceptable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention have an affinity to the GABA B receptor. The compounds were investigated in accordance with the tests given hereinafter.
- the Chinese Hamster Ovary (CHO) cells stably expressing human GABA ⁇ RlaR2a and G ⁇ l6 were seeded at 5xlO 4 cells/well in the poly-D-lysine treated, 96- well, black/clear-bottomed plates (BD Biosciences, Palo Alto, CA). 24 h later, the cells were loaded for 90 min at 37 0 C with 4 ⁇ M Flou-4 acetoxymethyl ester (Catalog No. F- 14202, Molecular Probes, Eugene, OR) in loading buffer (IxHBSS, 20 mM HEPES, 2.5 mM Probenecid). Hanks' Balanced Salt Solution (HBSS) (10X) (catalog No.
- HBSS Hanks' Balanced Salt Solution
- the enhancers were applied 15 min before the application of the GABA
- concentration-response curves of GABA (0.0003-30 ⁇ M) were determined in the absence and presence of 10 ⁇ M enhancer.
- the GABA-shift is defined as Log [EC 50 (GABA + 10 ⁇ M enhancer) / EC 50 (GABA alone)] .
- the % maximum enhancing effect (% Em 11x ) and potency (EC 5 o value) of each enhancer was determined from concentration-response curve of the enhancer (0.001-30 ⁇ M) in the presence of 10 nM GABA (EQo).
- the compounds of formula I, I-a and Ib as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
- the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- the compounds of formula I, I-a and I-b and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
- Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols.
- Suitable excipients for the manufacture of solutions and syrups include but are not limited to water, polyols, saccharose, invert sugar, glucose.
- Suitable excipients for injection solutions include but are not limited to water, alcohols, polyols, glycerol, vegetable oils.
- Suitable excipients for suppositories include but are not limited to natural or hardened oils, waxes, fats, semi- liquid or liquid polyols.
- the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
- a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
- 2,4-Di-t ⁇ t-butylphenol (28 g, 28.5 mmol) was dissolved in tetrahydrofuran (250 mL) under argon and cooled to -70°. A 1.6 M solution of butyllithium in hexane (85 mL, 135.7 mmol) was added and the solution was allowed to reach 20° C. Tetrahydrofuran was distilled off and replaced by 1,2-dichloroethane (250 mL), which was distilled off again and replaced with 1,2-dichloroethane (250 mL).
- the crude product was purified by chromatography on silica gel in heptane/ dichloromethane 2:1.
- the purified product (37 g) was recrystallized from cold heptane (150 mL), and dried at 50 0 C/ 1 mbar for 5 h.
- MS: m/z 330 (M).
- Example 11 (/?,5)-5,7-Bis-(l, l-dimethyl-propyl)-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one 2,4-Di-t ⁇ t-pentylphenol (2.37 g, 10 mmol) was dissolved under nitrogen atmosphere in 1,2-dichloroethane (50 mL) and cooled in ice. Then sodium trimethylsilanolate (1.134 g, 10 mmol) was added (not exothermic), and stirring without cooling was continued for Ih.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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BRPI0614920-0A BRPI0614920A2 (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with gaba-b-receptor affinity |
DE602006016817T DE602006016817D1 (en) | 2005-07-28 | 2006-07-18 | 2-HYDROXY-PROPIONIC DERIVATIVES AND 3-HYDROXY-BENZOFURAN-2-ON DERIVATIVES WITH AFFINITY FOR THE GABA-B RECEPTOR |
MX2008001200A MX2008001200A (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-o ne derivatives with affinity for the gaba-b-receptor. |
JP2008523313A JP2009502856A (en) | 2005-07-28 | 2006-07-18 | 2-Hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives having affinity for GABA-B-receptors |
CA002616685A CA2616685A1 (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor |
EP06792512A EP1915357B1 (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor |
AU2006274963A AU2006274963A1 (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the GABA-B-receptor |
AT06792512T ATE480529T1 (en) | 2005-07-28 | 2006-07-18 | 2-HYDROXY-PROPIONIC ACID DERIVATIVES AND 3-HYDROXY-BENZOFURAN-2-ONE DERIVATIVES WITH AFFINITY FOR THE GABA-B RECEPTOR |
IL188917A IL188917A0 (en) | 2005-07-28 | 2008-01-21 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor |
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EP05106979 | 2005-07-28 | ||
EP05106979.7 | 2005-07-28 |
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PCT/EP2006/064347 WO2007014843A1 (en) | 2005-07-28 | 2006-07-18 | 2-hydroxy-propionic acid derivatives and 3-hydroxy-benzofuran-2-one derivatives with affinity for the gaba-b-receptor |
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US (2) | US7396853B2 (en) |
EP (1) | EP1915357B1 (en) |
JP (1) | JP2009502856A (en) |
KR (1) | KR100959429B1 (en) |
CN (1) | CN101268062A (en) |
AT (1) | ATE480529T1 (en) |
AU (1) | AU2006274963A1 (en) |
BR (1) | BRPI0614920A2 (en) |
CA (1) | CA2616685A1 (en) |
DE (1) | DE602006016817D1 (en) |
ES (1) | ES2349310T3 (en) |
IL (1) | IL188917A0 (en) |
MX (1) | MX2008001200A (en) |
WO (1) | WO2007014843A1 (en) |
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WO2015169999A1 (en) | 2014-05-09 | 2015-11-12 | Orion Corporation | Pharmacologically active quinazolinedione derivatives |
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WO2020048826A1 (en) | 2018-09-03 | 2020-03-12 | Bayer Aktiengesellschaft | 5-substituted 1-oxa-3,9-diazaspiro[5.5]undecan-2-one compounds |
CN117794905A (en) * | 2021-08-06 | 2024-03-29 | 上海枢境生物科技有限公司 | Benzo ring-containing derivative, and preparation method and application thereof |
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EP0825193A1 (en) * | 1993-10-27 | 1998-02-25 | Neurogen Corporation | Certain fused pyrrolecarboxanilides; a new class of gaba brain receptor ligands |
WO2002083133A1 (en) * | 2001-04-16 | 2002-10-24 | University Of Virginia Patent Foundation | Novel oral general anesthetics and metabolitically resistant anticonvulsants |
WO2005026208A2 (en) * | 2003-09-12 | 2005-03-24 | Janssen Pharmaceutica N.V. | Chimeric gabab receptor |
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WO1999041229A1 (en) * | 1998-02-11 | 1999-08-19 | Guillermo Carvajal Sandoval | Halogenated phenyl alcohol amides (ligands of gabab receptor) having an anticonvulsant activity |
EP1255735A2 (en) | 2000-02-03 | 2002-11-13 | Eli Lilly And Company | Pyridine derivatives as potentiators of glutamate receptors |
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2006
- 2006-07-18 CN CNA2006800348761A patent/CN101268062A/en active Pending
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- 2006-07-18 EP EP06792512A patent/EP1915357B1/en not_active Not-in-force
- 2006-07-18 DE DE602006016817T patent/DE602006016817D1/en active Active
- 2006-07-18 WO PCT/EP2006/064347 patent/WO2007014843A1/en active Application Filing
- 2006-07-18 AT AT06792512T patent/ATE480529T1/en active
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- 2006-07-18 KR KR1020087004255A patent/KR100959429B1/en not_active IP Right Cessation
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EP0825193A1 (en) * | 1993-10-27 | 1998-02-25 | Neurogen Corporation | Certain fused pyrrolecarboxanilides; a new class of gaba brain receptor ligands |
WO2002083133A1 (en) * | 2001-04-16 | 2002-10-24 | University Of Virginia Patent Foundation | Novel oral general anesthetics and metabolitically resistant anticonvulsants |
WO2005026208A2 (en) * | 2003-09-12 | 2005-03-24 | Janssen Pharmaceutica N.V. | Chimeric gabab receptor |
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Cited By (1)
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WO2015169999A1 (en) | 2014-05-09 | 2015-11-12 | Orion Corporation | Pharmacologically active quinazolinedione derivatives |
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MX2008001200A (en) | 2008-03-18 |
KR20080027960A (en) | 2008-03-28 |
ATE480529T1 (en) | 2010-09-15 |
US20070027204A1 (en) | 2007-02-01 |
CA2616685A1 (en) | 2007-02-08 |
AU2006274963A1 (en) | 2007-02-08 |
CN101268062A (en) | 2008-09-17 |
JP2009502856A (en) | 2009-01-29 |
US20080234356A1 (en) | 2008-09-25 |
IL188917A0 (en) | 2008-04-13 |
EP1915357B1 (en) | 2010-09-08 |
KR100959429B1 (en) | 2010-05-25 |
US7504428B2 (en) | 2009-03-17 |
EP1915357A1 (en) | 2008-04-30 |
DE602006016817D1 (en) | 2010-10-21 |
ES2349310T3 (en) | 2010-12-29 |
BRPI0614920A2 (en) | 2011-04-19 |
US7396853B2 (en) | 2008-07-08 |
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