WO2006010968A1 - New aryloxy acetic acid amide derivatives - Google Patents
New aryloxy acetic acid amide derivatives Download PDFInfo
- Publication number
- WO2006010968A1 WO2006010968A1 PCT/HU2005/000081 HU2005000081W WO2006010968A1 WO 2006010968 A1 WO2006010968 A1 WO 2006010968A1 HU 2005000081 W HU2005000081 W HU 2005000081W WO 2006010968 A1 WO2006010968 A1 WO 2006010968A1
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- group
- alkyl
- substituted
- formula
- phenyl
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- 229960004927 neomycin Drugs 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 230000002385 psychotomimetic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 210000001055 substantia gelatinosa Anatomy 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- 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 invention relates to new aryloxy acetic acid amide derivatives of formula (I)
- R and R are the same or different and can be hydrogen atom or
- N'-( C 1-4 alkyl)-ureido group C 1-6 alkoxy-carbonyl-amido or di-( Ci -4 alkyl)-amino group with the proviso that only one of them can be hydrogen atom, or R 1 and R 2 form together a -NH-CO-NH-, -NH-N CH- or -NH-CO-O- chain attached to two neighbouring carbon atoms of the benzyl group, R 3 and R 4 mean the same or different C 1-4 alkyl groups which are substituted by phenyl group, or R 3 and R 4 mean together a C 4-6 alkylene chain which can be interrupted optionally by a nitrogen atom and which can contain a C-C double bound and which C 4-6 alkylene chain can substituted by one or two substituents from the following hydroxy group, phenyl or phenoxy group optionally substituted by a C 1-4 alkyl or trifluoro methyl group,
- N-methyl-D-aspartate (NMDA) receptors are ligand-gated cation-channels embedded in the cell membranes of neurons. Overactivation of NMDA receptors by glutamate, their natural ligand, can lead to calcium overload of cells.
- Antagonists of the NMDA receptors may be used for treating many disorders that are accompanied with excess release of glutamate, the main excitatory neurotransmitter in the central nervous system.
- the knowledge on the NMDA receptor structure, function and pharmacology has expanded owing to recent achievements of the molecular biology.
- the NMDA receptors are heteromeric assemblies built up from at least one NRl subunit and at least one of the four different NR2 subunits . (NR2A-D). Both spatial distributions in the CNS and the pharmacological sensitivity of NMDA receptors built up from various NR2 subunits are different. Particularly interesting of these is the NR2B subunit due to its restricted distribution (highest densities in the forebrain and substantia gelatinosa of the spinal cord). Compounds selective for this subtype are available [Curr. Pharm.
- NR2B subtype selective antagonists of NMDA receptors are expected to possess little or no untoward side effects that are typically caused by the non-selective antagonists of NMDA receptors, namely psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria and disturbances of cognitive and motor function.
- NR2B subtype selective NMDA antagonism can be achieved with compounds that specifically bind to, and act on, an allosteric modulatory site of the NR2B subunit containing receptors.
- This binding site can be characterised by displacement (binding) studies with. specific radioligands, such as [125I]-ifenprodil [J.Neurochem., 61, 120-126 (1993)] or [3H]-Ro 25,6981 [J. Neurochem., 70, 2147-2155 (1998)]. Since ifenprodil was the first, though not sufficiently specific, known ligand of this receptor, it has also been termed ifenprodil binding site.
- the patent document WOOl/30330 discloses a method to treat pain utilizing 2- methyl- or -ethyl-piperidino-benzimidazole derivatives as NMDA NR2B antagonists.
- Aralkyl- and aralkenyl-piperidino-derivates are described as NMDA receptor antagonists in the published patent application WO99/48891.
- the published PCT application WO 99/21539 discloses a method for treating disease-related or drug-induced dyskinesias using NMDA receptor antagonists.
- the used compounds consist of a substituted piperidine ring and a substituted aryl or heteroaryl group, which are coupled by a (hetero) alkylene chain or a direct chemical bound.
- the new aryloxy acetic acid amide derivatives of formula (I) of the present invention are functional antagonists of NMDA receptors, which target the NMDA receptors primarily via binding to the ifenprodil binding site. Therefore, they are believed to be NR2B subtype specific antagonists.
- NR2B selectivity of our compounds we tested them on cell lines stably expressing recombinant NMDA receptors with subunit compositions of NRl(-3)/NR2A.
- cDNAs of human NRl(-3) and NR2A subunits subcloned into inducible mammalian expression vectors were introduced into HEK 293 cells lacking NMDA receptors using a cationic lipid-mediated transfection method [Biotechniques, 1997 May ;22(5),: 982-7; Neurochemistry International, 43j 19-29. (2003)].
- NMDA antagonist potency in vitro by measurement of intracellular calcium concentration with a plate reader fluorimeter in cells expressing recombinant NMDA receptors
- test compounds diluted in extracellular medium from a DMSO stock solution, final DMSO concentration was ⁇ 0.1%) were added to the cells.
- Cytosolic calcium measurements were carried out with a plate reader fluorimeter (Fluoroskan Ascent, Labsystems): after recording baseline fluorescence (5min.), elevation of [Ca 2+ ]i was induced by application of lOO ⁇ M NMDA and the fluorescence was recorded for an additional 5 min. Inhibitory potency of the test compounds was assessed by measuring the reduction in the calcium elevation in the presence of different concentrations of the compounds. AU treatments on a single plate were measured in multiple wells. The average value of all wells of a treatment was used for analysis.
- Dose-response curves and ICso-values were calculated by using data derived from at least three independent experiments. Inhibitory potency of a compound at a single concentration point was expressed as percent inhibition of the NMDA response. Sigmoidal concentration-inhibition curves were fit to the data and IC 50 values were determined as the concentration that produces half of the maximal inhibition caused by the compound.
- NMDA antagonists acting at NR2B site include schizophrenia, Parkinson's disease, Huntington's disease, excitotoxicity evoked by hypoxia and ischemia, seizure disorders, drug abuse, and pain, especially neuropathic, inflammatory and visceral pain of any origin [Eur. J. Pharmacol., 429, 71-78 (2001)].
- NR2B selective antagonists may have utility in diseases where NMDA antagonists may be effective, such as amyotrophic lateral sclerosis [Neurol. Res., 2I 1 309-12 (1999)], withdrawal syndromes of e.g. alcohol, opioids or cocaine [Drug and Alcohol Depend., 5S ) 1 1-15 (2000)], muscular spasms [Neurosci. Lett., 73J 1 143-148 (1987)], dementia of various origins [Expert Opin. Investig. Drugs, 9 j 1397-406 (2000)], anxiety, depression, migraine, hypoglycemia, degenerative disorders of the retina (e.g.
- effective amounts of the compounds of the invention may be beneficially used for the treatment of traumatic injury of brain or spinal cord, tolerance and/or dependence to opioid treatment of pain, withdrawal syndromes of drugs of abuse e.g. alcohol, opioids or cocaine, ischemic CNS disorders, chronic neurodegenerative disorders, such as e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, pain and chronic pain states, such as e.g. neuropathic pain.
- drugs of abuse e.g. alcohol, opioids or cocaine
- ischemic CNS disorders chronic neurodegenerative disorders, such as e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, pain and chronic pain states, such as e.g. neuropathic pain.
- the new aryloxy acetic acid amide derivatives of formula (I) - wherein the meaning of R , R , R and R are as defined in claim 1 - and/or their salts formed with organic or inorganic acids or bases and solvates of these compounds can be prepared by reacting an aryloxy acetic acid of formula (II)
- a preferably method is when the reactive derivative of the aryloxy acetic acid of formula (II) is formed in situ by using of a carbodiimide e.g. by using l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide (EDC) as carbodiimide.
- a carbodiimide e.g. by using l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide (EDC) as carbodiimide.
- 0.25 mmol of an aryloxy acetic acid of formula (II) is solved in 1 ml of dimethylformamide.
- 0.2 mmol of compound of formula (III) in 1 ml of dimethylformamide, 0.25 mmol of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) in 0.5 ml of dimethylformamide and 0.04 mmol of 4-(dimethylamino)pyridine in 0.5 ml of dichloromethane were added and the mixture was vigorously shaken for 12 hours.
- the mixture was diluted with 2 ml of dichloromethane, and extracted with 4 ml of IM HCl three times, 4 ml of water three times, 4 ml of 8 % NaHCO 3 three times and 4 ml of water three times.
- the organic solution was concentrated to yield the final product (I).
- the forming of salts can be performed by known methods, by treating the aryloxy acetic acid amide derivative of formula (I) with acids or bases. From an obtained salt the free aryloxy acetic acid amide derivative of formula (I) can be freed, too by using known methods.
- Characterization and Purification Methods Compounds of the present invention were characterized by high performance liquid chromatography coupled to mass selective detector (LC/MS) using HP 1100 Binary Gradient chromatography system with Microplate Sampler (Agilent, Waldbronn), controlled by ChemStation software. HP diode array detector was used to acquire UV spectra at 225 and 240 nm. All experiments were performed using HP MSD (Agilent, Waldbronn) single quadruple spectrometer equipped with an electrospray ionisation source to determine the structure.
- the A eluent was water containing 0.1% trifluoroacetic acid (TFA) (Sigma, Germany), the B eluent was 95% acetonitrile (Merck, Germany) containing 0.1% TFA and 5% A eluent. Gradient elution was used, starting with 100% A eluent and processing to 100% B eluent over a period of 5 minutes. Semipreparative separation of the compounds of the present invention - purity below
- ingredients 0.01-15 % of active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
- active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol
- a 5 % solution of mannitol or lactose is made with bidistilled water for injection use, and the solution is filtered so as to have sterile solution.
- a 0.01-5 % solution of the active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I) is also made with bidistilled water for injection use, and this solution is filtered so as to have sterile solution.
- These two solutions are mixed under aseptic conditions, filled in .1 ml portions into ampoules, the content of the ampoules is lyophilized, and the ampoules are sealed under nitrogen. The contents of the ampoules are dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HU0401526A HUP0401526A2 (en) | 2004-07-29 | 2004-07-29 | Aryloxy acetic acid amide derivatives, pharmaceutical compositions comprising thereof, methods for their preparation and their use |
HUP0401526 | 2004-07-29 |
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WO2006010968A1 true WO2006010968A1 (en) | 2006-02-02 |
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PCT/HU2005/000081 WO2006010968A1 (en) | 2004-07-29 | 2005-07-21 | New aryloxy acetic acid amide derivatives |
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WO (1) | WO2006010968A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006066948A1 (en) * | 2004-12-20 | 2006-06-29 | Schering Aktiengesellschaft | Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents |
WO2007099828A1 (en) | 2006-02-23 | 2007-09-07 | Shionogi & Co., Ltd. | Nirogenous heterocyclic derivatives substituted with cyclic groups |
WO2008046573A1 (en) * | 2006-10-16 | 2008-04-24 | Grünenthal GmbH | Substituted sulfonamide derivatives for use as bradykinin 1 receptor modulators |
JP2010520876A (en) * | 2007-03-09 | 2010-06-17 | アストラゼネカ・アクチエボラーグ | Piperazine and piperidine mGluR5 potentiator |
JP2010532382A (en) * | 2007-06-29 | 2010-10-07 | エモリー・ユニバーシテイ | NMDA receptor antagonist for neuroprotection |
JP2010535756A (en) * | 2007-08-08 | 2010-11-25 | グレースウェイ ファーマシューティカルズ,エルエルシー | Phenoxy-pyrrolidine derivatives and uses and compositions thereof |
JP2011520815A (en) * | 2008-05-09 | 2011-07-21 | エモリー・ユニバーシテイ | NMDA receptor antagonist for the treatment of neuropsychiatric disorders |
WO2020244460A1 (en) * | 2019-06-03 | 2020-12-10 | 杭州维坦医药科技有限公司 | Heteroaromatic acetamide derivative, and preparation and use thereof |
Citations (1)
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FR1571198A (en) * | 1967-06-28 | 1969-06-13 |
-
2004
- 2004-07-29 HU HU0401526A patent/HUP0401526A2/en unknown
-
2005
- 2005-07-21 WO PCT/HU2005/000081 patent/WO2006010968A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR1571198A (en) * | 1967-06-28 | 1969-06-13 |
Non-Patent Citations (2)
Title |
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DATABASE BEILSTEIN Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002356754, Database accession no. BRN 851696 * |
POPESCU, FARMACIA (BUCHAREST), vol. 15, 1967, pages 661 - 663 * |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006066948A1 (en) * | 2004-12-20 | 2006-06-29 | Schering Aktiengesellschaft | Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents |
US7935706B2 (en) | 2006-02-23 | 2011-05-03 | Shionogi & Co., Ltd. | Nitrogen-containing heterocycle derivatives substituted with cyclic group |
WO2007099828A1 (en) | 2006-02-23 | 2007-09-07 | Shionogi & Co., Ltd. | Nirogenous heterocyclic derivatives substituted with cyclic groups |
EP2520567A3 (en) * | 2006-02-23 | 2012-12-12 | Shionogi & Co., Ltd. | Nitrogen-containing heterocycle derivatives substituted with cyclic group |
JPWO2007099828A1 (en) * | 2006-02-23 | 2009-07-16 | 塩野義製薬株式会社 | Nitrogen-containing heterocyclic derivatives substituted with cyclic groups |
EP2520567A2 (en) * | 2006-02-23 | 2012-11-07 | Shionogi & Co., Ltd. | Nitrogen-containing heterocycle derivatives substituted with cyclic group |
JP2010506868A (en) * | 2006-10-16 | 2010-03-04 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Substituted sulfonamide derivatives as bradykinin 1 receptor modulators |
WO2008046573A1 (en) * | 2006-10-16 | 2008-04-24 | Grünenthal GmbH | Substituted sulfonamide derivatives for use as bradykinin 1 receptor modulators |
US8580965B2 (en) | 2006-10-16 | 2013-11-12 | Gruenenthal Gmbh | Substituted sulfonamide compounds |
JP2010520876A (en) * | 2007-03-09 | 2010-06-17 | アストラゼネカ・アクチエボラーグ | Piperazine and piperidine mGluR5 potentiator |
JP2010532382A (en) * | 2007-06-29 | 2010-10-07 | エモリー・ユニバーシテイ | NMDA receptor antagonist for neuroprotection |
US9079852B2 (en) | 2007-06-29 | 2015-07-14 | Emory University | NMDA receptor antagonists for neuroprotection |
JP2010535756A (en) * | 2007-08-08 | 2010-11-25 | グレースウェイ ファーマシューティカルズ,エルエルシー | Phenoxy-pyrrolidine derivatives and uses and compositions thereof |
JP2013100377A (en) * | 2007-08-08 | 2013-05-23 | Medicis Pharmaceutical Corp | Phenoxy-pyrrolidine derivative and its use and compositions |
JP2011520815A (en) * | 2008-05-09 | 2011-07-21 | エモリー・ユニバーシテイ | NMDA receptor antagonist for the treatment of neuropsychiatric disorders |
WO2020244460A1 (en) * | 2019-06-03 | 2020-12-10 | 杭州维坦医药科技有限公司 | Heteroaromatic acetamide derivative, and preparation and use thereof |
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HU0401526D0 (en) | 2004-09-28 |
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