WO2005035522A1 - 1-‘2-(4-hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists - Google Patents
1-‘2-(4-hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists Download PDFInfo
- Publication number
- WO2005035522A1 WO2005035522A1 PCT/IB2004/003127 IB2004003127W WO2005035522A1 WO 2005035522 A1 WO2005035522 A1 WO 2005035522A1 IB 2004003127 W IB2004003127 W IB 2004003127W WO 2005035522 A1 WO2005035522 A1 WO 2005035522A1
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- WO
- WIPO (PCT)
- Prior art keywords
- piperidin
- hydroxy
- group
- ethyl
- hydroxyphenyl
- Prior art date
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Classifications
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- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Definitions
- This invention relates to novel 3,4-dihydroquinolin-2(7H)-one compounds. These compounds are useful as antagonists of NMDA (N-methyl-D-aspartate) NR2B receptor, and are thus useful for the treatment of pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety, migraine, or the like in mammalian, especially humans.
- the present invention also relates to a 10 pharmaceutical composition comprising the above compounds.
- Background Art Glutamate plays dual role in the central nervous system (CNS) as essential amino acid and the principal excitatory neurotransmitters.
- NMDA N-methyl-aspartate
- AMP A 2-amino-3-(methyl- 15 3-hydroxyisoxazol-4-yl)propionic acid
- kainate a class of receptors
- hyperalgesia and allodynia following peripheral tissue or nerve injury is not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depends on NMDA receptor-mediated central changes in synaptic excitability.
- NMDA 20 receptor antagonists have also been found to decrease both pain perception and sensitization.
- NMDA receptor inhibition has therapeutic utility in the treatment of pain and neurodegenerative diseases, there are significant 25 liabilities to many available NMDA receptor antagonists that can cause potentially serious side effects.
- NMDA subunits are differentially distributed in the CNS.
- NR2B is believed to be restricted to the forebrain and laminas I and LI of the dosal horn. The more discrete distribution of NR2B subunit in the CNS may support a reduced side-effect profile of agents that act selectively at this site.
- NMDA NR2B selective antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in human with a reduced side-effect profile than existing NMDA antagonists (S. Boyce, et al., Neuropharmacology, 38, pp.611-623 (1999)).
- International Publication Number WO 96/06081 discloses a variety of phenol compounds. Especially, a compound represented by the following formula is disclosed in it:
- HERG human ether-a-go-go related gene
- QT prolongation is known to have a potential liability to produce fatal cardiac arrhythmias of Torsades de Pointes (TdP) .
- TdP Torsades de Pointes
- the ability to prolong the cardiac action potential duration was identified as being due to an action at the HERG potassium channel.
- drugs withdrawn from the market due to QT prolongation such as Cisapride and Terfenadine, are known to be potent HERG potassium channel blocker (Expert Opinion of Pharmacotherapy.; 2, pp947-973, 2000).
- NMDA NR2B selective antagonists with analgesic activity by systemic administration and with reduced inhibitory activity at HERG potassium channel are NMDA NR2B selective antagonists with analgesic activity by systemic administration and with reduced inhibitory activity at HERG channel.
- Inhibitory activity at HERG channel was estimated from affinity for HERG type potassium channel was investigated by checking [ HJdofetilide binding, which can predict inhibitory activity at HERG channel (Eur. J. Pharmacol., 430, ppl47-148, 2001).
- the compounds of the present invention show a reduced QT prolongation by removing a methyl group from the carbon atom adjacent to nitrogen atom on piperidine ring of the formula (I).
- the present invention provides a compound of the following formula (I):
- R* and R2 independently represents a hydrogen atom, a halogen atom or an alkyl group having from 1 to 6 carbon atoms;
- R3 represents an aryl group having from 6 to 10 ring carbon atoms or a heteroaryl group having from 5 to 10 ring atoms which consists of from 1 to 4 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms; said aryl groups having from 6 to 10 ring carbon atoms and said heteroaryl groups having from 5 to 10 atoms are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents ⁇ ; said substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms or alkoxyalkyl groups having from 1 to 6 carbon atoms; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.
- the phenol compounds of this invention have an antagonistic action towards NMDA NR2B receptor subtype selectively and are thus useful in therapeutics, particularly for the treatment of stroke or brain injury, chronic neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis (ALS), epilepsy, convulsive disorder, pain, anxiety, human immunodeficiency virus (HIV) related neuronal injury, migraine, depression, schizophrenia, tumor, post-anesthesia cognitive decline (PACD), glaucoma, tinnitus, tradive dyskinesia, allergic encephalomyelitis, opioid tolerance, drug abuse, alcohol abuse, Irritable bowel syndrome (IBS), or the like in mammalian, especially humans.
- chronic neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis (ALS), epilepsy, convulsive disorder, pain, anxiety, human immunodeficiency virus (HI
- the compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain.
- Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
- the system operates through a specific set of primary sensory neurons and is exclusively activated by noxious stimuli via peripheral transducing mechanisms (Millan 1999 Prog. Neurobio. 57: 1-164 for an integrative Review).
- These sensory fibres are known as nociceptors and are characterized by small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus.
- nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
- A-delta fibres myelinated
- C fibres non-myelinated.
- the activity generated by nociceptor input is transferred after complex processing in the dorsal horn, either directly or via brain stem relay nuclei to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
- Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states.
- Pain tend to be quite heterogeneous and may present with various pain symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies. Therefore pain can be divided into a number of different areas because of differing pathophysiology, these include nociceptive, inflammatory, neuropathic pain etc.
- Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitise the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of nociceptors activates two types of afferent nerve fibres.
- Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic.
- cancer related acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy.
- Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumour related pain, (e.g.
- Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (LASP definition). Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies.
- Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp.
- IBD inflammatory bowel diseases
- Other types of pain include but are not limited to; - Musculo-skeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non- articular rheumatism, dystrophinopathy, Glycogenolysis, polymyositis, pyomyositis.
- - Central pain or 'thalamic pain' as defined by pain caused by lesion or dysfunction of the nervous system including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy.
- - Heart and vascular pain including but not limited to angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, scleredoma, skeletal muscle ischemia.
- Visceral pain and gastrointestinal disorders.
- the viscera encompasses the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system.
- GI disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including - for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
- the present invention provides a pharmaceutical composition for the treatment of disease conditions caused by overactivation of NMDA NR2B receptor, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Further, the present invention also provides a composition which comprises a therapeutically effective amount of the cycloalkylene amide compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier. Among them, the composition is preferably for the treatment of disease defined above.
- the present invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof, as a medicament. Also, the present invention provides a method for the treatment of disease conditions defined above, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Further, the present invention provides a method for the treatment of disease conditions defined above in a mammal, preferably human, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Yet further, the present invention provides the use of a therapeutically effective amount of a compound of formula (I) in the manufacture of a medicament for the treatment of the disease conditions defined above.
- halogen means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
- alkyl means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, wopropyl, n-butyl, iso- butyl, secondary-butyl, tertiary-butyl.
- alkoxy means alkyl-O-, including, but not limited to methoxy, ethoxy, n-propoxy, zs ⁇ propoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy.
- alkoxyalkyl means alkyl-O-alkyl, including, but not limited to methoxymethyl, methoxyethyl, methoxypropyl, methoxbutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxbutyl, n-propoxymethyl, n- propoxyethyl, n-propoxypropyl, n-propoxybutyl, zsopropoxymethyl, z-ropropoxyethyl, zs ⁇ propoxypropyl, z ' sopropoxybutyl, n-butoxymethyl, n-butoxyethyl, n-butoxypropyl, wo-butoxymethyl, /so-butoxyethyl, zso-butoxypropyl, wo-butoxybutyl, secondary- butoxymethyl, sec ⁇ J ry-butoxyethyl, sec ⁇ nJ ⁇ ry
- aryl means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 10 carbon atoms, including, but not limited to, phenyl or naphtyl, preferably phenyl.
- heteroaryl means a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic ring which consists of from 1 to 4 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, quinolyl
- ordinary protecting group means a protecting group, which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
- esters means a protecting group which can be cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. Whether a compound is such a derivative or not can be determined by administering it by intravenous injection to an experimental animal, such as a rat or mouse, and then studying the body fluids of the animal to determine whether or not the compound or a pharmaceutically acceptable salt thereof can be detected.
- groups for an ester of a hydroxy group include: lower aliphatic alkanoyl groups, for example: alkanoyl groups, such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7- dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexade
- treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
- treatment refers to the act of treating, as “treating” is defined immediately above.
- a preferred compound of formula (I) of this invention is that wherein Ri and
- R2 independently represents a hydrogen atom, a fluorine atom, a chlorine atom, or an alkyl group having from 1 to 4 carbon atoms. Most preferably R 1 and R ⁇ independently represent a hydrogen atom, a fluorine atom or an alkyl group having from 1 to 3 carbon atoms.
- a preferred compound of formula (I) of this invention is that wherein R- represents an aryl group having from 6 to 7 ring carbon atoms or a heteroaryl group having from 5 to 10 ring atoms which consists of from 1 to 2 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms.
- R ⁇ represents a phenyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidine group, a quinolyl group, an isoquinolyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a chromanyl group or an isochromanyl group.
- R ⁇ represents a phenyl group, a thiazolyl group, a pyridyl group, or an isochromanyl group.
- R 3 is preferably unsubstituted or substituted by one or two ⁇ groups, preferably in the meta and/or para position relative to the point of attachment to the piperidyl ring.
- R 3 is phenyl, it is preferably substituted by one ⁇ group, preferably halogen atoms, alkoxy groups having from 1 to 6 carbon atoms or alkoxyalkyl groups having from 1 to 6 carbon atoms.
- R 3 is monocyclic heteroaryl, it is preferably substituted by one or two groups, most preferably one, preferably halogen atoms, alkoxy groups having from 1 to 6 carbon atoms or alkoxyalkyl groups having from 1 to 6 carbon atoms.
- R 3 is 3 -pyridyl, it is preferably substituted by 6-alkoxy groups having from 1 to 6 carbon atoms.
- a preferred individual compound of this invention is selected from l-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-yl)- piperidin-4-ol methanesulfonate; 4-(3 ,4-Dihydro- lH-isochromen-7-yl)- 1 -[2-(3-fluoro-4-hydroxyphenyl)-2- hydroxyethyl]piperidin-4-ol methanesulfonate; l-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-ol methanesulfonate;
- a further preferred individual compound of this invention is selected from l-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-ol methanesulfonate;
- X represents a leaving group.
- suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine; sulfonic esters such as TfO (triflates), MsO (mesylates), TsO (tosylates); and the like.
- Y represents a hydrogen atom, a halogen atom such as, fluorine, chlorine, bromine or iodine; .L represents metal such as lithium, or MgY.
- PG and PG ⁇ independently represents a protecting group.
- the term "protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W.
- Step IA the organometallic compound of formula (1-2) can be prepared by reaction of a halide compound of formula (1-1).
- This reaction may be carried out in the presence of an organometallic reagent or a metal.
- organometallic reagents include; alkyllithiums such as n-butyllithium, sec- butyllithium and tert-butyllithium; aryllithiums such as phenyllithium and lithium naphtilide.
- suitable metal include magnesium.
- Preferred reaction inert solvents include, for example, hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
- Reaction temperatures are generally in the range of - 100 to 50 °C, preferably in the range of from -100 °C. to room temperature. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.
- Step IB an alcohol compound of formula (1-4) can be prepared by the nucleophilic addition of a ketone compound of formula (1-1) with the organometallic compound of formula (1-2). The reaction may be carried out in the presence of a solvent.
- solvents include for example, hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
- Reaction temperatures are generally in the range of -100 to 50 °C, preferably in the range of from -100 °C. to room temperature. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.
- Step 1C the desired compound of formula (1-5) may be prepared by the deprotection of the compound of formula 1-4, prepared as described in Step IB, according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991).
- Boc protection the removal of the protecting groups may be carried out under known conditions in the presence or the absence of catalytic amount of an acid in a reaction inert solvent.
- aqueous or nonaqueous organic reaction inert solvents include: ethyl acetate; alcohols, such as methanol and ethanol; ethers, such as tetrahydrofuran and dioxane; acetone; dimethylformamide; halogenated hydrocarbons, such as dichloromethane, dichloroethane or chloroform; and acetic acid or mixtures thereof.
- the reaction may be carried out at a temperature in the range from of 0 C to 200 C, preferably in the range of 20°C to 120°C. Reaction times are, in general, from 1 minute to 48 hours, preferably 5 minutes to 24 hours.
- Example of suitable catalysts include: hydrogen halide, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and, benzenesulfonic acid; ammonium salts, such as pyridium p-toluenesulfonate and ammonium chloride; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
- hydrogen halide such as hydrogen chloride and hydrogen bromide
- sulfonic acids such as p-toluenesulfonic acid and, benzenesulfonic acid
- ammonium salts such as pyridium p-toluenesulfonate and ammonium chloride
- carboxylic acid such as acetic acid and trifluoroacetic acid.
- the removal of the protecting groups may be carried out under, for example, known hydrogenolysis conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such
- reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid.
- a preferred metal catalyst is selected from, for example, palladium-carbon, palladiumhydroxide-carbon, platinumoxide, platinum-carbon, ruthenium-carbon, rhodium-aluminumoxide, tris[triphenyphosphine] rhodiumchlrodie.
- reaction inert aqueous or non-aqueous organic solvents include: alcohols, such as methanol, ethanol; ethers, such as tetrahydrofuran or dioxane; acetone; dimethylformamide; halogenated hydrocarbons, such as dichloromethane, dichloroethane or chloroform; and acetic acid or mixtures thereof.
- the reaction may be carried out at a temperature in the range from of 20 °C to 100 °C, preferably in the range of 20°C to 60°C. Reaction times are, in general, from 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- This reaction may be carried out under hydrogen atmosphere at a pressure ranging from 1 to 100 atom, preferably from 1 to 10 atom.
- the removal of the protecting groups may be carried out under known conditions.
- this reaction can be carried out by treatment with sodium hydroxide, lithium hydroxide, trimethylsilyl iodide or alkylthiolithium such as n-propylthiolithium in a reaction inert solvent.
- Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethlene gylcol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and 1,4-dioxane; halogenated hydrocarbons such as chloroform, dichloroethane, and 1,2-dichloroethane; amides such as NN-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulf oxide (DMSO).
- This reaction may be carried out at a temperature in the range from -10 to 200°C, usually from 0°C to 120°C for 30 minutes to 24 hours, usually 60 minutes to 10 hour.
- the desired beta-carbonyl piperidne compound of formula 1-7 may be prepared by the coupling of a halide compound of formula 1-6 with the piperidine compound of formula 1-5 in an inert solvent, e.g. aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, xylene and nitrobenzene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, isopropanol and butanol; and dimethylformamide (DMF), dimethylsulfoxide (DMSO), l,3-dimethyl-2-imidazolidinone(
- This reaction may be carried out in the presence of a base, e.g. an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine.
- a suitable additive e.g.
- an alcohol compound of formula (1-8) can be prepared by the reduction of the ketone compound of formula (1-7) with a reducing agent, e.g. NaBH/L, LiAlH L1BH4, or ZnBH4 in an inert solvent, e.g. methanol, ethanol, diglyme, or mixtures thereof.
- a reducing agent e.g. NaBH/L, LiAlH L1BH4, or ZnBH4
- an inert solvent e.g. methanol, ethanol, diglyme, or mixtures thereof.
- the reaction may be carried out at a temperature in the range from of 0 °C to 100 °C, preferably in the range of 20°C to 80°C. Reaction times are, in general, from 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
- Step IF In this Step, the desired compound of formula (I) may be prepared by the deprotection of the compound of formula (1-8).
- This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1C in Scheme 1. In the case of silyl derivatives protection, the removal of the protecting groups may be carried out under known conditions.
- this reaction can be carried out by treatment with tetrabutylammonium fluoride in tetrahydrofuran.
- This reaction can be also carried out under the acidic conditions in a reaction inert solvent.
- suitable aqueous or non-aqueous organic reaction inert solvents include: alcohols, such as methanol and ethanol; ethers, such as tetrahydrofuran and dioxane; acetone; dimethylformamide; and acetic acid or mixtures thereof.
- the reaction may be carried out at a temperature in the range from of -10 °C to 200 °C, preferably in the range of 0°C to 120°C.
- Reaction times are, in general, from 1 minute to 48 hours, preferably 5 minutes to 24 hours.
- suitable acids include: hydrogen halide, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and, benzenesulfonic acid; ammonium salts, such as pyridium p-toluenesulfonate and ammonium chloride; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
- the desired beta-carbonyl piperidne compound of formula 2-2 may be prepared by the coupling of a halide compound of formula 2-1 with the piperidine compound of formula 1-5.
- This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step ID in Scheme 1.
- Step 2B the protected compound of formula (1-7) may be prepared from the compound of formula (2-2) by converting the OH group into a protected O group.
- the step may be carried out by using, for example, the compound of formula (2-2), appropriate triethyl orthoformate, silyl halides, aralkyl halide, acid halides, acid anhydride and acids, such as benzyl, t-butyldimethylsilyl (TBS) chloride, t-butyldiphenylsilylchloride, Z-chloride and t-BocCl or Boc 2 O, using the methods described in Protective Groups in Organic Synthesis edited by T. W.
- TSS t-butyldimethylsilyl
- the reaction may be carried out in the presence or absence of a solvent, e.g. aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and DMF and DMSO.
- a catalyst e.g. para-toluenesulfonic acid, camphorsulfonic acid, and acetic acid.
- Step 2C and 2D the desired compound of formula (I) may be prepared by the reduction of the ketone compound of formula (1-7) followed by the deprotection of the compound of formula (1-8). These reactions are essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IE and
- Y represents a halogen atom such as, fluorine, chlorine, bromine or iodine
- .L represents metal such as lithium, or MgY.
- the organometallic compound of formula (3-2) can be prepared by reaction of a halide compound of formula (3-1). This reaction may be carried out in the presence of an organometallic reagent or a metal.
- suitable organometallic reagents include; alkyllithiums such as n-butyllithium, sec- butyllithium and tert-butyllithium; aryllithiums such as phenyllithium and lithium naphtilide.
- suitable metal include magnesium. .
- reaction inert solvents include, for example, hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
- Reaction temperatures are generally in the range of - 100 to 50 °C, preferably in the range of from -100 °C. to room temperature.
- Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.
- the desired beta-carbonyl piperidine compound of formula 2-2 may be prepared by the coupling of the amide compound of formula 3-2 with a Weinreb amide compound of formula 3-3.
- the reaction may be carried out in the presence of a solvent.
- suitable solvents include for example, hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
- Reaction temperatures are generally in the range of -100 to 50 °C, preferably in the range of from -100 °C. to room temperature.
- Step 3C the protected compound of formula (1-7) may be prepared from the compound of formula (2-2) by converting the OH group into a protected O group. These reactions are essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IE and 2B in Scheme 2.
- Step 3D and 3E the desired compound of formula (I) may be prepared by the reduction of the ketone compound of formula (1-7) followed by the deprotection of the compound of formula (1-8). These reactions are essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IE and IF in Scheme 1.
- R4 and R5 represents an alkyl group or R4 and R5 may be joined together to form an ethylene or a propylene group; said ethylene or propylene group are optionally substituted by hydroxy groups.
- Step 4A a desired beta-carbonyl piperidne compound of formula 4-2 may be prepared by the coupling of a halide compound of formula 1-6 with an ketal piperidine compound of formula 4-1. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step ID in Scheme 1.
- Step 4B an alcohol compound of formula (4-3) can be prepared by the reduction of the ketone compound of formula (4-2) with a reducing agent.
- This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IE in Scheme 1.
- a piperidone compound of formula (4-4) can be prepared by the deprotection of the ketal compound of formula (4-3) in the presence or the absence of a catalyst in a reaction-inert solvent.
- the hydrolysis reaction may be carried out in an aqueous or non-aqueous organic solvent.
- suitable solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; acetone; dimethylformamide; halogenated hydrocarbons, such as dichloromethane, dichloroethane or chloroform; acids, such as acetic acid, hydrogen chloride, hydrogen bromide and sulfuric acid.
- Example of suitable catalysts include: hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; ammonium salts, such as pyridium p-toluenesulfonate and ammonium chloride; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
- This reaction can be carried out at temperature of 0 C to 200 C, preferably from about 20 C to 120 C for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
- Step 4D the organometallic compound of formula (1-2) can be prepared by reaction of a halide compound of formula (1-1) in the same manner as and using the same reagents and reaction conditions as Step IA in Scheme 1.
- Step 4E the alcohol compound of formula (1-8) can be prepared by the nucleophilic addition of the ketone compound of formula (4-4) with the organometallic compound of formula (1-2). This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IB in Scheme 1.
- Step 4F the desired compound of formula (I) may be prepared by the deprotection of the compound of formula (1-8). This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1C or IF in Scheme 1.
- the starting materials in the aforementioned general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art.
- suitable solvents include a mixture of any two or more of those solvents described in each Step.
- the compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification.
- the optically active compounds of this invention can be prepared by several methods. For example, the optically active compounds of this invention may be obtained by chromatographic separation, enzymatic resolution or fractional crystallization from the final compounds.
- NR2B binding Assay The activity of the bicyclic amide compounds of the present invention, as NR2B antagonists, is determined by their ability to inhibit the binding of NR2B subunit at its receptor sites employing radioactive ligands.
- the NR2B antagonist activity of the bicyclic amide compounds is evaluated by using the standard assay procedure described in, for example, J. Pharmacol., 331, ppl 17-126, 1997. This method essentially involves determining the concentration of the individual compound required to reduce the amount of radiolabelled NR2B ligands by 50% at their receptor sites, thereby affording characteristic IC 50 values for each compound tested. More specifically, the assay is carried out as follows.
- Membranes were prepared by homogenization of forebrain of male CD rats weighing between 170-190 g by using glass-Teflon homogenizer in 0.32 M sucrose at 4°C. The crude nuclear pellet was removed by centrifugation at lOOOxg for 10 min, and the supernatant centrifuged at 17000xg for 25 min. The resulting pellet was resuspended in 5 mM Tris acetate pH 7.4 at 4°C for 10 min to lyse cellular particles and again centrifuged at 17000xg. The resulting pellet (P2 membrane) was washed twice in Tris acetate, resuspended at 5.5 mg protein/ml and stored at - 20°C until use.
- receptor saturation was determined by incubating [ 3 H]-CP-98,113 and 50 ⁇ g protein of P2 membrane for 60 minutes at room temperature in a final 100 ⁇ l of incubation buffer (50 mM Tris HCl, pH7.4). Total and non-specific bindings (in the presence of 10 ⁇ M of unlabeled CP-98,113) were determined in a range of [ 3 H]-CP-98113 concentrations (0.625 nM to 60nM). [ 3 H]-CP-98,113 is as follows:
- test compounds were incubated in duplicate with 5 nM [ 3 H]-CP-98,113 and 50 ⁇ g protein of P2 membrane for 60 minutes at room temperature in a final 100 ⁇ l of 50 mM Tris HCl buffer (pH7.4). Nonspecific binding was determined by 10 ⁇ M of unlabeled CP-98,113 (25 ⁇ l). The saturation derived K D gained in saturation assay was used for all Ki calculations. All incubations were terminated by rapid vacuum filtration over 0.2% polyethyleneimine soaked Whatman GF/B glass fibre filter paper using a
- SKATRON cell harvester followed by three washes with ice-cold filtration buffer (5 mM Tris HCl, pH 7.4.). Receptor-bound radioactivity was quantified by liquid scintillation counting using Packard LS counter. Competition assays were performed by counting Wallac GF/B filters on Betaplate scintillation counter (Wallac). All compounds prepared in the working examples as described below were tested by this method, and they showed Ki values from 2 nM to 20 nM with respect to inhibition of binding at the NR2B receptor.
- Human NR2B cell functional assay HEK293 cells stably expressing human NRlb/2B receptor were used for cell functional assay.
- Cells were grown in 75-cm 2 culture flasks, using Dulbecco's modified Eagle's medium (DMEM, high glucose) supplemented with 10% fetal bovine, 52 ⁇ g/ml Zeocin, 530 ⁇ g/ml Geneticin, 100 units/ml penicillin and 100 ⁇ g/ml streptomycin. Cells were maintained in a humidified atmosphere in 5% CO at 37°C, and 50-60% confluent cells were harvested by 0.05% trypsin containing 0.53 mM EDTA.
- DMEM Dulbecco's modified Eagle's medium
- NRlb/2B receptor was induced by 5 ⁇ M ponasteron A in DMEM (40 ml) in the presence of 400 ⁇ M ketamine to prevent excitotoxicity.
- the induction was performed for 19-24 hours, using 50-60% confluent cells.
- Cells were washed with 10 ml of Ca 2+ -free Krebs-Ringer Hepes buffer (KRH) containing 400 ⁇ M ketamine, and the loading of 5 ⁇ M fura-2 acetoxymethyl ester was made for 2hrs at room temperature in the presence of 400 ⁇ M ketamine in Ca 2+ -free KRH (10 ml).
- KRH Ca 2+ -free Krebs-Ringer Hepes buffer
- agonists final 100 ⁇ M glutamic acid and 10 ⁇ M glycine
- KRH containing 9 mM Ca 2+ final 1.8 mM
- Fura-2 fluorescence excitation wavelengths: 340 nm and 380 nm; emission wavelengths 510-520 nm
- the ⁇ fluorescence ratio F340/F380 i.e., the fluorescence ratio immediately post-agonist - the basal fluorescence ratio; calculated as AUC
- rat haloperidol-induced catalepsy assay Fasted male CD rats were used (7-8 weeks old). Test compound or vehicle was given subcutaneously then haloperidol 0.5 mg/kg s. ⁇ . Sixty minutes after haloperidol-injection, the duration of catalepsy was quantified by placing the animals forepaws on an elevated bar and determining the latency to remove both forepaws from the bar. The cutoff latency was 60 seconds. Experimenter was blind to treatments during testing.
- Human HERG transfected HEK293S cells were prepared and grown in-house. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4°C) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates were centrifuged at 48,000 x g at 4 °C for 20 min. The pellets were then resuspended, homogenized, and centrifuged once more in the same manner.
- the final pellets were resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl 2 (pH 7.4 at 4°C), homogenized, aliquoted and stored at -80°C until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac).
- Binding assays were conducted in a total volume of 200 ⁇ l in 96-well plates. Twenty ⁇ l of test compounds were incubated with 20 ⁇ l of [ H]-dofetilide (Amersham, final 5 nM) and 160 ⁇ l of membrane homogenate (25 ⁇ g protein) for 60 minutes at room temperature. Nonspecific binding was determined by 10 ⁇ M dofetilide at the final concentration. Incubation was terminated by rapid vacuum filtration over 0.5% presoaked GF/B Betaplate filter using Skatron cell harvester with 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl 2 , pH 7.4 at 4°C. The filters were dried, put into sample bags and filled with Betaplate Scint.
- TI is a value of ⁇ Dofetilide Binding Ki [ ⁇ M ]/ NR2B Binding Ki [nM]xl000 ⁇ value in the range of 500-3800, whereas a structurally similar comparative compound A showed a TI value of 220.
- IHEBO assay HEK 293 cells which stably express the HERG potassium channel were used for electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical journal, 74, pp230-241).
- the cells were harvested from culture flasks and plated onto glass coverslips in a standard MEM medium with 10% FCS.
- the plated cells were stored in an incubator at 37°C maintained in an atmosphere of 95%O 2 /5%CO 2 .
- Cells were studied between 15- 28hrs after harvest.
- HERG currents were studied using standard patch clamp techniques in the whole-cell mode.
- the cells were superfused with a standard external solution of the following composition (mM); NaCI, 130; KCl, 4; CaCl 2 , 2; MgCl 2 , 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH.
- a standard voltage protocol was applied to the cell to evoke membrane currents.
- the voltage protocol is as follows. The membrane was depolarized from a holding potential of -80mV to +20mV for 1000ms. This was followed by a descending voltage ramp (rate 0.5mV msec "1 ) back to the holding potential. The voltage protocol was applied to a cell continuously throughout the experiment every 4 seconds (0.25Hz). The amplitude of the peak current elicited around -40mV during the ramp was measured. Once stable evoked current responses were obtained in the external solution, vehicle (0.5% DMSO in the standard external solution) was applied for 10-20 min by a peristalic pump.
- the test compound of either 0.3, 1, 3, lO ⁇ M was applied for a 10 min period.
- the 10 min period included the time which supplying solution was passing through the tube from solution reservoir to the recording chamber via the pump. Exposing time of cells to the compound solution was more than 5min after the drug concentration in the chamber well reached the attempting concentration. There reversibility. Finally, the cells was exposed to high dose of dofetilide (5 ⁇ M), a specific IKr blocker, to evaluate the insensitive endogenous current. All experiments were performed at room temperature (23 ⁇ 1°C).
- CCI Model Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used.
- CCI chronic constriction injury
- VFHs von Frey hairs
- Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts (including disalts) thereof.
- Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L-tartrate, and tosylate salts
- Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
- a pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate.
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
- clathrates drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in non-stoichiometric amounts.
- references to compounds of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.
- the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.
- prodrugs of the compounds of formula (I).
- certain derivatives of compounds of formula (I) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to compounds of formula (I) having the desired activity.
- Such derivatives are referred to as “prodrugs”.
- Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985).
- Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.
- optical isomers including optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
- Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallization and chiOmatography.
- Conventional techniques for the preparation isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallization of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.
- the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula (I).
- An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
- isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as H and H, carbon, such as C and C, nitrogen, such as 15 N, oxygen, such as 17 O and 18 O, phosphorus, such as 32 P, sulphur, such as 35 S, fluorine, such as 18 F, and chlorine, such as 36 C1.
- isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
- isotopic variations of the compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
- the radioactive isotopes tritium, i.e. H, and carbon-14, i.e. C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- Isotopic variations of the compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.
- the compounds of formula (I) may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.
- the compounds of the invention may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
- excipient is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
- the compounds of the invention may be administered in combination, separately, simultaneously or sequentially, with one or more other pharmacologically active agents.
- Suitable agents particularly for the treatment of pain, include: (i) opioid analgesics, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; (ii) nonsteroidal antiinflammatory drugs (NSAIDs), e.g.
- opioid analgesics e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene
- benzodiazepines having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts
- Hi antagonists having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts;
- miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts
- skeletal muscle relaxants e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphrenadine and their pharmaceutically acceptable salts
- alpha-2-delta ligands e.g. gabapentin and pregabalin
- alpha-adrenergic active compounds e.g. doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1 ,2,3 ,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
- tricyclic antidepressants e.g. desipramine, imipramine, amytriptiline and nortriptiline;
- anticonvulsants e.g. carbamazepine and valproate;
- serotonin reuptake inhibitors e.g.
- fluoxetine paroxetine, citalopram and sertraline
- mixed serotonin-noradrenaline reuptake inhibitors e.g. milnacipran, venlafaxine and duloxetine
- noradrenaline reuptake inhibitors e.g. reboxetine
- Tachykinin (NK) antagonists particularly Nk-3, NK-2 and NK-1 antagonists, e.g.
- Muscarinic antagonists e.g oxybutin, tolterodine, propiverine, tropsium chloride and darifenacin
- COX-2 inhibitors e.g. celecoxib, rofecoxib and valdecoxib
- Non-selective COX inhibitors preferably with GI protection
- nitroflurbiprofen HCT-1026
- coal-tar analgesics in particular, paracetamol
- neuroleptics such as droperidol
- Vanilloid receptor agonists e.g. resinferatoxin
- Beta-adrenergic compounds such as propranolol
- Local anaesthetics such as mexiletine
- Corticosteriods such as dexamethasone
- serotonin receptor agonists and antagonists such as dexamethasone
- cholinergic (nicotinic) analgesics such as acetylinergic (nicotinic) analgesics
- miscellaneous analgesic agents such as Tramadol®.
- the invention further provides a combination comprising a compound of the invention or a pharmaceutically acceptable salt, solvate or pro-drug thereof, and a compound or class of compounds selected from the group (i)-(xxvii), above.
- a pharmaceutical composition comprising such a combination, together with a pharmaceutically acceptable excipient, diluent or carrier, particularly for the treatment of a disease for which an alpha-2-delta ligand is implicated.
- Combinations of the compounds of the present invention and other therapeutic agents may be administered separately, sequentially or simultaneously.
- the present invention extends to a kit comprising a compound of the invention, one or more other therapeutic agents, such as those listed above, and a suitable container.
- the compounds of the present invention may be formulated by any convenient means using well-known carriers and excipients.
- the present invention also provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers.
- the compounds of the invention may be administered orally.
- Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
- Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, films (including muco- adhesive), ovules, sprays and liquid formulations.
- Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
- the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).
- the composition of a typical tablet in accordance with the invention may comprise:
- a typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion.
- the tablet formulation may comprise one or more layers and may be coated or uncoated.
- excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti-oxidants, flavours and colourants.
- Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
- modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001).
- Other modified release formulations are described in US Patent No. 6,106,864.
- the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
- Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
- Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
- Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
- excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
- a suitable vehicle such as sterile, pyrogen-free water.
- parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
- solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents.
- Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
- the compounds of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally.
- Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
- Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
- topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.
- Formulations for topical administration may be formulated to be immediate and/or modified release.
- Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
- compounds of the invention may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.
- the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as dichlorofluoromethane.
- a dry powder either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids
- atomiser preferably an atomiser using electrohydrodynamics to produce a fine mist
- nebuliser with or without the use of a suitable propellant, such as dichlorofluoromethane.
- the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
- the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
- the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
- comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
- a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from l ⁇ g to lOmg of the compound of the invention per actuation and the actuation volume may vary from l ⁇ l to lOO ⁇ l.
- a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
- Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
- Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
- the dosage unit is determined by means of a valve which delivers a metered amount.
- Units in accordance with the invention are typically arranged to administer a metered dose or "puff.
- Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
- the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
- Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
- the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
- Other formulations suitable for ocular and andial administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
- a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
- a preservative such as benzalkonium chloride.
- Such formulations may also be delivered by iontophoresis.
- Formulations for ocular/andial administration may be formulated to be immediate and/or modified release.
- Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted, or programmed release.
- the compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability.
- Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
- the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
- the compounds of the invention can be administered via either the oral, parenteral or topical routes to mammals.
- these compounds are most desirably administered to humans in doses ranging from 0.1 mg to 3000 mg, preferably from 1 mg to 500 mg, which may be administered in a single dose or in divided doses throughout the day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
- These dosages are based on an average human subject having a weight of about 65 to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
- a dosage level that is in the range of from 0.01 mg to 10 mg per kg of body weight per day is most desirably employed for treatment of pain associated with inflammation.
- the invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25 °C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 °C; reactions were monitored by thin layer chromatography (tic) and reaction times are given for illustration only; melting points (m.p.) given are uncorrected (polymorphism may result in different melting points); the structure and purity of all isolated compounds were assured by at least one of the following techniques: tic (Merck silica gel 60 F 254 precoated TLC plates or Merck NH 2 F 254s precoated HPTLC plates), mass spectrometry, nuclear magnetic resonance (NMR), infrared red absorption spectra (IR) or microanalysis.
- Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex ® DU3050 (Amino Type, 30-50 ⁇ m).
- Low-resolution mass spectral data (El) were obtained on a Automass 120 (JEOL) mass spectrometer.
- Low-resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) mass spectrometer. Melting point was obtained using Seiko Instruments Inc. Exstar 6000.
- IR spectra were measured by a Shimazu infrared spectrometer (IR-470).
- Optical rotations were measured using a JASCO DIP-370 Digital Polarimeter (Japan Spectroscopic CO, Ltd.). Chemical symbols have their usual meanings; b.p. (boiling point), m.p. (melting point), 1 (liter(s)), ml (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles), eq. (equivalent(s)).
- Example 1 l-r2-(3-Fluoro-4-hvdroxyphenyl)-2-hvdroxyethyll-4-(6-methoxypyridin-3-yl)- piperidin-4-ol methanesulfonate 1-A: l-r4-(Benzyloxy)-3-fluorophenyll-2-chloroethanone To a stirred solution of 2-chloro-l-(3-fluoro-4-hydroxyphenyl)ethanone (J.
- Example 1 from 2-[4-(3,4-dihydro-lH-isochromen-7-yl)-4-hydroxypiperidin-l-yl]- l- ⁇ 3-fluoro-4-[(triisopropylsilyl)oxy]phenyl ⁇ ethanone: 907 mg (63%) as yellow solid.
- Example 2 from l-(3-fluoro-4-hydroxyphenyl)-2-[4-(3-fluorophenyl)-4- hydroxypiperidin-1-yl] ethanone: 1.38 g (95%) as yellow solid.
- Example 4 4-(3 ,4-Dihydro- lH-isochromen-7-yl)- 1 - r2-hydroxy-2-(4-hvdroxy-3- methylphenyl)ethyl1piperidin-4-ol 4-A: 1 - r4-(Benzyloxy)-3 -methylphenyll -2-bromoethanone To a stirred solution of l-[4-(benzyloxy)-3-methylphenyl]ethanone (WO
- Example 1 from l-[4-(benzyloxy)-3-methylphenyl]-2-bromoethanone and 4-(3,4- dihydro-lH-isochromen-7-yl)piperidin-4-ol: 391 mg (42%) as a yellow solid.
- 1H NMR (300 MHz, CDC1 3 ) ⁇ 7.48-7.22 (m, 6H), 7.16-7.04 (m, 4H), 6.94 (d,
- Example 5 4-(3-Fluorophenyl)-l-r2-hvdroxy-2-(4-hvdroxy-3-methylphenyl)ethyl1piperidin-4-ol 5-A: l-r4-(Benzyloxy)-3-methylphenyll-2-r4-( ' 3-fluorophenyl)-4- hydroxypiperidin- 1 -yl] ethanone
- the title compound was prepared according to the procedure described in Example 1 from l-[4-(benzyloxy)-3-methylphenyl]-2-bromoethanone and 4-(3- fluorophenyl)piperidin-4-ol: 1.4 g (quant.) as an orange solid.
- 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.47-6.93 (m, 12H), 5.11 (s, 2H), 5.20-4.60 (m, 3H), 2.79-2.19 (m, 6H), 2.21 (s, 3H), 2.05-1.95 (m, 2H), 1.62-1.52 (m, 2H) ppm.
- Example 1 from l-[4-(benzyloxy)-2-fluorophenyl]-2-bromoethanone and 4-(3,4- dihydro-lH-isochromen-7-yl)piperidin-4-ol: 792 mg (quant.) as a yellow solid 1H NMR (270 MHz, DMSO-d 6 ) ⁇ 7.54-6.94 (m, UH), 5.22 (s, 2H), 4.72 (br.s,
- Example 1 from l-[4-(benzyloxy)-2-fluorophenyl]-2-bromoethanone and 4-(6- methoxypyridin-3-yl)piperidin-4-ol dihydrochloride: 386 mg (43%) as a yellow solid
- Example 11 l-r2-hydroxy-2-(4-hvdroxyphenyl)ethyll-4-(6-methoxypyridin-3-yl)piperidin-4-ol 11-A: 1 - r4-(Benzyloxy)phenyl1 -2- r4-hydroxy-4-(6-methoxypyridin-3 - yDpiperidin- 1 -yl] ethanone
- Example 14 l-r2-Hvdroxy-2-(4-hvdroxy-3-methylphenyl)ethyl]-4-(5-methyl-l,3-thiazol-2- yl)piperidin-4-ol 14-A: Ethyl 4-(5-Methyl- 1 ,3-thiazol-2-yl)-4-hydroxypiperidine- 1 - carboxylate
- the title compound is prepared from 5-methylthiazole (14.2 g) inseared of 7- > bromoisochroman according to the method described in Example 2 part A as oil (13.8 g).
- Example 1 from 2-[4-hydroxy-4-(3-methoxyphenyl)piperidin-l-yl]-l- ⁇ 3-methyl-4- [(triisopropylsilyl)oxy]phenyl ⁇ ethanone): 1.01 g (quant.) as a yellow solid.
- Example 2 from l-(2-hydroxy-2- ⁇ 3-methyl-4-[(triisopropylsilyl)oxy]phenyl ⁇ ethyl)- 4-(3-methoxyphenyl)piperidin-4-ol: 433 mg (61%) as a white solid.
- Example 1 from l- ⁇ 2,5-dimethyl-4-[(triisopropylsilyl)oxy]phenyl ⁇ -2-[4-(3- fluorophenyl)-4-hydroxypiperidin-l-yl]ethanone: 0.98 g (95%) as a yellow solid.
- Example 2 from l-(2- ⁇ 3-ethyl-4-[(triisopropylsilyl)oxy] ⁇ henyl ⁇ -2-hydroxyethyl)-4- (6-methoxypyridin-3-yl)piperidin-4-ol: 376 mg (50%) as a yellow oil.
- Example 16 from 5-fluoro-2-methylphenol: 2.7 g (27%) as a brown oil.
- Example 18 from tert-butyl 4-(6-fluoro-5-methoxypyridin-2-yl)-4- hydroxypiperidine-1 -carboxylate: 623 mg (72%) as a white solid.
- Example CJ-26562-27 from 2-bromo-l- ⁇ 3-methyl-4-[(triisopropylsilyl)oxyphenyl]- ethanone and 4-(6-fluoro-5-methoxypyridin-2-yl)piperidin-4-ol dihydrochloride: 699 mg (quant.) as a yellow solid.
- Example CJ-26562-27 from 2-[4-(6-fluoro-5-methoxypyridin-2-yl)-4- hydroxypiperidin-l-yl]-l- ⁇ 3-methyl-4-[(triisopropylsilyl)oxy]phenyl ⁇ ethanone: 649 mg (94%) as a yellow solid.
- Example 18 from tert-butyl 4-hydroxy-4-(6-propoxypyridin-3-y ⁇ )piperidine-l- carboxylate: 2.5 g (quant.) as a yellow solid.
- Example CJ-26562-27 from 2-[4-hydroxy-4-(6-propoxypyridin-3-yl)piperidin-l-yl]- l- ⁇ 3-methyl-4-[(triisopropylsilyl)oxy]phenyl ⁇ ethanone: 666 mg (94%) as a yellow oil.
- Example 4 from l- ⁇ 2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl ⁇ ethanone (12 g) as oil.
- Example 2 from l-(2,-chloro-4-hydroxyphenyl)ethanone (10.8 g) as a colorless oil.
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Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002541831A CA2541831A1 (en) | 2003-10-08 | 2004-09-27 | 1-'2-(4-hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists |
US10/575,383 US20070021414A1 (en) | 2003-10-08 | 2004-09-27 | 1-'2-(4-Hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists |
JP2006530732A JP2007508289A (en) | 2003-10-08 | 2004-09-27 | 1- [2- (4-Hydroxyphenyl) -2-hydroxyethyl] -piperidin-4-ol compounds as NMDA receptor antagonists |
MXPA06004038A MXPA06004038A (en) | 2003-10-08 | 2004-09-27 | 1-aC??2-(4-HYDROXYPHENYL)-2-HYDROXYETHYL!-PIPERIDIN-4-OL COMPOUNDS AS NMDA RECEPTOR ANTAGONISTS. |
BRPI0415109-7A BRPI0415109A (en) | 2003-10-08 | 2004-09-27 | 1- [2- (4-hydroxyphenyl) -2-hydroxyethyl] -piperidin-4-ol compounds as nmda receptor antagonists |
EP04769481A EP1673366A1 (en) | 2003-10-08 | 2004-09-27 | 1-"2-(4-hydroxyphenyl)-2-hydroxyethyl]-piperidin-4-ol compounds as nmda receptor antagonists |
Applications Claiming Priority (2)
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US50964303P | 2003-10-08 | 2003-10-08 | |
US60/509,643 | 2003-10-08 |
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WO2005035522A1 true WO2005035522A1 (en) | 2005-04-21 |
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PCT/IB2004/003127 WO2005035522A1 (en) | 2003-10-08 | 2004-09-27 | 1-‘2-(4-hydroxyphenyl)-2-hydroxyethyl!-piperidin-4-ol compounds as nmda receptor antagonists |
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US (1) | US20070021414A1 (en) |
EP (1) | EP1673366A1 (en) |
JP (1) | JP2007508289A (en) |
BR (1) | BRPI0415109A (en) |
CA (1) | CA2541831A1 (en) |
MX (1) | MXPA06004038A (en) |
WO (1) | WO2005035522A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008065141A1 (en) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
WO2008104580A1 (en) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2080758A2 (en) | 2007-11-29 | 2009-07-22 | Bayer CropScience AG | Halogen substituted delta-1-pyrrolines |
WO2011029920A1 (en) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
WO2011110613A1 (en) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
WO2013156614A1 (en) | 2012-04-20 | 2013-10-24 | Ucb Pharma S.A. | Methods for treating parkinson's disease |
EP2865670A1 (en) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
EP3461819A1 (en) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
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WO1996006081A1 (en) * | 1994-08-18 | 1996-02-29 | Pfizer Inc. | Neuroprotective 3-(piperidinyl-1)-chroman-4,7-diol and 1-(4-hydrophenyl)-2-(piperidinyl-1)-alkanol derivatives |
WO1997023216A1 (en) * | 1995-12-22 | 1997-07-03 | Warner-Lambert Company | 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
US5710168A (en) * | 1991-10-23 | 1998-01-20 | Pfizer Inc. | 2-piperidino-1-alkanol derivatives as neuroprotective agents |
WO1999021539A1 (en) * | 1997-10-24 | 1999-05-06 | Warner-Lambert Company | Method for treating disease-related or drug-induced dyskinesias |
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2004
- 2004-09-27 WO PCT/IB2004/003127 patent/WO2005035522A1/en active Search and Examination
- 2004-09-27 JP JP2006530732A patent/JP2007508289A/en not_active Withdrawn
- 2004-09-27 US US10/575,383 patent/US20070021414A1/en not_active Abandoned
- 2004-09-27 MX MXPA06004038A patent/MXPA06004038A/en unknown
- 2004-09-27 BR BRPI0415109-7A patent/BRPI0415109A/en not_active IP Right Cessation
- 2004-09-27 EP EP04769481A patent/EP1673366A1/en not_active Withdrawn
- 2004-09-27 CA CA002541831A patent/CA2541831A1/en not_active Abandoned
Patent Citations (4)
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US5710168A (en) * | 1991-10-23 | 1998-01-20 | Pfizer Inc. | 2-piperidino-1-alkanol derivatives as neuroprotective agents |
WO1996006081A1 (en) * | 1994-08-18 | 1996-02-29 | Pfizer Inc. | Neuroprotective 3-(piperidinyl-1)-chroman-4,7-diol and 1-(4-hydrophenyl)-2-(piperidinyl-1)-alkanol derivatives |
WO1997023216A1 (en) * | 1995-12-22 | 1997-07-03 | Warner-Lambert Company | 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
WO1999021539A1 (en) * | 1997-10-24 | 1999-05-06 | Warner-Lambert Company | Method for treating disease-related or drug-induced dyskinesias |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008065141A1 (en) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
EP2481408A2 (en) | 2007-03-01 | 2012-08-01 | Probiodrug AG | New use of glutaminyl cyclase inhibitors |
WO2008104580A1 (en) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2865670A1 (en) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
EP2080758A2 (en) | 2007-11-29 | 2009-07-22 | Bayer CropScience AG | Halogen substituted delta-1-pyrrolines |
WO2011029920A1 (en) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
WO2011110613A1 (en) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
WO2013156614A1 (en) | 2012-04-20 | 2013-10-24 | Ucb Pharma S.A. | Methods for treating parkinson's disease |
EP3461819A1 (en) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
Also Published As
Publication number | Publication date |
---|---|
US20070021414A1 (en) | 2007-01-25 |
EP1673366A1 (en) | 2006-06-28 |
JP2007508289A (en) | 2007-04-05 |
CA2541831A1 (en) | 2005-04-21 |
BRPI0415109A (en) | 2006-11-28 |
MXPA06004038A (en) | 2006-06-28 |
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