EP2438070A1 - Glycin-b-antagonisten - Google Patents
Glycin-b-antagonistenInfo
- Publication number
- EP2438070A1 EP2438070A1 EP10722324A EP10722324A EP2438070A1 EP 2438070 A1 EP2438070 A1 EP 2438070A1 EP 10722324 A EP10722324 A EP 10722324A EP 10722324 A EP10722324 A EP 10722324A EP 2438070 A1 EP2438070 A1 EP 2438070A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dioxo
- βalkyl
- phenyl
- pyrimidine
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- the present invention relates to novel pyrazolopyrimidine derivatives which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
- Glutamate is a major excitatory transmitter in the central nervous system and is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: ⁇ -amino-3- hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors.
- AMPA ⁇ -amino-3- hydroxy-5-methyl-4-isoazolepropionic acid
- NMDA N-methyl-D-aspartate
- Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the
- Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation.
- the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time. Thus, glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level.
- glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
- glycine B antagonists such as glycine B antagonists restricted to action in the peripheral nervous system (PNS) may be useful for the treatment and/or prevention of pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD) 1 irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
- IBD inflammatory bowel diseases
- IBS irritative
- Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- acute insults including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- Chronic insults such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;
- neurodegenerative disorders including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid
- Parkinson's dementia mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced
- psychological/psychiatric disorders including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children;
- SAD attention deficit hyperactivity disorder
- ADS attention deficit syndrome
- PTSD posttraumatic stress disorder
- drug/alcohol abuse including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse;
- diseases of the gastro-intestinal tract and metabolic diseases including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;
- eye diseases including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;
- diseases of the respiratory tract including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;
- pyrazolopyrimidine derivatives including pyrazolo[1 ,5-a]pyrimidine- 2,7-dione derivatives, have been previously described.
- Pyrazolo[1 ,5-a]pyrimidine-2,7- dione derivatives have generally been described in different tautomeric forms, i.e., as pyrazolo[1 ,5-a]pyrimidine-2,7-diol derivatives.
- R 1 , R 2 , and R 3 independently are H, CN, alkyl, alkoxy, (un)substituted aryl, etc.; or one of R 1 or R 2 is oxo and the other is H; or R 1 and R 2 together form an (un)substituted alicyclic or aromatic ring optionally containing at least one heteroatom selected from N, O, or S and is optionally annelated with an alicyclic or aromatic ring; and R 4 may be (un)substituted aryl or heterocyclyl.
- 5-(2,3-difluoro- phenylsulfanylmethyl)-pyrazolo[1 ,5-a]pyrimidine-2,7-diol is disclosed as an example:
- A represents N or CR (wherein R represents H, C-
- T 1 and T 4 are N and the other is C
- T 2 and T 3 are N or C(CH 2 ) n R 2
- X, Y, and Z are N or C(CH2) n R 3
- R 1 is optionally substituted cyclohexyl, piperidinyl, phenyl, naphthyl, heteroaryl, etc. or R 1 is Ci -6 alkyl optionally substituted by optionally substituted cyclohexyl, piperidinyl, phenyl, naphthyl, heteroaryl, etc.
- R 2 and R 3 are H, halogen, CF 3 , OCF 3 , Ci -6 alkyl, etc.
- R Me, Ph, 3-Pyridyl, 4-Pyridyl.
- pyrazolopyrimidine derivatives are glycine B antagonists. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve excitotoxicity and malfunctioning of glutamatergic neurotransmission. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
- An additional object of the invention is the provision of processes for producing the pyrazolopyrimidine derivatives.
- R 1 represents hydrogen, trifluoromethyl, C h alky!, COOH, Ci -6 alkoxycarbonyl, hydroxy- Ci. 6 alkoxycarbonyl, aryl-Ci- ⁇ alkoxycarbonyl, heteroaryl-d-ealkoxycarbonyl aryl, heteroaryl, aryl-d- ⁇ alkyl, heteroaryl-Ci- ⁇ alkyl, aryl-C 2 - 6 alkenyl, heteroaryl-C 2 - 6 alkenyl, arylamino, heteroarylamino, aryl-C- ⁇ -6 alkylamino; heteroaryl- Ci- 6 alkylamino; acylamino, arylsulfonylamino, Ci- ⁇ alkylaminocarbonyl, cyclo-Ca- ⁇ alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylaminocarbonylamino, aryl-Ci-
- R 2 represents Ci- 6 alkyl, aryl, heteroaryl, cyclo-Ca- ⁇ alkyl, aryl-Ci- ⁇ alkyl, or heteroaryl- C L ⁇ alkyl;
- R 3 represents hydrogen, Ci -6 alkyl, or trifluoromethyl
- aryl represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, C-i- ⁇ alkyl, heteroaryl, C-i- ⁇ alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C 3 -i 2 alkoxy, aryloxy, heteroaryloxy, aryl- Ci -6 alkoxy, heteroaryl-Ci- ⁇ alkoxy, amino-d- ⁇ alkyl, hydroxy-Ci -6 alkyl, carboxy-Ci- ⁇ alkyl, carbamoyl-Ci -6 alkyl, Ci- 6 alkoxy-Ci -6 alkyl, hydroxy-Ci -6 alkoxy, Ci.
- heteroaryl is optionally substituted by one or more substituents selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroaryl, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Ca- ⁇ alkoxy, aryloxy, heteroaryloxy, aryl-C-i- ⁇ alkoxy, heteroaryl- C- ⁇ .
- substituents selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroaryl, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Ca- ⁇ alkoxy, aryloxy, heteroaryloxy, aryl-C-i- ⁇ alkoxy, heteroary
- R 1 represents hydrogen then R 2 does not represent methyl, unsubstituted pyridyl or phenyl which is unsubstituted or monosubtituted by a group selected from methoxy, methyl and nitro;
- R 1 does not represent thienyl, aryl-Ci- ⁇ alkyl, or heteroarylCi -6 alkyl
- the compound of Formula I may not represent 1 ,2-dihydro-7-hydroxy-5-methyl-2-oxo- pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid, propyl ester.
- R 1 represents COOH; Ci- 6 alkoxycarbonyl; aryl-Ci- 6 alkoxycarbonyl; heteroaryl-Ci -6 alkoxycarbonyl; aryl; arylamino; aryl-Ci- ⁇ alkylamino; heteroaryl-Ci- ⁇ alkylamino; acylamino; arylsulfonylamino; arylaminocarbonyl; heteroarylaminocarbonyl; aryl-Ci- ⁇ alkylaminocarbonyl; aryl- heterocyclyl-Ci -6 alkyl; heteroaryl-heterocyclyl-Ci- ⁇ alkyl; cyclo-Ca- ⁇ alkylaminocarbonyl; Ci- 6 alkylaminocarbonyl; hydroxy-d- ⁇ alkylaminocarbonyl; or arylaminocarbonylamino; and R 2 represents Ci. 6 alkyl, optional
- R 1 represents aryl-Ci- 6 alkoxycarbonyl; heteroaryl-Ci- 6 alkoxycarbonyl; aryl-Ci- ⁇ alkylamino; heteroaryl-Ci- 6 alkylamino; arylcarbonylamino; heteroarylcarbonylamino; arylsulfonylamino; arylaminocarbonyl; heteroarylaminocarbonyl; aryl-heterocyclyl-C-i- ⁇ alkyl; heteroaryl-heterocyclyl-Ci- ⁇ alkyl; or aryl-Ci- ⁇ alkylaminocarbonyl, wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, Ci. 6 alkyl, d- ⁇ alkoxy, carboxy, and hydroxyl-Ci- ⁇ alkyl.
- R 1 represents aryl-Ci -6 alkylamino or heteroaryl-Ci- 6 alkylamino wherein the d- ⁇ alkyl moiety is substituted by 1 or more carboxy groups.
- optical isomers polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts, hydrates, and solvates thereof.
- the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
- Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
- peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome
- Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- acute insults including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- Chronic insults such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;
- neurodegenerative disorders including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid
- Parkinson's dementia mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced
- psychological/psychiatric disorders including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction
- diseases of the gastro-intestinal tract and metabolic diseases including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;
- eye diseases including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;
- diseases of the respiratory tract including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;
- the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
- the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission.
- a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
- the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
- a further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
- the compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds.
- suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.
- the invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula I as defined above, comprising reaction of a compound of Formula II:
- AIk represents an alkyl group (e.g., Me, Et), optionally in the presence of base in an appropriate solvent (e.g., sodium hydroxide or potassium hydroxide in aqueous alcohol, sodium ethylate in ethanol, or piperidine in DMF), to yield a compound of Formula I, which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate.
- an appropriate solvent e.g., sodium hydroxide or potassium hydroxide in aqueous alcohol, sodium ethylate in ethanol, or piperidine in DMF
- the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj. j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
- C h alky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
- Ci -6 alkyl represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms
- examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, n-hexyl, 2-hexyl, 3-hexyl, 1-m ethyl pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- dimethylbutyl, 3-dimethylbutyl, 2-ethylbutyl, and 3-ethylbutyl.
- alkyl groups may optionally be substituted by one or more halogen atoms and/or one or more carboxy or carbamoyl moieties; examples of halogenated alkyl moieties include -CF 3 , -C 2 F 5 , -CBr 3 , and -CCI 3 .
- C 2-6 alkenyr represents straight or branched chain alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms.
- cycloC 3 -i 2 alkyr represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl, wherein the "cycloC 3 .i 2 alkyl"- ⁇ ng is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) fluorine, chlorine, and/or bromine atoms.
- di-(C 1-6 alkyl)amino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C h alky! groups, which may be the same or different, as defined above.
- di- Ci- ⁇ alkylamino groups include dimethylamino, diethylamino and N-methyl-N- isopropylamino.
- aryl represents phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents, which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroaryl, d- ⁇ alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C 3 -i 2 alkoxy, aryloxy, heteroaryloxy, aryl-d- ⁇ alkoxy, heteroaryl-Ci- ⁇ alkoxy, amino-Ci- ⁇ alkyl, hydroxy-Ci- ⁇ alkyl, carboxy-Ci.
- substituents which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluor
- Ci- ⁇ alkoxy-Ci- ⁇ alkyl carbamoyl-d- ⁇ alkyl, Ci- ⁇ alkoxy-Ci- ⁇ alkyl, hydroxy-C-i- ⁇ alkoxy, Ci- ⁇ alkoxy-Ci- ⁇ alkoxy, carboxy-Ci- ⁇ alkoxy, Ci- ⁇ alkoxycarbonyl, Ci -6 alkylamino, cyclo- C 3 -i 2 alkylamino, arylamino, heteroarylamino, aryl-d- ⁇ alkylamino, heteroaryl- Ci- ⁇ alkylamino, hydroxy-Ci- ⁇ alkylamino, carboxy-Ci- ⁇ alkylamino, Ci- ⁇ alkylamino- Ci- ⁇ alkyl, di-(Ci- 6 alkyl)amino, acylamino, di-(Ci- 6 alkyl)amino-Ci- 6 alkyl, carboxy- Ci- 6 alkylamino-Ci.
- Ci- ⁇ alkylamino-Ci- ⁇ alkoxy di-(Ci- 6 alkyl)amino-Ci- 6 alkoxy, carboxy-Cv ⁇ alkylamino-Ci- ⁇ alkoxy, Ci- ⁇ alkylsulfonylamino, arylsulfonylamino, d-ealkylsulfonylamino-Ci- ⁇ alkyl, Ci- ⁇ alkyl-aminosulfonyl, di-(Ci- 6 alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, Ci- ⁇ alkylaminocarbonyl-Ci- ⁇ alkyl, cyclo- C 3 -i 2 alkylaminocarbonyl-Ci- 6 alkyl, arylaminocarbonyl-d- ⁇ alkyl, heteroarylaminocarbonyl-C-i- ⁇ alkyl, ary
- heteroaryl represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen or a bicyclic ring system having one 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents, which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, Ci.
- substituents which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, trifluoromethyl, Ci.
- Ci -6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, heteroaryl, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C 3- i 2 alkoxy, aryloxy, heteroaryloxy, aryl- Ci- ⁇ alkoxy, heteroaryl-d- ⁇ alkoxy, amino-d- ⁇ alkyl, hydroxy-Ci -6 alkyl, carboxy-d- ⁇ alkyl, carbamoyl-Ci- ⁇ alkyl, d- ⁇ alkoxy-d- ⁇ alkyl, hydroxy-d- ⁇ alkoxy, d- ⁇ alkoxy-d- ⁇ alkoxy, carboxy-Ci- ⁇ alkoxy, d- ⁇ alkoxycarbonyl, Ci- 6 alkylamino, cyclo-Ca- ⁇ alkylamino, arylamino, heteroarylamino, aryl-d- ⁇ alkylamino, heteroaryl-d -6
- Ci- ⁇ alkylamino-Ci- ⁇ alkoxy di-(Ci. 6 alkyl)amino-Ci. 6 alkoxy, carboxy-d- ⁇ alkylamino- Ci -6 alkoxy, Ci -6 alkylsulfonylamino, arylsulfonylamino, d- 6 alkylsulfonylamino-d- 6 alkyl, Ci- 6 alkyl-aminosulfonyl, di-(Ci- 6 alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, d-ealkylaminocarbonyl-d- ⁇ alkyl, cyclo-
- acyl represents d- ⁇ alkylcarbonyl, trifluoroacetyl, C 2-6 alkenylcarbonyl, C 2 - 6 alkynylcarbonyl, hydroxy-d- ⁇ alkylcarbonyl, carboxy-d- ⁇ alkylcarbonyl, d- ⁇ alkoxy-Ci- ⁇ alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-Cs- ⁇ alkylcarbonyl, cyclo-Ca- ⁇ alkyl- Ci- ⁇ alkylcarbonyl, cyclo-C-a- ⁇ alkoxy-d- ⁇ alkylcarbonyl, aryloxy-Ci- ⁇ alkylcarbonyl, heteroaryloxy-Ci-ealkylcarbonyl, aryl-d- ⁇ alkylcarbonyl, heteroaryl-Ci- ⁇ alkylcarbonyl, aryl-d -6 alkoxycarbonyl, heteroaryl-Ci- ⁇ alkyl
- heterocyclyl represents a saturated 4-7 membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclyl is optionally substituted with one or two oxo moieties
- heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuryl, thiazolidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.
- halogen represents fluorine, chlorine, bromine and iodine.
- analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 1 H,4H-pyrazolo[1 ,5-a]pyrimidine-2,7-dione), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
- reference molecule such as 1 H,4H-pyrazolo[1 ,5-a]pyrimidine-2,7-dione
- Synthesis and screening of analogs e.g., using structural and/or biochemical analysis, to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
- analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
- prodrug is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug.
- Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I.
- Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy, amino, and thio groups.
- Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
- compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
- pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
- compositions of the present invention may be in the form of pharmaceutically acceptable salts.
- “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
- stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures.
- Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases.
- Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
- enantiomers may be separated by chromatographic techniques using chiral stationary phases.
- Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselective ⁇ . Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.
- the present invention encompasses tautomeric forms of compounds of Formula I.
- the compounds of the present invention may, for example, exist in the following tautomeric forms:
- salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
- salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
- the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
- hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids.
- the salt may be converted to the free base by treatment with alkali.
- the active ingredients of the compounds of the present invention may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
- Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed.
- Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
- excipient applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered.
- Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions.
- excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
- A.R. Gennaro, 20 th Edition describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".
- the excipients may also be combinations of solids and liquids.
- the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
- Suitable dosage ranges are 1-1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
- treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
- the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
- terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
- the compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
- the compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition).
- the orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion- controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
- the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (
- binding agents e.g., pregelatinized maize
- the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like.
- Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
- the tablets may be coated by methods well known in the art.
- the compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
- the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
- the compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the instant compounds may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
- the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
- a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
- the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- the formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
- Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- the compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
- compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration.
- the pack may, for example, comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration.
- the glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
- the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
- a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
- the appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
- Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD 50 /ED 50 .
- Compositions that exhibit large therapeutic indices are preferred.
- Scheme 1 describes the preparation of compounds of Formula I
- Scheme 2 describes additional methods for preparing starting materials and intermediates for use in the preparation of compounds of Formula I. All of the starting materials are prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which procedures would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined below or as in the claims.
- AIk alkyl (e.g., Me, Et)
- the compounds of general Formula I may be prepared by reacting a compound of the formula 2 with the compound of the formula 3 in the presence of an appropriate base such as, for example, sodium hydroxide or potassium hydroxide in aqueous alcohol solution, or sodium ethylate in ethyl alcohol, or piperidine in dimethylformamide. Alternatively, reaction may be performed by heating the reagents 2 and 3 without solvent.
- Aminopyrazole 2 may be prepared by reaction of alkyl cyanoacetate 1 with hydrazine or with hydrazine hydrate, or by cyclization of intermediate hydrazide of substituted cyanoacetic acid, respectively.
- Alternative methods for preparing aminopyrazole derivatives (2) are shown in Scheme 2. Scheme 2 - Synthesis of starting materials and intermediates
- R 4 aryl, heteroaryl, aryl-C,_ 6 alkyl, heteroaryl-C
- [0068]4-(Substituted)carbamoyl derivatives of aminopyrazole 2 (2B) may be prepared by amidation of alkyl ester of aminopyrazolonecarboxylic acid 2A with amine 7.
- Compounds of the formula 2A may be prepared according to well known procedures, such as by acylation of 5-amino-2,3-dihydro-1 H-pyrazol-3-one (2a) with alkyl chloroformate 4a [Papini et al. Gazzetta Chimica Italiana. 1954, 84, 769-780.] or by reacting malonate derivative 6 with hydrazine [Gethosenko B. B.; Miller S. I. J. Org. Chem.
- 4-(Substituted)amido derivatives of aminopyrazole 2 (2C) may be prepared according to procedures shown in Scheme 2. Reduction of alkyl cyanoacetate derivative 8 with sodium ditionite provides alkyl aminocyanoacetate 1A which may be acylated by a compound 4B to yield an alkyl acylamino-cyanoacetate 1B [Caille J. C, Didierlaurent S., Lefrancois D., Lelievre M. H., Sury C, Aszodi J.. Synthesis. 1995, 6, 635-637. and Cabon G., Gaucher B., Gegout A., Heulle S., Masquelin T. Chimia.
- reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
- DCM dichloromethane
- DMF N 1 N- dimethylformamide
- HCI hydrochloric acid
- DMSO dimethyl sulfoxide
- NH 4 OH ammonium hydroxide solution
- MeCN acetonitrile
- AcOH as acetic acid
- EtOH as ethanol
- MeOH as methanol
- Si ⁇ 2 silica gel
- Phenylacetyl chloride (4.44 gr, 28.7 mmol) is added to a cooled (0 0 C) mixture of monomethyl monopotassium malonate (8.96 gr, 57.4 mmol, 2.0 equiv.), magnesium chloride (6.00 gr, 63 mmol, 2.2 equiv.) and triethylamine (17.5 ml, 126 mmol, 4.4 equiv.) in acetonitrile (100 ml). The mixture is stirred at 0 0 C for 3 h then aqueous 2N HCI is added and the mixture is stirred for another hour. The layers are separated and the aqueous layer is extracted with EtOAc (2x).
- Methyl 3-oxo-4-phenylbutanoate (404 mg, 2.10 mmol, 1.2 equiv.) is added to a suspension/solution of ethyl 5-amino-3-oxo-2,3-dihydro-1 H-pyrazole-4-carboxylate (300 mg, 1.76 mmol) in acetic acid (7 ml). The mixture is heated at 80 0 C for 2 h. Then it is allowed too cool, diluted with water and concentrated to dryness. The orange residue is triturated with MeOH and filtered to afford 108 mg of an off-white powder. The filtrate is again concentrated and the residue is triturated with EtOH and filtered to afford a total yield of 389.6 mg (71%) of an off-white powder.
- Ethyl 5-amino-3-oxo-2,3-dihydro-1 H-pyrazole-4-carboxylate (12.25 g, 71.5 mmol) is dispersed in acetic acid (70 ml) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate (19.46 g, 86 mmol, 1.2 equiv.) is added. The mixture is heated to 100 0 C for 2 days. The resulting suspension is filtered off and washed with diisopropyl ether to give an off-white solid. The solid is stirred with acetic acid (30 ml) at 100 0 C for 5 min. Hot filtration affords 6.7 g (28%) of the product as an off-white solid.
- Potassium monoethyl malonate (20 g, 118 mmol, 2.05 equiv.) is dispersed in anhydrous acetonitrile (200 ml) and magnesium chloride (13.64 g, 143 mmol, 2.5 equiv.) and triethylamine (18.38 ml, 132 mmol, 2.3 equiv.) are added at O °C. After 10 min, cyclopentanecarbonyl chloride (6.97 ml, 57.3 mmol) is added and the orange suspension is stirred at 0 0 C.
- the reaction mixture is concentrated in vacuo and the residue is partitioned between DCM and aqueous 0.5 M KHSO 4 solution.
- the organic layer is washed with aqueous 0.5 M KHSO 4 solution and brine, dried over Na 2 SO 4 and concentrated to dryness to afford a brown oil.
- the oily residue is purified by flash column chromatography (3-30% EtOAc in heptane) to give 8.12 g (77%) of the product as an orange oil.
- N-(5-Cyclopentyl-2,7-dioxo-1 ,2,4,7-tetrahydropyrazolo[1 ,5-a]pyrimidin-3- yl)acetamide (548 mg, 1.983 mmol) is dissolved in 3M methanolic HCI (20 ml, 60.0 mmol) and heated to reflux temperature for 1.5 h. After 1 h a suspension is formed. The reaction mixture is allowed to cool to rt and the suspension is filtered off to give 408 mg (88%) of the title compound as an off-white solid.
- Benzoyl chloride (124 ⁇ l, 1.06 mmol, 2.5 equiv.) is added slowly to a solution of 3-amino-5-cyclopentylpyrazolo[1 ,5-a]pyrimidine-2,7(1 H,4H)-dione (100 mg, 0.427 mmol) in aqueous NaOH solution (2.13 ml, 4.27 mmol, 10 equiv.). The mixture is stirred at rt for 15 minutes in which time a green solid is formed. The reaction mixture is neutralized using concentrated HCI solution and the resulting pink suspension is concentrated in vacuo.
- reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes.
- Representative pharmaceutical compositions follow.
- Tablets suitable for oral administration which contain the active ingredient, may be prepared by conventional tabletting techniques.
- any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
- a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
- Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:
- the film coating material consists of:
- a suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
- a suitable formulation for an injectable solution is as follows:
- a suitable formulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
- Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
- 18O g aerosol solution contain:
- TDS formulation 100 g solution contain:
- Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain:
- Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
- MDL-105,519 (Baron et al., J Pharmacol Exp Ther 1996, 279(1 ), 62-68; Baron et al., European Journal of Pharmacology, 1997, 323(2-3), 181-192; Hoffner & Wanner, Neuroscience Letters, 1997, 226(2), 79-82) is a selective, high affinity antagonist at the NMDA receptor glycine site.
- Tissue preparation is performed according to Foster & Wong (Br J Pharmacol, 1987, 91 , 403-409) with some modifications.
- Anaesthetised male Sprague- Dawley rats (200-250 g, Janvier, Le Genest-lsle, France) are decapitated and their brains removed rapidly.
- the cortex is dissected out and processed as described by Parsons, et al. (J Pharmacol Exp Ther, 1997, 283(3), 1264-1275).
- the cortices are homogenized in 20 volumes of ice-cold 0.32 M sucrose (Sigma-Aldrich, Taufkirchen, Germany) using a glass-Teflon homogenizer.
- the homogenate is centrifuged at 1000 x g for 10 minutes, the pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes.
- the resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g.
- the supernatant and the buffy coat are then centrifuged three times (48,000 x g for 20 minutes) in the presence of 50 mM Tris-HCI, pH 8.0 (assay buffer). All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 7.5, the membrane suspension is frozen rapidly at -8O 0 C.
- the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 7.5, and centrifugation at 48,000 x g for 20 minutes.
- the final pellet is suspended in assay buffer.
- the amount of protein in the final membrane preparation is determined according to the method of Lowry, et al. (J. Biological Chemistry, 1951 , 193, 256-275) with some modifications (Hartree, Analytical Biochemistry, 1972, 48, 422-427).
- the final protein concentration used for our studies is 400 ⁇ g/ ml.
- a robotic system designed for binding assays (Tecan GmbH, Crailsheim, Germany) is loaded with the membrane solution, solutions for bound control (buffer/DMSO 20%), unlabeled glycine (1 mM) for evaluation of non-specific binding, all compounds to be tested (at 20-fold concentrations), radioligand and respective 96-well plates.
- a final [ 3 H]-MDL-105,519 concentration of 2 nM is selected.
- the assay plates are loaded with membrane solution and are shaken at 4 0 C.
- the mother plates are then prepared by pipetting the compounds into assay buffer/20% DMSO to obtain the desired final concentrations (dose response curve with five different concentrations, e.g. 10, 3, 1 , 0.3, and 0.1 ⁇ M).
- the compounds are added (including the bound and the non-specific binding control).
- the final DMSO concentration is 1 %.
- the assay plates are incubated and shaken at 4°C for 1 h, before the mixture is exhausted as rapidly as possible via a vacuum manifold using the Multiscreen HTS glass fibre (type B) filter plates (Millipore, Schwalbach, Germany) under a constant vacuum of 450 mbar.
- the membranes are washed four times with cold assay buffer (100 ⁇ L).
- 50 ⁇ L of Ultima Gold scintillation cocktail (PerkinElmer, Rodgau-J ⁇ gesheim, Germany) is added to the wet filter plates and incubated at room temperature overnight before counting the disintegration per minutes using a liquid scintillation counter (MicroBeta, PerkinElmer, Rodgau-J ⁇ gesheim, Germany). Analysis of data
- the measured radioactivity of the radioligand alone is set as 100 % bound control and the non-specific binding of the radioligand (which could not displaced by glycine, 1 mM) represented the 0 % control.
- Antagonistic potencies of the test compounds are functionally evaluated using electrophysiological whole cell patch-clamp recordings and/or fluorometric intracellular Ca 2+ -imaging (FLIPR) screens.
- Hippocampi are pre-incubated for 8 min with a 0.66% trypsin (Sigma- Aldrich) and 0.1% (20 U/ml) DNAase solution (Sigma-Aldrich) in Ca 2+ -free Phosphate Buffered Saline (PBS-CF) and washed 3 times with HBSS-CMF. Cells are then mechanically dissociated by trituration in a PBS-CF solution containing 0.05% (10 U/ml) DNAase and 0.3% of the trypsin inhibitor ovomucoid (all from Sigma-Aldrich).
- the cells are then centrifuged at 180 x g for 10 minutes, and the cell pellet re-suspended in basal Minimum Essential Medium (MEM, Invitrogen, Düsseldorf, Germany), again carefully triturated to ensure maximal dissociation and finally plated in the flexiPERM inserts (Thermo Fisher Scientific, Langenselbold, Germany) at a density of 15 x 10 3 cells/cm 2 (0.5 ml/insert) onto poly-DL-ornithine (Sigma) and mouse laminin (Invitrogen) pre- coated plastic petri dishes. After 1 hour the cells become attached to the bottom of the dish and the inserts may be removed.
- MEM basal Minimum Essential Medium
- the cells are then nourished with 2 ml MEM supplemented with 5% foetal calf serum (FCS) and 5% horse serum and incubated at 37 0 C with 95% air and 5% CO 2 at 95% humidity.
- FCS foetal calf serum
- FCS foetal calf serum
- horse serum 5%
- CO 2 5% CO 2 at 95% humidity.
- glial mitosis is inhibited by adding 10 ⁇ l of AraC (5 ⁇ M endconcentration).
- the medium is completely exchanged after an additional 2 DIV and again, but only partly (50 %), after 8 DIV.
- the cells are Used for electrophysiological recordings after 11-15 DIV.
- DRG dorsal root ganglia
- Solutions are delivered via a home-made gravity driven very fast perfusion system ( ⁇ 10 ms) including valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist.
- a home-made gravity driven very fast perfusion system ⁇ 10 ms
- valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist.
- the intracellular solution used consists of: 120 mM CsCI, 10 mM EGTA, 1 mM MgCI 2 , 200 ⁇ M CaCI 2 , 10 mM glucose and 22 mM tetraethyl ammonium chloride (TEA-CL).
- the corresponding extracellular bath solution contains: 140 mM NaCI, 3 mM KCI, 10 mM glucose, 10 mM HEPES, 1.5 mM CaCb and 4.5 mM sucrose (all from Sigma-Aldrich) pH 7.3, and is supplemented with 0.3 ⁇ M tetrodotoxin (TTX, Tocris, Bristol, U.K.) to block voltage-activated sodium channels and 0.25 ⁇ M bicuculline (Sigma-Aldrich) to block GABA A receptors.
- TTX tetrodotoxin
- concentration-dependency of blockade 5 control traces are recorded with application of NMDA (200 ⁇ M) and D-Serine (1 ⁇ M) for 5 seconds in order to reduce the effect of rundown, then the highest concentration of the test-substance is applied for 1 minute before applying the agonists for 5 seconds in the presence of antagonist. Three recordings are made in the presence of the antagonist and 3 recovery traces are recorded after it's removal. The procedure is repeated for three to four further concentrations of antagonist with declining concentrations e.g. 10, 3, 1 , 0.3, and 0.1 ⁇ M. For the final recovery, agonists are again applied five times after wash-out of the test substance.
- Primary neurons are prepared from cortices of embryonal rats at day 17 of pregnancy as described by Dichter (Brain Res., 1987, 149, 279). Sprague-Dawley rat embryos (E 17) are decapitated and neocortices are dissected, trypsinized and carefully triturated. The cell suspension is plated on poly-D-lysine pre-coated 96-well Plates (Greiner, Frickenhausen, Germany) at a cell density of 55.000 cells /well.
- the neurons are cultivated in Neurobasal media containing B27-Supplement and 0.5 ⁇ M L-Glutamine (Biochrom) at 37°C in a humidified atmosphere of 5% CO 2 / 95% air. Medium is exchanged completely at day 4 and to 50% on day 7. At the time of experiments neurons are 11 - 13 days in vitro. Calcium FLIPR studies
- Compounds of the present invention have an IC 50 range of about 0.5 nM to about 100 ⁇ M.
- the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.
- the instant pyrazolopyrimidine derivatives represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS disorders, which involve excessive glutamate induced excitation.
- peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
- pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain
- peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS
- These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- acute insults including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
- Chronic insults such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld- Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;
- neurodegenerative disorders including Morbus Huntington, Alzheimer's disease Creutzfeld- Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid
- Parkinson's dementia mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced
- psychological/psychiatric disorders including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children;
- SAD attention deficit hyperactivity disorder
- ADS attention deficit syndrome
- PTSD posttraumatic stress disorder
- drug/alcohol abuse including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse;
- eye diseases including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;
- diseases of the respiratory tract including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;
- the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
- Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
- compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP10722324A EP2438070A1 (de) | 2009-06-04 | 2010-06-04 | Glycin-b-antagonisten |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US21777309P | 2009-06-04 | 2009-06-04 | |
EP09007403A EP2264035A1 (de) | 2009-06-04 | 2009-06-04 | Glycin-B-Antagonisten |
PCT/EP2010/003385 WO2010139483A1 (en) | 2009-06-04 | 2010-06-04 | Glycine b antagonists |
EP10722324A EP2438070A1 (de) | 2009-06-04 | 2010-06-04 | Glycin-b-antagonisten |
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EP2438070A1 true EP2438070A1 (de) | 2012-04-11 |
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EP09007403A Ceased EP2264035A1 (de) | 2009-06-04 | 2009-06-04 | Glycin-B-Antagonisten |
EP10722324A Withdrawn EP2438070A1 (de) | 2009-06-04 | 2010-06-04 | Glycin-b-antagonisten |
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EP09007403A Ceased EP2264035A1 (de) | 2009-06-04 | 2009-06-04 | Glycin-B-Antagonisten |
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EP (2) | EP2264035A1 (de) |
WO (1) | WO2010139483A1 (de) |
Families Citing this family (10)
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WO2012149157A2 (en) * | 2011-04-26 | 2012-11-01 | Bioenergenix | Heterocyclic compounds for the inhibition of pask |
RU2014120166A (ru) | 2011-10-20 | 2015-11-27 | ГЛЭКСОСМИТКЛАЙН ЭлЭлСи | Замещенные бициклические аза-гетероциклы и их аналоги в качестве модуляторов сиртуина |
CN102503945A (zh) * | 2011-11-28 | 2012-06-20 | 华东理工大学 | 能够抑制表皮生长因子受体的化合物及其应用 |
US9278973B2 (en) | 2012-10-25 | 2016-03-08 | Bioenergenix Llc | Heterocyclic compounds for the inhibition of PASK |
WO2017093354A1 (en) * | 2015-11-30 | 2017-06-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nmdar antagonists for the treatment of diseases associated with angiogenesis |
EP3386591B1 (de) * | 2015-12-09 | 2020-06-24 | Cadent Therapeutics, Inc. | Heteroaromatische nmda-rezeptormodulatoren und verwendungen davon |
US10500205B2 (en) | 2015-12-09 | 2019-12-10 | Cadent Therapeutics, Inc. | Thienopyrimidinone NMDA receptor modulators and uses thereof |
ES2975336T3 (es) | 2016-12-22 | 2024-07-04 | Novartis Ag | Moduladores del receptor NMDA y usos de los mismos |
PE20210948A1 (es) | 2018-08-03 | 2021-05-24 | Cadent Therapeutics Inc | Moduladores del receptor nmda heteroaromatico y usos de los mismos |
CN112194660B (zh) * | 2020-10-20 | 2021-12-03 | 常州大学 | 一种pde2抑制剂苯基吡唑并嘧啶类化合物及其制备方法 |
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DE19611476A1 (de) * | 1996-03-22 | 1997-09-25 | Basf Ag | Neue heterocyclische substituierte Imidazolo-chinoxalinone, ihre Herstellung und Verwendung |
DK0915880T3 (da) * | 1996-07-24 | 2008-02-11 | Bristol Myers Squibb Pharma Co | Azolotriaziner og pyrimidiner |
US5776935A (en) * | 1996-07-25 | 1998-07-07 | Merz & Co. Gmbh & Co. | Pyrido-phtalazin diones and their use against neurological disorders associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission |
CA2669579A1 (en) | 2006-11-23 | 2008-05-29 | Novartis Ag | 5-sulfanylmethyl-pyrazolo [1,5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists |
CN101671336B (zh) * | 2009-09-23 | 2013-11-13 | 辽宁利锋科技开发有限公司 | 芳杂环并嘧啶衍生物和类似物及其制备方法和用途 |
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2009
- 2009-06-04 EP EP09007403A patent/EP2264035A1/de not_active Ceased
-
2010
- 2010-06-04 WO PCT/EP2010/003385 patent/WO2010139483A1/en active Application Filing
- 2010-06-04 EP EP10722324A patent/EP2438070A1/de not_active Withdrawn
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WO2010139483A1 (en) | 2010-12-09 |
EP2264035A1 (de) | 2010-12-22 |
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