US20100280019A1 - Isoxazoles - Google Patents
Isoxazoles Download PDFInfo
- Publication number
- US20100280019A1 US20100280019A1 US12/766,125 US76612510A US2010280019A1 US 20100280019 A1 US20100280019 A1 US 20100280019A1 US 76612510 A US76612510 A US 76612510A US 2010280019 A1 US2010280019 A1 US 2010280019A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- methyl
- compound
- isoxazol
- group
- 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.)
- Abandoned
Links
- 0 [1*]C1=NOC([2*])=C1COC1=NC=C(C(=O)N([3*])N([4*])[5*])C=C1 Chemical compound [1*]C1=NOC([2*])=C1COC1=NC=C(C(=O)N([3*])N([4*])[5*])C=C1 0.000 description 20
- QPLQFKONWFQPDK-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN3CCOCC3)C=C2)C(C2=NC=C(F)C=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN3CCOCC3)C=C2)C(C2=NC=C(F)C=C2)=NO1 QPLQFKONWFQPDK-UHFFFAOYSA-N 0.000 description 2
- HNCNLQQDKCNSRC-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN)C=C2)C(C2=CC=CC=C2)=NO1 HNCNLQQDKCNSRC-UHFFFAOYSA-N 0.000 description 1
- ABJGKRLNIJFUTF-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN3CCCC3)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN3CCCC3)C=C2)C(C2=CC=CC=C2)=NO1 ABJGKRLNIJFUTF-UHFFFAOYSA-N 0.000 description 1
- CKIZDCAIMNAWAJ-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN3CCCCC3)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN3CCCCC3)C=C2)C(C2=CC=CC=C2)=NO1 CKIZDCAIMNAWAJ-UHFFFAOYSA-N 0.000 description 1
- MMVHXHAGZSPENH-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN3CCOCC3)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN3CCOCC3)C=C2)C(C2=CC=CC=C2)=NO1 MMVHXHAGZSPENH-UHFFFAOYSA-N 0.000 description 1
- NARUNGMFAKKTJS-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NN3CCS(=O)(=O)CC3)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NN3CCS(=O)(=O)CC3)C=C2)C(C2=CC=CC=C2)=NO1 NARUNGMFAKKTJS-UHFFFAOYSA-N 0.000 description 1
- AIYICXJLGCBDQH-UHFFFAOYSA-N CC1=C(COC2=NC=C(C(=O)NNS(C)(=O)=O)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NC=C(C(=O)NNS(C)(=O)=O)C=C2)C(C2=CC=CC=C2)=NO1 AIYICXJLGCBDQH-UHFFFAOYSA-N 0.000 description 1
- SOGONBVZMZDSDL-UHFFFAOYSA-N CC1=C(COC2=NN=C(C(=O)NN3CCOCC3)C=C2)C(C2=CC=CC=C2)=NO1 Chemical compound CC1=C(COC2=NN=C(C(=O)NN3CCOCC3)C=C2)C(C2=CC=CC=C2)=NO1 SOGONBVZMZDSDL-UHFFFAOYSA-N 0.000 description 1
- FXVHSZIOLJANPK-UHFFFAOYSA-N CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN(C)C)C=C1 Chemical compound CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN(C)C)C=C1 FXVHSZIOLJANPK-UHFFFAOYSA-N 0.000 description 1
- CWOYAFNYNVVILN-UHFFFAOYSA-N CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN2CCCC2)C=C1 Chemical compound CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN2CCCC2)C=C1 CWOYAFNYNVVILN-UHFFFAOYSA-N 0.000 description 1
- LTQMZMUKWHWFMK-UHFFFAOYSA-N CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN2CCOCC2)C=C1 Chemical compound CCCCC1=NOC(C)=C1COC1=NC=C(C(=O)NN2CCOCC2)C=C1 LTQMZMUKWHWFMK-UHFFFAOYSA-N 0.000 description 1
- LQMGFOZCJPSYBM-VOTSOKGWSA-N COC(=O)/C=C/OC(=O)C1=CC=C([N+](=O)[O-])C=C1 Chemical compound COC(=O)/C=C/OC(=O)C1=CC=C([N+](=O)[O-])C=C1 LQMGFOZCJPSYBM-VOTSOKGWSA-N 0.000 description 1
- RMEDXVIWDFLGES-UHFFFAOYSA-N COC(=O)C1=CN=C(Cl)C=C1 Chemical compound COC(=O)C1=CN=C(Cl)C=C1 RMEDXVIWDFLGES-UHFFFAOYSA-N 0.000 description 1
- GUSWJGOYDXFJSI-UHFFFAOYSA-N ClC1=NN=C(Cl)C=C1 Chemical compound ClC1=NN=C(Cl)C=C1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- GABA gamma-aminobutyric acid
- GABA A receptors which are members of the ligand-gated ion channel superfamily
- GABA B receptors which are members of the G-protein linked receptor family.
- the GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of ⁇ , ⁇ and ⁇ subunits.
- ⁇ 1 ⁇ 2 ⁇ 2 mimics many effects of the classical type-I BzR subtypes, whereas ⁇ 2 ⁇ 2 ⁇ 2, ⁇ 3 ⁇ 2 ⁇ 2 and ⁇ 5 ⁇ 2 ⁇ 2 ion channels are termed type-II BzR.
- ⁇ -CCM benzodiazepine receptor inverse agonist
- ⁇ -CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans.
- GABA A ⁇ 5 receptor partial or full inverse agonist which is relatively free of activity at GABA A ⁇ 1 and/or ⁇ 2 and/or ⁇ 3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity.
- GABA A ⁇ 5 inverse agonists which are not free of activity at GABA A ⁇ 1 and/or ⁇ 2 and/or ⁇ 3 receptor binding sites but which are functionally selective for ⁇ 5 containing subunits.
- inverse agonists which are selective for GABA A ⁇ 5 subunits and are relatively free of activity at GABA A ⁇ 1, ⁇ 2 and ⁇ 3 receptor binding sites are preferred.
- Literature has been published to establish the link between GABA A ⁇ 5 subunits and the treatment of various diseases of the Central Nervous System, like Neuroscience Letts., 2005, 381, 108-13, Neuropsychobiology, 2001, 43(3), 141-44, Amer. J. Med. Genetics, 2004, 131B, 51-9, Autism 2007, 11(2): 135-47, Investigacion Clinica, 2007, 48, 529-41, Nature Neuroscience, 2007, 10, 411-13, Neuroscience Letts., 2008, 433, 22-7 and Cell 2008, 135, 549-60.
- the present invention provides isoxazoles having affinity and selectivity for GABA A ⁇ 5 receptor, their manufacture, pharmaceutical compositions containing them and their use as pharmaceuticals.
- the present invention provides isoxazoles of formula I
- R 4 and R 5 together with the nitrogen atom to which they are attached, form a heterocyclyl, optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, lower-alkyl and lower-alkoxy;
- the present invention provides compounds of formula I and their pharmaceutically acceptable salts and esters and pharmaceutical compositions containing them.
- the invention also provides methods for the manufacture of the compounds and compositions of the invention.
- the invention further provides methods for the treatment or prevention of diseases related to the GABA A ⁇ 5 receptor.
- the compounds of present invention are preferably inverse agonists of GABA A ⁇ 5.
- the compounds of present invention and their pharmaceutically acceptable salts and esters can be used, alone or in combination with other drugs, as cognitive enhancers or for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attention
- substituted means that the specified group or moiety can bear 1, 2, 3, 4, 5 or 6 substituents. Where any group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same.
- unsubstituted means that the specified group bears no substituents.
- optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents.
- substituents independently chosen from the group of possible substituents.
- one or more means from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. 1, 2, 3, 4 or 5 substituents are preferred, unless specifically defined otherwise.
- halogen refers to fluorine, chlorine, bromine and iodine, with fluorine being preferred.
- lower-alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as those groups specifically illustrated by the examples herein below.
- Preferred lower-alkyl groups are methyl and n-butyl.
- lower-alkoxy denotes a group —O—R wherein R is lower-alkyl as defined above.
- cycloalkyl refers to a monovalent saturated cyclic hydrocarbon radical of 3 to 7 ring carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, as well as those groups specifically illustrated by the examples herein below.
- heterocyclyl refers to a monovalent 3 to 7 membered saturated or partly unsaturated monocyclic ring containing one, two or three ring heteroatoms selected from N, O and S. One or two ring heteroatoms are preferred. Preferred are 4 to 6 membered heterocyclyl comprising one or two ring heteroatoms selected from N, O and S. S is optionally substituted by two oxo groups.
- heterocyclyl moieties are pyrrolidinyl, tetrahydro-furanyl, tetrahydro-pyranyl, tetrahydro-thienyl, tetrahydro-pyridinyl, tetrahydro-pyryl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and dihydro-oxazolyl, as well as those groups specifically illustrated by the examples herein below.
- heterocyclyls are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.
- Particularly preferred heterocyclyls are morpholin-4-yl, pyrrolidin-1-yl and 1,1-dioxo-thiomorpholin-4-yl.
- aryl refers to a monovalent aromatic carbocyclic ring system, comprising 6 to 14, preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic.
- Examples for aryl are phenyl, naphthyl, biphenyl or indanyl, as well as those groups specifically illustrated by the examples herein below.
- Preferred aryl is phenyl.
- Aryl can also be substituted e.g. as defined below and in the claims.
- heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which comprises 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur, such as furyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzoimidazolyl, indolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl or isoquinolinyl, as well as those groups specifically illustrated by the examples herein below. Heteroaryl
- lower-alkyl substituted by halogen refers to lower-alkyl groups which are mono- or multiply substituted with halogen.
- Examples of lower-alkyl substituted by halogen groups are e.g. CFH 2 , CF 2 H, CF 3 , CF 3 CH 2 , CF 3 (CH 2 ) 2 , (CF 3 ) 2 CH or CF 2 H—CF 2 , as well as those groups specifically illustrated by the examples herein below.
- lower-alkyl substituted by hydroxy denotes a lower-alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group.
- Examples of lower-alkyl substituted by hydroxy include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl and n-hexyl substituted by one or more hydroxy group(s), in particular with one, two or three hydroxy groups, preferably with one or two hydroxy groups.
- “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
- Compounds of formula I can form pharmaceutically acceptable acid addition salts.
- pharmaceutically acceptable salts are salts of compounds of formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
- physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid
- organic acids such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
- pharmaceutically acceptable salts refers to such
- salts examples include alkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca— and trimethylammoniumsalt.
- pharmaceutically acceptable salts also refers to such salts.
- esters embraces derivatives of the compounds of formula I, in which a carboxy group has been converted to an ester.
- esters are preferred esters.
- pharmaceutically acceptable esters furthermore embraces compounds of formula I in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
- “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
- R 4 and R 5 together with the nitrogen atom to which they are attached, form a heterocyclyl, optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, lower-alkyl and lower-alkoxy;
- the compounds of formula I can have one or more asymmetric carbon atom and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
- optically active forms can be obtained for example by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant). The invention embraces all of these forms.
- the present invention provides compounds of formula I wherein
- R 4 and R 5 together with the nitrogen atom to which they are attached, form a heterocyclyl, optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, lower-alkyl and lower-alkoxy;
- X is CH or N, preferably CH.
- R 1 is preferably lower-alkyl, aryl or heteroaryl substituted with halogen. Even more preferred compounds of the present invention are those, wherein R 1 is n-butyl, phenyl or 5-fluoro-pyridin-2-yl. Most preferred are compounds wherein R 1 is phenyl or 5-fluoro-pyridin-2-yl.
- R 2 is lower-alkyl.
- Preferred compounds of the present invention are those, wherein R 2 is methyl.
- R 3 is hydrogen or lower-alkyl.
- Preferred compounds of the present invention are those, wherein R 3 is hydrogen.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, lower-alkyl and SO 2 -lower-alkyl.
- Preferred compounds of the present invention are those, wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl and SO 2 -methyl. Even more preferred are compounds wherein R 4 is hydrogen and R 5 is SO 2 -methyl. Evenly preferred are embodiments wherein both R 4 and R 5 are identically either hydrogen or methyl.
- R 4 and R 5 together with the nitrogen atom to which they are attached, form a heterocyclyl.
- Preferred compounds of the present invention are those, wherein R 4 and R 5 , together with the nitrogen atom to which they are attached, form a heterocyclyl selected from the group consisting of morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl and 1,1-dioxo-thiomorpholin-4-yl.
- R 4 and R 5 together with the nitrogen atom to which they are attached, form a heterocyclyl selected from the group consisting of morpholin-4-yl, pyrrolidin-1-yl and 1,1-dioxo-thiomorpholin-4-yl.
- preferred compounds are the compounds of formula I described in the examples as individual compounds as well as pharmaceutically acceptable salts as well as pharmaceutically acceptable esters thereof. Furthermore, the substituents as found in the specific examples described below, individually constitute separate preferred embodiments of the present invention.
- Particularly preferred compounds of formula I of present invention are those selected from the group consisting of:
- the invention further provides a process for the manufacture of compounds of formula I as defined above, which process comprises:
- reaction of a compound of formula II with HNR 3 NR 4 R 5 to obtain a compound of formula I can be carried out under conditions as described in the examples or under conditions well known to the person skilled in the art.
- the reaction can be performed in the presence of trimethylaluminium in a suitable solvent like dioxane at elevated temperatures e.g. at 85-95° C.
- reaction of a compound of formula III with HNR 3 NR 4 R 5 to obtain a compound of formula I can be carried out under conditions as described in the examples or under conditions well known to the person skilled in the art.
- the reaction can be performed in the presence of Hünigs Base (N,N-diisopropylethylamine) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate in a suitable solvent like dimethylformamide at room temperature.
- the reaction can be performed in the presence of 1,1′-carbonyldiimidazole in a suitable solvent like dimethylformamide at elevated temperatures e.g. at 80° C.
- reaction can be performed in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N1-hydroxybenzotriazole and Hünigs Base (N,N-diisopropylethylamine) in a suitable solvent like dichloromethane at room temperature.
- the saponification of a compound of formula II to obtain a compound of formula III can be carried out under conditions as described in the examples or under conditions well known to the person skilled in the art.
- the reaction can be performed in the presence of sodiumhydroxide in a suitable solvent like water at room temperature.
- the reaction can be performed in the presence of lithiumhydroxide in a suitable solvent like methanol, tetrahydrofuran or water at room temperature.
- the present invention also provides compounds of formula I as defined above, when prepared by a process as described above.
- the corresponding salts with acids can be obtained by standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a suitable solvent such as e.g. dioxan or THF and adding an appropriate amount of the corresponding acid.
- a suitable solvent such as e.g. dioxan or THF
- the products can usually be isolated by filtration or by chromatography.
- the conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base.
- One possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g.
- the conversion of compounds of formula I into pharmaceutically acceptable esters can be carried out e.g. by treatment of a suitable carboxy group present in the molecule with a suitable alcohol using e.g. a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), N,N-dicylohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) or O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluoroborate (TPTU), or by direct reaction with a suitable alcohol under acidic conditions, as for example in the presence of a strong mineral acid like hydrochloric acid, sulfuric acid and the like.
- a condensating reagent
- the compounds of formula I in this invention can be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
- novel compounds of the present invention and their pharmaceutically acceptable salts and esters possess valuable pharmacological properties and are ligands for GABA A ⁇ 5 receptors.
- the compounds of the present invention can therefore be used, either alone or in combination with other drugs, for the treatment or prevention of diseases which are modulated by ligands for GABA A receptors containing the ⁇ 5 subunit.
- These diseases include, but are not limited to acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke, attentional disorders and need for cognition enhancement.
- ALS amyotrophic lateral sclerosis
- the invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
- the invention likewise embraces compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment or prevention of diseases which are related to the GABA A ⁇ 5 receptor, particularly for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attentional disorders or for use as cognitive enhancers
- the invention relates to a method for the treatment or prevention of diseases which are related to the GABA A ⁇ 5 receptor, particularly for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attentional disorders or for cognition enhancement, which method comprises administering a compound as defined above to a
- the invention also embraces the use of compounds as defined above for the treatment or prevention of diseases which are related to the GABA A ⁇ 5 receptor, particularly for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attentional disorders or for cognition enhancement.
- diseases which are related to the GABA A ⁇ 5
- the invention also relates to the use of compounds as described above for the preparation of medicaments for the treatment or prevention of diseases which are related to the GABA A ⁇ 5 receptor, particularly for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attentional disorders or for the preparation of cognitive enhancers.
- the treatment or prevention of cognitive disorders Alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, Down syndrome, and neurofibromatosis type I, is preferred.
- Particularly preferred is the treatment or prevention of Alzheimer's disease.
- Particularly preferred is the treatment or prevention of Down syndrome.
- Particularly preferred is the treatment or prevention of neurofibromatosis type I.
- the affinity of compounds at GABA A receptor subtypes was measured by competition for [ 3 H]flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of composition ⁇ 1 ⁇ 3 ⁇ 2, ⁇ 2 ⁇ 3 ⁇ 2, ⁇ 3 ⁇ 3 ⁇ 2 and ⁇ 5 ⁇ 3 ⁇ 2.
- Radioligand binding assays were carried out in a volume of 200 mL (96-well plates) which contained 100 mL of cell membranes, [ 3 H]-Flumazenil at a concentration of 1 nM for ⁇ 1, ⁇ 2, ⁇ 3 subunits and 0.5 nM for ⁇ 5 subunits and the test compound in the range of 10-10 ⁇ 3 ⁇ 10 ⁇ 6 M.
- Nonspecific binding was defined by 10 ⁇ 5 M diazepam and typically represented less than 5% of the total binding.
- Assays were incubated to equilibrium for 1 hour at 4° C.
- the compounds of the accompanying examples were tested in the above described assay, and the preferred compounds were found to possess a K i value for displacement of [ 3 H]-Flumazenil from ⁇ 5 subunits of the rat GABA A receptor of 100 nM or less. Most preferred are compounds with a K i (nM) ⁇ 35. In a preferred embodiment the compounds of the invention are binding selective for the ⁇ 5 subunit relative to the ⁇ 1, ⁇ 2 and ⁇ 3 subunit.
- test results obtained by the above described assay measuring binding affinity to HEK293 cells expressing human (h) receptors, are shown in table 1 below.
- the present invention also provides pharmaceutical compositions containing compounds of the invention, for example compounds of formula I and their pharmaceutically acceptable acid addition salts, and a pharmaceutically acceptable carrier.
- Such pharmaceutical compositions can be in the form of tablets, coated tablets, drag ⁇ es, hard and soft gelatin capsules, solutions, emulsions or suspensions.
- the pharmaceutical compositions also can be in the form of suppositories or injection solutions.
- the pharmaceutical compounds of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
- suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragées and hard gelatin capsules.
- Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
- Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
- Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
- Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
- compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 to 1000 mg per person of a compound of formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
- the active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
- the mixture is returned to the mixer, the talc is added thereto and mixed thoroughly.
- the mixture is filled by machine into hard gelatine capsules.
- the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09159150 | 2009-04-30 | ||
EP09159150.3 | 2009-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
US20100280019A1 true US20100280019A1 (en) | 2010-11-04 |
Family
ID=42229188
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/766,125 Abandoned US20100280019A1 (en) | 2009-04-30 | 2010-04-23 | Isoxazoles |
US12/766,202 Active 2030-05-01 US8227461B2 (en) | 2009-04-30 | 2010-04-23 | Isoxazoles |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/766,202 Active 2030-05-01 US8227461B2 (en) | 2009-04-30 | 2010-04-23 | Isoxazoles |
Country Status (15)
Country | Link |
---|---|
US (2) | US20100280019A1 (fr) |
EP (1) | EP2424863B1 (fr) |
JP (1) | JP5478714B2 (fr) |
KR (1) | KR101438261B1 (fr) |
CN (1) | CN102395583B (fr) |
AR (1) | AR077534A1 (fr) |
AU (1) | AU2010243652B2 (fr) |
BR (1) | BRPI1016192A8 (fr) |
CA (1) | CA2750678C (fr) |
ES (1) | ES2431389T3 (fr) |
IL (1) | IL214251A0 (fr) |
MX (1) | MX2011011303A (fr) |
SG (1) | SG175316A1 (fr) |
TW (1) | TW201043621A (fr) |
WO (1) | WO2010125042A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100286159A1 (en) * | 2009-05-05 | 2010-11-11 | Lucas Matthew C | Pyridazines |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK2767536T3 (en) * | 2007-12-04 | 2015-10-19 | Hoffmann La Roche | Isoxazolo-pyridine derivatives |
JP2013544808A (ja) * | 2010-11-05 | 2013-12-19 | エフ.ホフマン−ラ ロシュ アーゲー | 中枢神経系疾患の処置のための活性医薬化合物の使用 |
US20150374705A1 (en) | 2012-02-14 | 2015-12-31 | Shanghai Institues for Biological Sciences | Substances for treatment or relief of pain |
WO2014001278A1 (fr) | 2012-06-26 | 2014-01-03 | Aniona Aps | Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa |
WO2014001280A1 (fr) | 2012-06-26 | 2014-01-03 | Aniona Aps | Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa |
WO2014001279A1 (fr) | 2012-06-26 | 2014-01-03 | Aniona Aps | Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa |
RU2014149123A (ru) | 2012-06-26 | 2016-08-20 | Саниона Апс | Фенилтриазольное производное и его применение для модуляции ГАМКА-рецепторного комплекса |
CN104411699B (zh) | 2012-06-26 | 2017-06-13 | 萨尼奥纳有限责任公司 | 苯基三唑衍生物及其用于调节gabaa 受体复合体的用途 |
BR102019014802A2 (pt) | 2018-07-20 | 2020-02-04 | Boehringer Ingelheim Int | difluorometil-fenil triazóis |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3525205A1 (de) * | 1984-09-11 | 1986-03-20 | Hoechst Ag, 6230 Frankfurt | Pflanzenschuetzende mittel auf basis von 1,2,4-triazolderivaten sowie neue derivate des 1,2,4-triazols |
GB9808663D0 (en) | 1998-04-23 | 1998-06-24 | Merck Sharp & Dohme | Therapeutic agents |
US6660753B2 (en) | 1999-08-19 | 2003-12-09 | Nps Pharmaceuticals, Inc. | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
IT1314191B1 (it) | 1999-10-18 | 2002-12-06 | Recordati Chem Pharm | Derivati isossazolcarbossamidici |
US6511987B1 (en) | 1999-11-12 | 2003-01-28 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
PA8535601A1 (es) | 2000-12-21 | 2002-11-28 | Pfizer | Derivados benzimidazol y piridilimidazol como ligandos para gabaa |
GB0108475D0 (en) | 2001-04-04 | 2001-05-23 | Merck Sharp & Dohme | New compounds |
CN1671386A (zh) | 2001-07-05 | 2005-09-21 | H·隆德贝克有限公司 | 作为mch选择性拮抗剂的取代苯胺基哌啶 |
ATE381542T1 (de) | 2001-08-13 | 2008-01-15 | Phenex Pharmaceuticals Ag | Nr1h4-kern-rezeptor-bindende verbindungen |
AU2002353844A1 (en) | 2001-11-20 | 2003-06-10 | Eli Lilly And Company | Beta 3 adrenergic agonists |
GB0128160D0 (en) | 2001-11-23 | 2002-01-16 | Merck Sharp & Dohme | Novel compounds |
WO2004048349A1 (fr) | 2002-11-22 | 2004-06-10 | Smithkline Beecham Corporation | Agonistes de recepteur farnesoide x |
GB0318447D0 (en) | 2003-08-05 | 2003-09-10 | Merck Sharp & Dohme | Therapeutic agents |
EP1756086B1 (fr) | 2004-06-01 | 2008-06-04 | F.Hoffmann-La Roche Ag | Pyridin-4-yl-ethynyl-imidazoles et pyrazoles, antagonistes du recepteur mglur5 |
JP2008502687A (ja) | 2004-06-14 | 2008-01-31 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
CA2581945C (fr) | 2004-10-01 | 2011-01-18 | Henrietta Dehmlow | Derives d'ether substitues par du hexafluoroisopropanol |
WO2006044617A1 (fr) | 2004-10-15 | 2006-04-27 | The Scripps Research Institute | Inhibiteurs oxadiazole cetone d'hydrolase d'amide d'acide gras |
US20070060589A1 (en) | 2004-12-21 | 2007-03-15 | Purandare Ashok V | Inhibitors of protein arginine methyl transferases |
ATE484416T1 (de) | 2005-07-20 | 2010-10-15 | Prospective Concepts Ag | Pneumatisch verstellbare seitenwangen für fahrzeugsitze |
AU2006298867A1 (en) * | 2005-09-19 | 2007-04-12 | F. Hoffmann-La Roche Ag | Isoxazolo derivatives as GABA A alpha5 inverse agonists |
WO2007052843A1 (fr) | 2005-11-04 | 2007-05-10 | Takeda Pharmaceutical Company Limited | Compose amide heterocyclique et son utilisation |
WO2007076260A2 (fr) | 2005-12-19 | 2007-07-05 | Smithkline Beecham Corporation | Agonistes de recepteur de farnesoide x |
BRPI0707427A2 (pt) | 2006-02-03 | 2011-05-03 | Lilly Co Eli | composto ou um sal farmaceuticamente aceitável do mesmo, método para tratar dislipidemia, aterosclerose, e diabetes e complicações da mesma, para elevar os nìveis plásmicos de hdl, e para diminuir triglicerìdeos plásmicos, composição farmacêutica, e, uso de um composto ou de um sal farmaceuticamente aceitável do mesmo |
JP2007230909A (ja) | 2006-03-01 | 2007-09-13 | Univ Of Tokyo | 置換イソキサゾール誘導体 |
ES2328185T3 (es) * | 2006-05-31 | 2009-11-10 | F. Hoffmann-La Roche Ag | Derivados de aril-4-etinil-isoxazol. |
EP1894928A1 (fr) | 2006-08-29 | 2008-03-05 | PheneX Pharmaceuticals AG | Composes heterocycliques de liaison au fxr |
EP1894924A1 (fr) | 2006-08-29 | 2008-03-05 | Phenex Pharmaceuticals AG | Composés hétérocycliques de liason du FXR |
US7943653B2 (en) * | 2007-08-13 | 2011-05-17 | Janssen Pharmaceutica N.V. | Substituted 5-vinylphenyl-1-phenyl-pyrazole cannabinoid modulators |
DK2767536T3 (en) * | 2007-12-04 | 2015-10-19 | Hoffmann La Roche | Isoxazolo-pyridine derivatives |
US7943619B2 (en) * | 2007-12-04 | 2011-05-17 | Hoffmann-La Roche Inc. | Isoxazolo-pyridazine derivatives |
CN101883769B (zh) * | 2007-12-04 | 2012-08-08 | 弗·哈夫曼-拉罗切有限公司 | 异噁唑-吡嗪衍生物 |
EP2427458B1 (fr) * | 2009-05-05 | 2014-05-07 | F.Hoffmann-La Roche Ag | Dérivés d'isoxazole-pyridazine |
WO2010127978A1 (fr) * | 2009-05-07 | 2010-11-11 | F. Hoffmann-La Roche Ag | Dérivés d'isoxazole-pyridine en tant que modulateurs de gaba |
-
2010
- 2010-04-23 US US12/766,125 patent/US20100280019A1/en not_active Abandoned
- 2010-04-23 US US12/766,202 patent/US8227461B2/en active Active
- 2010-04-27 CA CA2750678A patent/CA2750678C/fr not_active Expired - Fee Related
- 2010-04-27 BR BRPI1016192A patent/BRPI1016192A8/pt not_active Application Discontinuation
- 2010-04-27 ES ES10715840T patent/ES2431389T3/es active Active
- 2010-04-27 CN CN201080016615.3A patent/CN102395583B/zh not_active Expired - Fee Related
- 2010-04-27 SG SG2011077500A patent/SG175316A1/en unknown
- 2010-04-27 EP EP10715840.4A patent/EP2424863B1/fr not_active Not-in-force
- 2010-04-27 MX MX2011011303A patent/MX2011011303A/es active IP Right Grant
- 2010-04-27 AU AU2010243652A patent/AU2010243652B2/en not_active Expired - Fee Related
- 2010-04-27 WO PCT/EP2010/055591 patent/WO2010125042A1/fr active Application Filing
- 2010-04-27 JP JP2012506532A patent/JP5478714B2/ja active Active
- 2010-04-27 TW TW099113368A patent/TW201043621A/zh unknown
- 2010-04-27 KR KR1020117025276A patent/KR101438261B1/ko not_active IP Right Cessation
- 2010-04-29 AR ARP100101438A patent/AR077534A1/es not_active Application Discontinuation
-
2011
- 2011-07-21 IL IL214251A patent/IL214251A0/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100286159A1 (en) * | 2009-05-05 | 2010-11-11 | Lucas Matthew C | Pyridazines |
US8410104B2 (en) * | 2009-05-05 | 2013-04-02 | Hoffmann-La Roche Inc. | Pyridazines |
Also Published As
Publication number | Publication date |
---|---|
IL214251A0 (en) | 2011-09-27 |
CN102395583B (zh) | 2015-04-01 |
WO2010125042A1 (fr) | 2010-11-04 |
US20100280020A1 (en) | 2010-11-04 |
CN102395583A (zh) | 2012-03-28 |
CA2750678A1 (fr) | 2010-11-04 |
ES2431389T3 (es) | 2013-11-26 |
MX2011011303A (es) | 2011-11-18 |
CA2750678C (fr) | 2014-11-04 |
JP5478714B2 (ja) | 2014-04-23 |
SG175316A1 (en) | 2011-12-29 |
KR101438261B1 (ko) | 2014-09-05 |
AR077534A1 (es) | 2011-09-07 |
EP2424863A1 (fr) | 2012-03-07 |
JP2012524762A (ja) | 2012-10-18 |
TW201043621A (en) | 2010-12-16 |
EP2424863B1 (fr) | 2013-09-18 |
KR20120016069A (ko) | 2012-02-22 |
US8227461B2 (en) | 2012-07-24 |
BRPI1016192A8 (pt) | 2017-10-10 |
AU2010243652B2 (en) | 2013-02-07 |
AU2010243652A1 (en) | 2011-09-15 |
BRPI1016192A2 (pt) | 2016-04-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8227461B2 (en) | Isoxazoles | |
US8357703B2 (en) | Pyridines | |
US8389550B2 (en) | Isoxazoles / O-pyridines with ethyl and ethenyl linker | |
US8222246B2 (en) | Substituted isoxazoles | |
US8415379B2 (en) | Pyridines | |
US7399769B2 (en) | Aryl-isoxazol-4-yl-imidazo[1,5-a]pyridine derivatives | |
US8410104B2 (en) | Pyridazines | |
US7902201B2 (en) | Isoxazolo-pyrazine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |