CN102516165A - Substituted pyridine derivatives - Google Patents

Substituted pyridine derivatives Download PDF

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Publication number
CN102516165A
CN102516165A CN2011103097414A CN201110309741A CN102516165A CN 102516165 A CN102516165 A CN 102516165A CN 2011103097414 A CN2011103097414 A CN 2011103097414A CN 201110309741 A CN201110309741 A CN 201110309741A CN 102516165 A CN102516165 A CN 102516165A
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base
alkene
alkane
alkynes
cycloalkanes
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C·W·托诺
N·坎津
M·罗特兰德
W·P·沃森
D·R·格雷弗
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H Lundbeck AS
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H Lundbeck AS
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    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Abstract

The present invention relates to pyridine derivatives of the general formula (I) and their use as openers of the KCNQ family potassium ion channels for the treatment of CNS disorders.

Description

Substituted pyridine derivate
The application is dividing an application of following application: the applying date: on March 2nd, 2006; Application number: 200680006831.3 (PCT/DK2006/000123); Denomination of invention: " substituted pyridine derivate ".
Technical field
The present invention relates to compound as KCNQ family potassium-channel opener (opener).This compound is used to treat to KCNQ family potassium-channel open responsive illness and disease, and a kind of in these diseases is epilepsy.
Background technology
Ionic channel is to regulate ion (potassium ion, calcium ion, cl ions and the sodium ion that comprise the cell of coming in and going out) mobile cellular proteins.These passages are present in all animal and humans' the cell, and influence comprises the various processes of neurone transmission, Muscle contraction and emiocytosis.
The mankind have more than 70 kinds the gene of coding potassium channel hypotype, and (Jentsch Nature Reviews Neuroscience 2000,1,21-30), each hypotype has very big difference aspect 26S Proteasome Structure and Function.The neurone potassium channel of finding in the brain mainly is responsible for keeping negative resting membrane electric potential, and after action potential the repolarization of controlling diaphragm.
A hypotype of potassium channel gene is a KCNQ family.In 5 KCNQ genes 4 undergo mutation be the reason that causes the disease that comprises irregular pulse, deafness and epilepsy (Jentsch Nature Reviews Neuroscience 2000,1,21-30).
It is generally acknowledged the molecule relevant with potassium channel in KCNQ4 genes encoding cochlea external hair cell and the vestibular organ I type hair cell, the sudden change of this gene can cause causing hereditary hearing impairment.
KCNQ1 (KvLQT1) assembles formation heart delayed rectification appearance K (+) electric current jointly with the product of heart KCNE1 (minimum K (+)-channel protein) gene.The sudden change of this passage can cause heredity 1 type long QT syndrome (inherited long QT syndrome type 1 (LQT1)), and relevant with a kind of deafness (Robbins Pharmacol Ther 2001,90,1-19).
Gene KCNQ2 and KCNQ3 are found in 1988; (Rogawski Trends in Neurosciences 2000 undergos mutation in a kind of genotype epilepsy that is called benign neonatal familial convulsions (benign familial neonatal convulsions); 23,393-398).(Cooper etc. in the taper neurone of the cortex that is confined to the people by KCNQ2 encoded protein matter and KCNQ3 albumen and hippocampus (produce with epileptic seizures and fill the air relevant brain district); Proceedings National Academy of Science USA 2000; 97,4914-4919).
KCNQ2 and KCNQ3 are two potassium channel subunits, when at vivoexpression, can form " M-electric current ".The M-electric current is the potassium current of a kind of non-inactivation of in many neuronal cell types, finding.In various cell types, it mainly be through in the scope that begins at action potential as the electric current of unique maintenance with the irritability of controlling diaphragm (Marrion Annual Review Physiology 1997,59,483-504).The adjusting of M-electric current is very remarkable to the effect of neuronal excitability, and for example the activation of electric current will reduce neuronal excitability.The opener of these KCNQ passages; Or the activator of M-electric current; To reduce excessive neuronal activity, therefore can be used for treating epileptic seizures is the disease and the illness of characteristic with other with excessive neuronal activity (for example neurone hyperexcitability), comprises convulsions illness, epilepsy and neuropathic pain.
EP554543 discloses retigabine (D-23129; Urethanum) and analogue N-(2-amino-4-(4-luorobenzyl amino)-phenyl).Retigabine is that the wide spectrum and the effective anticonvulsion compound of anticonvulsant properties are all arranged in a kind of external and the body.In comprising epileptic seizures that electricity brings out, various anticonvulsion test by the chemically induced epileptic seizures of pentetrazole, Picrotoxin and N-methyl-D-aspartate (NMDA); And in genetic animal model DBA/2 mouse; It is effective (Rostock etc. that retigabine oral administration and intraperitoneal give behind rat and the mouse; Epilepsy Research 1996,23,211-223).In addition, retigabine is effectively in the amygdala kindling model (amygdala kindling model) of complex partial property epilepsy outbreak, further specifies the validity of this compound to anticonvulsion treatment.In recent clinical trial, retigabine also demonstrate reduce effectiveness aspect epileptic's epileptic seizures sickness rate (Bialer etc., Epilepsy Research 2002,51,31-71).
Retigabine also shows K (+) electric current that activates in the neuronal cell, and the pharmacological property of this induced current shows consistent with the pharmacological property of the M-passage of having announced, recently M-passage and KCNQ2/3K (+) passage heteromultimers is linked together.Activation of this prompting KCNQ2/3 passage possibly be that (Wickenden etc., Molecular Pharmacology 2000,58 591-600), and can have similar applications by the other medicines that same mechanism is had an effect for the reason of this certain anti-convulsant activity of medicine.
Also once had report to point out, in the neuropathic pain model, KCNQ 2 is raised (Wickenden etc. with KCNQ 3 passages; Society for Neuroscience Abstracts 2002; 454.7), and think potassium channel modulating agents to neuropathic pain and epilepsy have activity (Schroder etc., Neuropharmacology 2001; 40,888-898).
Retigabine also shows animal model useful (Blackburn-Munro and the Jensen European Journal of Pharmacology 2003 to neuropathic pain; 460; 109-116), therefore point out the KCNQ channel opener to can be used for treating painful diseases, comprise neuropathic pain.
There is report to point out that KCNQ passage mRNA is in the location (Goldstein etc., Society for Neuroscience Abstracts2003,53.8) in brain and other cns district relevant with pain.
Except that effect to neuropathic pain; KCNQ 2-5mRNA means that in the expression of gasserian ganglion, DRGs and trigeminal nerve caudatum the opener of these passages also can influence migrainous sense process (sensory processing) (Goldstein etc.; Society for Neuroscience Abstracts 2003,53.8).
Recent report confirms that except that the mRNA of KCNQ 2, the mRNA of KCNQ 3 and KCNQ5 expresses in stellate cell and neurogliocyte.Therefore, the synaptic activity that KCNQ 2, KCNQ3 and KCNQ 5 passages can assist to regulate CNS helps the neuroprotective (Noda etc., Society for Neuroscience Abstracts2003,53.9) of KCNQ channel opener.
Because showing, retigabine prevents epileptic state that brain edge neurodegeneration and kainic acid the bring out expression (Ebert etc. of apoptosis mark afterwards in rat; Epilepsia 2002; 43 supplementary issues 5; 86-95), therefore, retigabine and other KCNQ regulator can prevent the epilepsy of neurodegeneration aspect.This maybe be relevant with the epilepsy process that stops the patient, that is to say it is antiepileptic.The retigabine process that also the display delay hippocampus is lighted in another epilepsy generation model rat (Tober etc., European Journal Of Pharmacology 1996,303,163-169).
Therefore, it is believed that these character of retigabine and other KCNQ regulator can prevent that the neurone that is brought out by excessive neuronal activation from damaging, these compounds can be used for treating neurodegenerative disease, can alleviate epileptic's the state of an illness (or epilepsy).
Known anticonvulsion compound (for example benzene diaza
Figure BSA00000591788100041
class and Wy-1485) is used to treat alcohol withdrawal syndrome clinically; And other anticonvulsion compound (for example gabapentin) is very effective (Watson etc. to this syndromic animal model; Neuropharmacology1997; 36; 1369-1375), therefore estimate that other anticonvulsion compound (for example KCNQ opener) also is effective to this symptom.
For example KCNQ 2 and KCNQ 3 Subunit mRNA (Saganich etc., Journal of Neuroscience 2001,21 have been found in hippocampus and the amygdala in the brain district relevant with mood behavior (for example bipolar disorder) with the anxiety behavior; 4609-4624); Report that retigabine has activity (Hartz etc., Journal of Psychopharmacology 2003,17 in some anxiety-like behavior animal model; Supplementary issue 3; A28, B16), and the anticonvulsion compound of other clinical use is used to treat bipolar disorder.Therefore, the KCNQ opener can be used to treat anxiety disorder and bipolar disorder.
WO 200196540 discloses the purposes of M-current setting agent in insomnia that forms through KCNQ2 and KCNQ3 genetic expression, and WO 2001092526 then discloses the KCNQ5 regulator and can be used for treating somnopathy.
WO01/022953 has introduced retigabine in prevention and the treatment neuropathic pain purposes in allodynia, hyperpathia property pain, phantom pain, the neuropathic pain with diabetic neuropathy relevant and the neuropathic pain of being correlated with migraine for example.
WO02/049628 has introduced retigabine in the treatment anxiety disorder purposes in stress disorder, gross stress reaction (acute stress reaction), adjustment disorder, hypochondria, separation anxiety diaorder (separation anxiety disorder), agoraphobia and the simple terror after anxiety, generalized anxiety disorder, terrified property anxiety (panic anxiety), obsessive-compulsive disorder, social phobia, behavior anxiety (performance anxiety), the wound for example.
WO97/15300 has introduced retigabine and has treated such as the purposes in the following neurodegenerative disease: alzheimer's disease (Alzheimer ' s disease); Huntington Chorea (Huntington ' s chorea); Sclerosis is multiple sclerosis and amyotrophic lateral sclerosis for example; Creutz Fil spy-jacob's syndrome (Creutzfeld-Jakob disease); Parkinson's disease (Parkinson ' s disease); The encephalopathic of bringing out behind AIDS or rubella virus, simplexvirus, burgdorferi (borrelia) and the unknown pathogenic infection; Bringing out property of wound neurodegeneration; The neurodegenerative disease of ultra state of excitation of neurone (for example drug withdrawal or poisoning) and peripheral nervous system (for example polyneuropathy and polyneuritis (polyneuritides)).
Find that also the KCNQ channel opener is effectively to the treatment of apoplexy, can expect that therefore selectivity KCNQ opener also can effectively treat apoplexy (Schroder etc., Pflugers Arch., 2003; 446 (5): 607-16; Cooper and Jan, Arch Neurol., 2003,60 (4): 496-500; Jensen, CNS Drug Rev., 2002,8 (4): 353-60).
The KCNQ passage be presented at expression in the dopaminergic loop and cholinergic loop in the brain relevant with reward of brain system, particularly brain ventral tegmental area (ventral tegmental area) (Cooper etc., J Neurosci, 2001,21,9529-9540).Therefore, expection KCNQ channel opener is effective in relating to the hyperexcitability disease of reward of brain system (for example cocaine abuse, nicotine withdrawal and alcohol are given up).
Potassium channel by the KCNQ4 subunit is formed is expressed (Kubisch etc., Cell., February 5 in 1999 in inner ear; Therefore 96 (3): 437-46), expect that the opening of these passages can treat tinnitus.
Therefore, be starved of the effectively new compound of KCNQ family potassium channel openers of conduct.
Also need be with respect to the compound of known KCNQ family's potassium channel openers (for example retigabine), the significantly improved new compound of character.
One or more parameters below needing to improve:
Transformation period, clearance rate, selectivity, with interaction, bioavailability, effect, preparation property, chemicalstability, metabolic stability, membrane permeability, solubleness and the therapeutic index of other medicines.The improvement of these parameters for example can improve:
Improve dosage regimen through reducing by one day required administration number of times,
Be convenient to give the patient multiple medicine,
Spinoff reduces,
Therapeutic index improves,
Tolerance is improved, perhaps
Conformability is improved.
Summary of the invention
An object of the present invention is to provide compound as effective KCNQ family potassium channel openers.
Compound of the present invention is the substituted pyridine derivate of following formula I, is free alkali or its salt:
Figure BSA00000591788100061
Wherein:
R 1, R 2, R 3With q as giving a definition.
The present invention provides formula I compound, as medicine.
The present invention provides pharmaceutical composition, and said compsn comprises formula I compound and pharmaceutically acceptable carrier or thinner.
The present invention provides the purposes of formula I compound in the medicine of preparation treatment epileptic seizures disease (seizure disorder), anxiety disorder, neuropathic pain and migraine property pain disease (migraine pain disorder) or neurodegenerative disease.
The present invention also relates to the purposes of formula I compound in the method for treatment epileptic seizures disease, anxiety disorder, neuropathic pain and migraine property pain disease or neurodegenerative disease in addition.
Substituent definition
Term " heteroatoms " is meant nitrogen, oxygen or sulphur atom.
" halogen " is meant fluorine, chlorine, bromine or iodine.
" cyanic acid " is meant C ≡ N, and it is connected to the rest part of molecule through carbon atom.
Term " C 1-6-alkane (alkene/alkynes) base " be meant C 1-6-alkyl, C 2-6-thiazolinyl or C 2-6-alkynyl.
Term " C 1-6Alkyl " be meant side chain or unbranched alkyl with 1-6 carbon atom; include but not limited to methyl, ethyl, third-1-base, third-2-base, 2-methyl-third-1-base, 2-methyl-third-2-base, 2,2-dimethyl--third-1-base, fourth-1-base, fourth-2-base, 3-methyl-Ding-1-base, 3-methyl-Ding-2-base, penta-1-base, penta-2-base, penta-3-base, oneself-1-base, oneself-2-base and oneself-3-base.
Term " C 2-6Thiazolinyl " be meant side chain or unbranched thiazolinyl with 2-6 carbon atom and two keys, include but not limited to vinyl, propenyl and crotonyl.
Term " C 2-6Alkynyl " be meant to have 2-6 carbon atom and a triple-linked side chain or unbranched alkynyl, include but not limited to ethynyl, proyl and butynyl.
Term " C 1-8-alkane (alkene/alkynes) base " be meant C 1-8-alkyl, C 2-8-thiazolinyl or C 2-8-alkynyl.
Term " C 1-8-alkyl " be meant side chain or unbranched alkyl with 1-8 carbon atom; include but not limited to methyl, ethyl, third-1-base, third-2-base, 2-methyl-third-1-base, 2-methyl-third-2-base, 2; 2-dimethyl--third-1-base, fourth-1-base, fourth-2-base, 3-methyl-Ding-1-base, 3-methyl-Ding-2-base, penta-1-base, penta-2-base, penta-3-base, oneself-1-base, oneself-2-base, oneself-3-base, 2-methyl-4,4-dimethyl--penta-1-base with heptan-1-is basic.
Term " C 2-8-thiazolinyl " be meant side chain or unbranched thiazolinyl with 2-8 carbon atom and two keys, include but not limited to vinyl, propenyl and crotonyl.
Term " C 2-8-alkynyl " be meant to have 2-8 carbon atom and a triple-linked side chain or unbranched alkynyl, include but not limited to ethynyl, proyl and butynyl.
Term " C 3-8-cycloalkanes (alkene) base " be meant C 3-8-naphthenic base or C 3-8-cycloalkenyl group.
Term " C 3-8-naphthenic base " be meant monocycle carbocyclic ring or bicyclic carbocyclic with 3-8 carbon atom, include but not limited to for example 2-two ring [2.2.1] heptyl of cyclopropyl, cyclopentyl, cyclohexyl, two suberyl.
Term " C 3-8-cycloalkenyl group " be meant monocycle carbocyclic ring or bicyclic carbocyclic with 3-8 carbon atom and two keys, include but not limited to cyclopentenyl and cyclohexenyl.
Term " C 3-8-heterocycle alkane (alkene) base " be meant C 3-8-Heterocyclylalkyl or C 3-8-heterocycloalkenyl.
Term " C 3-8-Heterocyclylalkyl " be meant monocycle or dicyclo ring system, wherein this ring is selected from 2-7 carbon atom and 1 or 2 heteroatomic atomic buildings by 3-8, and heteroatoms independently is selected from nitrogen, oxygen and sulphur atom.C 3-8The instance of-Heterocyclylalkyl is tetramethyleneimine, azepan (azepan), morpholine, piperidines, piperazine and THF.
Term " C 3-8-heterocycloalkenyl " be meant the monocycle ring system or the dicyclo ring system that contain two keys, wherein this ring is selected from 2-7 carbon atom and 1 or 2 heteroatomic atomic buildings by 3-8, and heteroatoms independently is selected from nitrogen, oxygen and sulphur atom.C 3-8The instance of-heterocycloalkenyl is pyrrolin, dihydrofuran-and dihydro-thiophene.
Work as C 3-8-heterocycle alkane (alkene) is when base comprises nitrogen, then C 3-8-heterocycle alkane (alkene) base is connected to the rest part of molecule through heterocyclic carbon atom or nitrogen-atoms.
Work as C 3-8When-heterocycle alkane (alkene) base does not comprise nitrogen, C then 3-8-heterocycle alkane (alkene) base is connected to the rest part of molecule through the heterocyclic carbon atom.
Term " halogen-C 1-6-alkane (alkene/alkynes) base " be meant by the substituted C of halogen 1-6-alkane (alkene/alkynes) base includes but not limited to trifluoromethyl.
Equally, " halogen-C 3-8-cycloalkanes (alkene) base " be meant by the substituted C of halogen 3-8-cycloalkanes (alkene) base includes but not limited to Cyclopropanoyl Chloride and chlorine hexanaphthene.
Equally, " halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base " be meant through C 1-6-alkane (alkene/alkynes) base is connected to the halogen-C of molecule rest part 3-8-cycloalkanes (alkene) base.
Term " C 1-6The basic oxygen base of-alkane (alkene/alkynes) " be meant the C that is connected to the molecule rest part through Sauerstoffatom 1-6-alkane (alkene/alkynes) base.
Equally, " C 3-8The basic oxygen base of-cycloalkanes (alkene) " be meant the C that is connected to the molecule rest part through Sauerstoffatom 3-8-cycloalkanes (alkene) base.
Term " C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " aryl-C 1-6-alkane (alkene/alkynes) base ", " aryl-C 3-8-cycloalkanes (alkene) base ", " aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " heteroaryl-C 1-6-alkane (alkene/alkynes) base ", " heteroaryl-C 3-8-cycloalkanes (alkene) base ", " heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " NR 4R 5-C 1-6-alkane (alkene/alkynes) base ", " NR 4R 5-C 3-8-cycloalkanes (alkene) base ", " NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ", " C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes) ", " C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base ", " C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base " and " C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base " in, term " C 1-6-alkane (alkene/alkynes) base ", " C 3-8-cycloalkanes (alkene) base ", " aryl ", " C 3-8-heterocycle alkane (alkene) base ", " heteroaryl ", " C 1-6The basic oxygen base of-alkane (alkene/alkynes) " and " C 3-8The basic oxygen base of-cycloalkanes (alkene) " as above definition.
Term " heteroaryl " is meant monocycle or the dicyclo heteroaromatic system that is selected from pyridyl, thienyl, furyl, pyrryl, pyrazolyl, triazolyl, tetrazyl,
Figure BSA00000591788100091
azoles base, imidazolyl, thiazolyl, benzofuryl, benzothienyl and indyl.
Term aryl is meant monocycle or the bicyclic aromatic system that is selected from phenyl and naphthyl.
Term " optional substituted aryl-C 1-6-alkane (alkene/alkynes) base " be meant wherein aryl moiety optional by for example 1,2 or 3 independently be selected from the substituted aryl-C of following substituting group 1-6-alkane (alkene/alkynes) base: halogen, cyanic acid, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).
Equally, " optional substituted aryl-C 3-8-cycloalkanes (alkene) base " be meant wherein aryl moiety optional by for example 1,2 or 3 independently be selected from the substituted aryl-C of following substituting group 3-8-cycloalkanes (alkene) base: halogen, cyanic acid, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).
Equally, " optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base " be meant wherein aryl moiety optional by for example 1,2 or 3 independently be selected from the substituted aryl-C of following substituting group 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base: halogen, cyanic acid, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).
Embodiment
The present invention relates to substituted pyridine derivate as the kcnq potassium channel opener.
The present invention relates to the compound that following general formula I is represented, this compound is free alkali or its salt:
Figure BSA00000591788100101
Wherein
Q is 0 or 1;
R 1And R 2Be selected from halogen, cyanic acid, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base and halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 4And R 5Be selected from hydrogen, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
In an embodiment of formula I compound, q is 0;
In another embodiment of formula I compound, q is 1.
In another embodiment of formula I compound, R 1And R 2Be selected from halogen, cyanic acid, halogen-C independently of one another 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
In another embodiment, R 1And R 2Be selected from halogen, cyanic acid, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
In another embodiment, R 1And R 2Be selected from halogen, cyanic acid and C independently of one another 1-6-alkane (alkene/alkynes) base and C 1-6The basic oxygen base of-alkane (alkene/alkynes);
In another embodiment, R 1And R 2Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 1Be C 1-6-alkane (alkene/alkynes) base, for example methyl;
In another embodiment, R 2Be C 1-6-alkane (alkene/alkynes) base, for example methyl;
In another embodiment, R 1Be C 1-6The basic oxygen base of-alkane (alkene/alkynes) is methoxyl group for example, R 2Be halogen;
In another embodiment, R 1Be halogen, R 2Be C 1-6The basic oxygen base of-alkane (alkene/alkynes) is methoxyl group for example.
Usually, R 1And R 2Two all is C 1-6-alkane (alkene/alkynes) base, for example methyl.
In another embodiment of formula I compound, R 3Be selected from C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base and halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base and NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base and NR 4R 5-C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base and heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Usually, R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base and heteroaryl-C 1-6-alkane (alkene/alkynes) base.
Further give an example R not limiting under the situation of the present invention 3An embodiment be C 1-8-alkane (alkene/alkynes) base;
R 3Another embodiment be C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
R 3Another embodiment be optional substituted aryl-C 1-6-alkane (alkene/alkynes) base;
R 3Another embodiment be optional substituted aryl-C 3-8-cycloalkanes (alkene) base;
R 3Another embodiment be heteroaryl-C 1-6-alkane (alkene/alkynes) base.
In another embodiment of formula I compound, R 4And R 5Be selected from C independently of one another 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 4And R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base and hydrogen;
In another embodiment, R 4And R 5Two all is C 1-6-alkane (alkene/alkynes) base;
In another embodiment, R 4And R 5Two all is hydrogen.
In another embodiment of formula I compound, be selected from separately or as any heteroaryl of mentioning than the integral part of large-substituent: pyridyl, furyl, pyrryl, pyrazolyl, triazolyl, tetrazyl,
Figure BSA00000591788100131
azoles base, imidazolyl, thiazolyl, benzofuryl, benzothienyl and indyl; In another embodiment, be thienyl separately or as any heteroaryl of mentioning than the integral part of large-substituent.
In another embodiment of formula I compound, any aryl independent or that conduct is mentioned than the integral part of large-substituent is a phenyl;
In another embodiment, be naphthyl separately or as any aryl of mentioning than the integral part of large-substituent.
In another embodiment of formula I compound, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent, can be replaced by 1 or 2 substituting group.
Further give an example not limiting under the situation of the present invention, an embodiment relates to these compounds of formula I, is unsubstituted separately or as any optional substituted aryl of mentioning than the integral part of large-substituent wherein;
In another embodiment, replaced by 1 substituting group separately or as any optional substituted aryl of mentioning than the integral part of large-substituent;
In another embodiment, replaced by 2 substituting groups separately or as any optional substituted aryl mentioned than the large-substituent integral part.
In another embodiment of formula I compound, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent, can be selected from following substituting group and be replaced: cyanic acid, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
In another embodiment, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent, can be selected from following substituting group and be replaced: halogen, C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base and C 1-6The basic oxygen base of-alkane (alkene/alkynes).
Further give an example not limiting under the situation of the present invention, an embodiment relates to these compounds of formula I, is wherein replaced by halogen separately or as any optional substituted aryl of mentioning than the integral part of large-substituent;
In another embodiment, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent by C 1-6-alkane (alkene/alkynes) base replaces;
In another embodiment, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent by halogen-C 1-6-alkane (alkene/alkynes) base replaces;
In another embodiment, separately or as any optional substituted aryl of mentioning than the integral part of large-substituent by C 1-6The basic oxygen base of-alkane (alkene/alkynes) replaces.
Another embodiment relates to the formula I compound as free alkali or its salt, and said compound is selected from the compound in the following table:
Figure BSA00000591788100141
Figure BSA00000591788100151
Figure BSA00000591788100161
Each of these compounds all as concrete embodiment, and is required each is all protected.
The present invention also comprises the salt of The compounds of this invention, is generally pharmacy acceptable salt.Salt of the present invention comprises acid salt, metal-salt, ammonium salt and alkylated ammonium.
Salt of the present invention is preferably acid salt.Acid salt of the present invention is preferably the pharmacy acceptable salt of The compounds of this invention and non-toxic acid formation.Acid salt comprises mineral acid and organic acid salt.The instance of suitable inorganic acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, thionamic acid, nitric acid etc.Suitable organic acid instance comprises formic acid; Acetate; Trichoroacetic acid(TCA); Trifluoroacetic acid; Propionic acid; Phenylformic acid; Styracin; Hydrocerol A; Fumaric acid; Oxyacetic acid; Methylene-succinic acid; Lactic acid; Methanesulfonic; Toxilic acid; Oxysuccinic acid; Propanedioic acid; Racemic melic acid; Oxalic acid; TNP; Pyruvic acid; Whitfield's ointment; Succsinic acid; Methylsulfonic acid; Ethyl sulfonic acid; Tartrate; Xitix; Pounce on nurse acid; The dimethylene Whitfield's ointment; Ethionic acid; Glyconic acid; Citraconic acid; Aspartic acid; Triple Pressed Stearic Acid; Palmitinic acid; EDTA; Oxyacetic acid; Para-amino benzoic acid; L-glutamic acid; Phenylsulfonic acid; Tosic acid; Theophylline acetate and 8-halo theophylline (for example 8-bromine theophylline) etc.Other instance of pharmaceutically acceptable mineral acid or organic acid comprises J.Pharm.Sci.1977, the pharmacy acceptable salt that 66,2 (being attached to this paper by reference) are listed.
The hydrate that also comprises the acid salt that The compounds of this invention can form.
The instance of metal-salt comprises lithium salts, sodium salt, sylvite, magnesium salts etc.
The instance of ammonium salt and alkylated ammonium comprises ammonium salt, methyl ammonium salt, dimethyl ammonium, leptodactyline, ethyl ammonium salt, hydroxyethyl ammonium salt, diethylammonium ammonium salt, normal-butyl ammonium salt, sec.-butyl ammonium salt, tertiary butyl ammonium salt, tetramethyl ammonium etc.
In addition, The compounds of this invention can be non-solvation form, also with the solvation form of medicine acceptable solvent (for example water, ethanol etc.).Generally speaking, to the object of the invention, the solvation form is considered to be equal to the non-solvent form.
Compound of the present invention can have one or more asymmetric centers; Any optically active isomer (being enantiomer or diastereomer); No matter be independent, pure or partial-purified optically active isomer or their any mixture (comprising racemic mixture); Be the mixture of steric isomer, all comprise within the scope of the present invention.
Racemic modification can be split as optically active enantiomorph through currently known methods, for example separates its diastereomeric salt with opticity acid, discharges the optically active amines compound with alkaline purification.With racemate resolution is that the another kind of method of optically active enantiomorph is based on the enterprising circumstances in which people get things ready for a trip spectrometry of opticity matrix and handles.Racemic compound of the present invention also can be split as their optically active enantiomorph through fractional crystallization.The compounds of this invention also can split through forming the diastereomer verivate.Can use other method of fractionation optically active isomer well known by persons skilled in the art.Such method comprises the method that following document is introduced: J.Jaques, A.Collet and S.Wilen " Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, New York (1981).Optically active compounds also can use the opticity raw material or prepare through stereospecific synthesis.
In addition, when having two keys in the molecule or wholly or in part during saturated ring system, can forming the molecular geometry isomer.No matter any geometrical isomer is independent, pure or partial-purified geometrical isomer or their mixture, all comprises within the scope of the present invention.Equally, have the molecule that hinders the chemical bond that rotates and to form geometrical isomer.These geometrical isomers are also included within the scope of the invention.
In addition, part of compounds of the present invention possibly exist with different tautomeric forms, and any tautomeric forms that said compound can form all comprises within the scope of the present invention.
The present invention also comprises the prodrug of The compounds of this invention, after administration, through the chemical conversion of metabolic process, becomes pharmaceutically active substances.Generally speaking, such prodrug is the functional derivatives of compound of Formula I, and it is easy to be converted in vivo required formula I compound.For example " Design of Prodrugs " H.Bundgaard writes, and Elsevier has introduced the routine of suitable prodrug derivant in 1985 and selected and the preparation method.
The present invention also comprises the active metabolite of The compounds of this invention.
Compound of the present invention has affinity to the KCNQ2 receptor subtype, tests the EC that records by following " through the relative discharge (Relative efflux through the KCNQ2 channel) of KCNQ2 passage " 50＜15000nM, for example EC 50＜10000nM.An embodiment relates to the formula I compound that these have affinity to the KCNQ2 receptor subtype, tests the EC that records by following " through the relative discharge of KCNQ2 passage " 50＜2000nM, for example EC 50＜1500nM.Further give an example not limiting under the situation of the present invention, an embodiment relates to the compound that these have affinity to the KCNQ2 receptor subtype, the EC that records by following " through the relative discharge of KCNQ2 passage " test 50＜200nM, for example EC 50＜150nM.
An embodiment relates to such formula I compound, in following " maximal electroshock (Maximum electroshock) " test, and its ED 50＜15mg/kg.Further give an example not limiting under the situation of the present invention, an embodiment relates to such compound, in following " maximal electroshock " test, and its ED 50＜5mg/kg.
An embodiment relates to such formula I compound; In following " electricity irritation epileptic seizures threshold value test (Electrical seizure-threshold test) " and " pharmaceutical chemicals stimulates epileptic seizures threshold value test (Chemical seizure-threshold test) ", its ED 50＜5mg/kg.
An embodiment relates to such formula I compound, and said compound nearly all is free from side effects or spinoff can be ignored clinically.Therefore, in the model of unwanted calmness, hypothermia and ataxia effect, some compound of the present invention is tested.
An embodiment relates to such formula I compound; Therapeutic index between anticonvulsion effect of said compound and spinoff is big, and spinoff is for example tested the measured autonomic activities ability (locomotor activity) or the extent of damage of ataxia effect (ataxic effect) through bull stick.The expection patient is strong to the tolerance of this compounds, and permission is used high dosage and can not observed spinoff.Therefore it is good to expect the conformability of treatment, can allow to give high dosage, so that the patient who uses other medicines to have side effects is carried out more efficiently treatment.
Therefore as already mentioned, compound of the present invention is had an effect to KCNQ family, the particularly potassium channel of KCNQ2 subunit, thinks that they can be used for increasing the ionic current of the voltage-dependent potassium channel of Mammals (for example people).It is generally acknowledged that compound of the present invention is applicable to that treatment increases responsive disease to potassium channel (for example KCNQ family potassium-channel) ionic current.This disease is preferably central nervous system disease.
On the one hand, compound of the present invention can be used as unique treatment compounds effective and gives.
On the other hand, the integral part that compound of the present invention can be used as combination therapy gives, and that is to say, compound of the present invention can be treated compounds effective (compound that for example has anticonvulsant properties) coupling with other.The effect that other this type has a compound of anticonvulsant properties can include but not limited to the activity of following aspect:
Ionic channel, for example sodium channel, potassium channel or calcium channel
Excitatory amino acid system, the for example blocking-up of nmda receptor or adjusting
Inhibitory nerve mediator system, the blocking-up of the for example increase of GABA release, or GABA picked-up
Membrane stabilizing action.
Existing anticonvulsant drug includes but not limited to tiagabine; Carbamzepine; Sodium Valproate; Lamotrigine; Gabapentin; Pregabalin; Ethosuximide; UCB-L 059; Phenytoin Sodium Salt; Topiramate; Zonisamide and benzene diaza
Figure BSA00000591788100191
class and barbiturates.
One aspect of the present invention provides as the formula I compound free alkali of medicine or its salt.
In one embodiment, the present invention relates to formula I compound free alkali or the purposes of its salt in treat-ment.
One embodiment of the invention provide the pharmaceutical composition that comprises formula I compound free alkali or its salt and pharmaceutically acceptable carrier or thinner.Said composition can comprise the formula I compound in any above-mentioned embodiment.
Another embodiment of the present invention relates to formula I compound free alkali or its salt and is used for treating the purposes of the pharmaceutical composition of disease in preparation, wherein the kcnq potassium channel opener for example the KCNQ2 potassium channel openers be useful.Usually, this type disease is selected from epileptic seizures disease, anxiety disorder, neuropathic pain and migraine property pain disease, neurodegenerative disease, apoplexy, cocaine abuse, nicotine withdrawal, alcohol and gives up and tinnitus.
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of epileptic seizures disease in preparation purposes.
Usually, subject epileptic seizures disease is selected from acute epileptic seizures, convulsions, epileptic state and epilepsy for example epilepsy syndrome and epileptic seizures (epileptic seizure).
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of anxiety disorder in preparation purposes.
Usually, subject anxiety disorder is selected from anxiety and illness and the disease relevant with following illness: panic attack, agoraphobia, with the agoraphobia of the panic disorder of the panic disorder of agoraphobia, no agoraphobia, no panic disorder history, terror, social phobia and other anxiety disorder and other anxiety disorder of not enumerating of bringing out of stress disorder after terror, obsession, the wound, acute stress sexual dysfunction, generalized anxiety disorder, the anxiety disorder that causes because of the general medical science illness, anxiety disorder that material brings out, separation anxiety diaorder, adjustment disorder, behavior anxiety, hypochondria, the anxiety disorder that causes because of the general medical science illness and material merely merely.
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of neuropathic pain and migraine property pain disease in preparation purposes.
Usually, subject neuropathic pain is selected from allodynia, hyperpathia property pain, phantom pain, the neuropathic pain relevant with diabetic neuropathy, the neuropathic pain of being correlated with trigeminal neuralgia and the neuropathic pain relevant with migraine with migraine property pain disease.
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of neurodegenerative disease in preparation purposes.
Common subject neurodegenerative disease is selected from alzheimer's disease; Huntington Chorea; Multiple sclerosis; Amyotrophic lateral sclerosis; Creutz Fil spy-jacob's syndrome; Parkinson's disease; Encephalopathic that AIDS brings out or rubella virus; Simplexvirus; The encephalopathic of bringing out behind burgdorferi and the unknown pathogenic infection; The neurodegeneration that wound is brought out; The neurodegenerative disease (for example polyneuropathy and polyneuritis) of ultra state of excitation of neurone (for example drug withdrawal or poisoning) and peripheral nervous system.
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of bipolar disorder in preparation purposes.
Another embodiment of the present invention relates to formula I compound free alkali or its salt are used for treating the pharmaceutical composition of somnopathy (for example insomnia) in preparation purposes.
The term relevant with disease used herein " treatment " also comprises prevention, suppresses and alleviates, and is determined on a case-by-case basis.
The compound of demonstration effect during the present invention is provided at and tests below at least one:
" through the relative discharge of KCNQ2 passage " test
This test is used to measure the effect of compound at destination channel.
" maximal electroshock " test
This test is measured by non-specific CNS through the method for electricity stimulates the epileptic seizures of bringing out.
" epileptic seizures that pilocarpine brings out (Pilocarpine induced seizure) " test
The epileptic seizures that pilocarpine brings out is difficult to send out with existing many epilepsys usually
The medicine of doing is treated, and is " drug resistant epilepsy outbreak " model therefore.
" test of electricity irritation epileptic seizures threshold value " and " pharmaceutical chemicals stimulates the test of epileptic seizures threshold value "
These model measurement threshold values begin to start in the threshold point epileptic seizures, therefore are whether detection compound postpones the model that epileptic seizures starts.
" amygdala are lighted " tested this test and is used for the measuring diseases process, and when accepting further to stimulate, the same with intact animal, the epileptic seizures meeting of this animal pattern is more serious.
" the electric physiology patch clamp record (Electrophysiological patch-clamp recording) of Chinese hamster ovary celI " and " electrophysiological recording of ovocyte KCNQ2, KCNQ2/KCNQ3 or KCNQ5 passage " are tested KCNQ2, KCNQ2/KCNQ3 or the KCNQ5 electric current of these trial sheet voltage-activateds.
Pharmaceutical composition
The invention still further relates to pharmaceutical composition.Compound of the present invention can be separately as free alkali or its salt or is united with single agent or multi-agent with pharmaceutically acceptable carrier or thinner and to give.Pharmaceutical composition of the present invention can be prepared according to routine techniques with pharmaceutically acceptable carrier or thinner and any other known auxiliary material or vehicle; Remington:The Science and Practice of Pharmacy for example, the 19th edition, Gennaro edits; Mack Publishing Co.; Easton, PA, disclosed technology in 1995.
Pharmaceutical composition can be prepared the administration that is used for any suitable pathways especially; For example in per os, rectum, nose, lung, part (comprising oral cavity and hypogloeeis), transdermal, the brain pond, administrations such as intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, intravenously and corium under), the preferred oral administration.Should understand, preferred approach will depend on the character and the selected activeconstituents of the general health situation of being treated the patient and age, the disease of treating.
Therefore, The compounds of this invention mixes with pharmaceutically acceptable carrier and the pharmaceutical composition processed, is prone to give with the various formulations that are suitable for said route of administration.Through the known method of pharmacy field, can make preparation be unit dosage easily.
Compound of the present invention generally uses free alkali or its pharmacy acceptable salt.An instance is the acid salt with compound of free alkali effectiveness.When compound of the present invention contains free alkali, can be by ordinary method, the salt for preparing free alkali with the solution or the suspension of stoichiometric pharmaceutically acceptable s.t. free alkali of the present invention.Representational instance as stated.
Pharmaceutical composition for oral administration can be solid or liquid.The solid dosage of oral administration for example comprises that capsule, tablet, dragee, pill, lozenge, powder, granule and tabloid (tablette) are for example with the form of powder or pilule or for example pack in the hard gelatin capsule with the form of dragee (troche) or lozenge.In suitable, pharmaceutical composition for oral administration can be used dressing (for example enteric coating) preparation, perhaps can be according to method preparation well known in the art so that the activeconstituents of controlled release (for example slowly-releasing or extended release) to be provided.The liquid dosage form of oral administration comprises for example solution, emulsion, suspensoid, syrup and elixir.
The preparation of the present invention that is suitable for oral administration is independently unit for example capsule or tablet, contains the activeconstituents of predetermined amount respectively, can comprise suitable vehicle.In addition, can be used for the form that oral preparation can be powder or granule, or the solution of waterborne liquid or non-aqueous liquid or suspensoid, or oil-in-water or water in oil liquid emulsion.
Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The instance of solid carrier has lactose, terra alba, sucrose, Schardinger dextrins, talcum powder, gelatin, agar, pectin, Sudan Gum-arabic, Magnesium Stearate, Triple Pressed Stearic Acid, cellulosic lower alkyl ether, W-Gum, yam starch, natural gum etc.The instance of liquid vehicle has syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.
Carrier or thinner can comprise any slowly-releasing raw material known in the art, for example glyceryl monostearate or distearin, single with or use with wax.
Can use any auxiliary material or the additive that are usually used in these purposes, for example tinting material, correctives, sanitas etc., condition is that they and activeconstituents are compatible.
The amount of solid carrier can change, but usually at about 25mg between about 1g.If the use liquid vehicle can syrup, emulsion, Gelseal or aseptic injection be with the prepare of liquid preparation (for example water-based or non-aqueous liquid suspensoid or solution).
Can be through with activeconstituents and commonly used auxiliary material or mixing diluents, subsequently in conventional tabletting machine to the mixture compressing tablet, prepare tablet.
The pharmaceutical composition of parenteral admin comprises sterile aqueous and non-aqueous injection solution agent, dispersion agent, suspensoid or emulsion, and faces the sterile powder injection with preceding reprovision at aseptic injection with solution or dispersion agent.The slow release type injection formulations is also included within the scope of the present invention.
As for parenteral admin, then can use the solution that is dissolved in the The compounds of this invention in aseptic aqueous solution, aqueous solution of propylene glycol, the vitamin E aqueous solution, til or the peanut oil.If desired, these aqueous solution can suitably cushion, importantly with enough salt solution or glucose so that isoosmotic liquid diluent to be provided.The aqueous solution is particularly suited for intravenously, intramuscular, subcutaneous and intraperitoneal administration.Known by one of skill in the art standard technique can obtain used sterile aqueous media easily.
The injection solution agent can be prepared as follows: activeconstituents and possible additive are dissolved in part solvent for injection (preferred sterilized water), and regulator solution is to volume required, with suitable ampoule or the bottle of packing into behind the solution sterilization.Can add the conventional any suitable additive that uses in this area, for example tonicity agents, sanitas, inhibitor etc.
Other suitable form of medication comprises suppository, sprays, ointment, ointment, gelifying agent, inhalation, skin patch, implant etc.
Typical oral dosage scope is about 0.001mg/kg body weight/day to about 100mg/kg body weight/day; Preferred about 0.01mg/kg body weight/day is to about 50mg/kg body weight/day; More preferably from about 0.05mg/kg body weight/day to about 10mg/kg body weight/day is divided potion or multi-agent (for example 1-3 agent) administration.Accurately dosage will depend on administration frequency and administering mode, treated character and the severity of patient's sex, age, body weight and general health situation, the disease of treating, subject any disease accompanied and conspicuous to those skilled in the art other factors.
Known by one of skill in the art method can provide the unit dosage of preparation easily.For oral administration one or many every day (for example every day 1-3 time), typical unit dosage can comprise 0.01mg to about 1000mg, for example about 0.01mg to 100mg, and preferably about 0.05mg is about 500mg extremely, more preferably from about 0.5mg about 200mg extremely.
For parenteral approach (for example in the intravenously, sheath, intramuscular and similar route of administration), its typical doses is about and is used for the half the of oral administration dosage.
Be the representative instance of pharmaceutical formulation of the present invention below:
1) tablet, contain 5.0mg The compounds of this invention (calculating with free alkali):
Figure BSA00000591788100241
Figure BSA00000591788100251
2) tablet, contain 0.5mg The compounds of this invention (calculating with free alkali):
Figure BSA00000591788100252
3) syrup, every milliliter contains:
4) injection liquid, every milliliter contains:
Figure BSA00000591788100254
Figure BSA00000591788100261
Term " the present invention () compound " be meant any formula I compound in the embodiment described herein.
On the other hand, the present invention relates to the preparation method of the following compound of the present invention.
The preparation of The compounds of this invention
The present invention relates to the compound that following general formula I is represented as free alkali or its salt:
Figure BSA00000591788100262
Wherein
Q is 0 or 1;
R 1And R 2Be selected from halogen, cyanic acid, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base and halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 4And R 5Be selected from hydrogen, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
The compound of general formula I of the present invention, wherein R 1, R 2, R 3As above define with q, can be through method shown in the following flow process and the preparation of following method.
General formula I to the compound of general formula X V, R 1, R 2, R 3With q suc as formula defining among the I.
The compound of general formula I I, general formula VII, general formula VIII, general formula I X, general formula X, general formula X I and general formula X II maybe can obtain from commercial sources, or through the known standard method preparation of this area chemist.
Flow process 1
Compound of formula III (flow process 1) can be prepared as follows: under the suitable temp (for example room temperature or reflux temperature); At suitable solvent (for example methyl-sulphoxide, N; Dinethylformamide or ethanol) in; Add or do not add alkali (for example trialkylamine, salt of wormwood or lithium alkoxide, sodium alkoxide or potassium alcoholate), add or when not adding catalyzer (for example Soiodin), make the compound and two-(2-halogenated ethyl) ether reaction of general formula I I.
General formula I V compound (flow process 1) can be prepared as follows: under the suitable temp; In suitable solvent (for example Glacial acetic acid min. 99.5, diacetyl oxide, trifluoroacetic acid, the vitriol oil or its mixture), compound of formula III is carried out the known nitration reaction of this area chemist, for example react with concentrated nitric acid, Sodium Nitrite or SODIUMNITRATE; For example referring to P.B.D.de la Mare and J.H.Ridd; " Preparative methods of nitration " in Aromatic substitutions, 48-56 page or leaf, Butterworths Scientific Publications; London, 1959.
Flow process 2
Figure BSA00000591788100281
Can be by the known nitration reaction of this area chemist described in the flow process 1 preparation general formula I V compound, with general formula I I compound general formula V compound (flow process 2).
Can make general formula V compound and suitably substituted pair-(2-halogenated ethyl) ether reaction by method described in the flow process 1 preparation compound of formula III, prepare general formula I V compound (flow process 2).
Flow process 3
Figure BSA00000591788100282
General formula VI compound (flow process 3) can be prepared as follows: under suitable temp or the ultrasonic radiation; In suitable solvent (for example methyl alcohol, ethanol, ETHYLE ACETATE or THF); In acid (for example acetate or aqueous hydrochloric acid) when existing, with appropriate reductant (for example zinc powder or iron powder), perhaps at suitable hydrogenation catalyst (for example palladium/activated carbon) when existing; Through hydrogen or ammonium formiate, be amino with the nitroreduction of general formula I V compound.Perhaps, can under the condition that this area chemist knows, tin chloride (II) or V-Brite B be used as reductive agent.
Compound of Formula I (flow process 3) can be prepared as follows: under the suitable temp (for example room temperature or reflux temperature); In suitable solvent (for example ETHYLE ACETATE, two
Figure BSA00000591788100283
alkane, THF, acetonitrile or ether); Add or when not adding alkali (for example pyridine, trialkylamine, salt of wormwood, Natural manganese dioxide or lithium alkoxide, sodium alkoxide or potassium alcoholate), general formula VI compound and suitable electrophilic reagent (such as but not limited to suitable substituted carboxylic acyl fluorides (carboxylic acid fluoride), carboxyl acyl chloride, carboxylic acylbromide, carboxylic acyl iodides, carboxylic acid anhydride, active ester, chloro-formic ester) are reacted.Can under the known condition of this area chemist, prepare active ester and carboxylic acid anhydride, for example referring to F.Albericio and L.A.Carpino with suitable substituted carboxylic acid; " Coupling reagents and activation (coupling reagent and activation) "; Methods in enzymology:Solid-phase peptide synthesis, 104-126 page or leaf, Academic Press; New York, 1997.Can under the condition that this area chemist knows,, prepare acid halide with suitable substituted carboxylic acid activation with reagent (such as but not limited to THIONYL CHLORIDE 97, oxalyl chloride, phosphorus tribromide or phosphorus triiodide).
Flow process 4
Figure BSA00000591788100291
Under the suitable temp (for example reflux temperature), in suitable solvent (for example YLENE), can make the reaction of general formula VII compound and sodium amide, preparation general formula I I compound (flow process 4), for example referring to J.Lecocq, Bull.Soc.Chim.Fr., 1950,188.
Flow process 5
R 2For the general formula VII compound (flow process 5) of F, Cl, Br or I can be prepared as follows: under suitable temp (for example-78 ℃ or room temperature), in suitable solvent (for example heptane or THF), with suitable alkali (for example butyllithium or di-t-butyl (2; 2,6,6-tetramethyl piperidine subbase) the zincic acid lithium); Add suitable electrophilic reagent (for example fluorine, chlorine, bromine, iodine, carbon tetrabromide or Sesquichloratum) immediately, general formula VIII compound is passed through metallization, and react with the known suitable electrophilic reagent of this area chemist immediately; For example referring to F.Mongin and G.Qu é guiner, Tetrahedron, 2001; 57,4059.
Can replace through above-mentioned metallization and electrophilic aromatics immediately, by general formula I X compound general formula VII compound, wherein R 1Be F, Cl, Br or I (flow process 5).
Flow process 6
Figure BSA00000591788100302
Can pass through the known cross-coupling reaction of this area chemist, for example Negishi coupling (E.-I.Negishi, A.O.King and N.Okukado, J.Org.Chem., 1977; 42,1821), Sonogashira coupling (K.Sonogashira, Y.Tohda and N.Hagihara, Tet.Lett.; 1975,16,4467), perhaps other transition metal-catalyzed cross-coupling reaction; The for example catalytic reaction of copper (W.Dohle, D.M.Lindsay and P.Knochel, Org.Lett., 2001; 3,2871), by general formula X compound general formula VII compound, wherein R 2Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
Can pass through above-mentioned cross-coupling reaction, by general formula X I compound general formula VII compound, wherein R 1Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
In addition, can pass through the catalytic cyanogenation of the known nickel of this area chemist, for example referring to L.Cassar, J.Organomet.Chem., 1973,54, C57-C58 is by general formula X compound general formula VII compound, wherein R 2Be cyanic acid (flow process 6).
Can pass through the catalytic cyanogenation of above-mentioned nickel, by general formula X I compound general formula VII compound, wherein R 1Be cyanic acid (flow process 6).
Can pass through above-mentioned cross-coupling reaction or cyanogenation, by R 1=R 2The general formula X compound of=Br, preparation general formula VII compound, wherein R 1=R 2(flow process 6).
Flow process 7
Figure BSA00000591788100311
In addition, through the known nitration reaction of this area chemist described in the flow process 1 of preparation general formula I V compound, by R1 and R2 be halogen general formula X II 2,4,6-three haloperidids prepare the compound (flow process 7) of general formula X III, wherein R1 and R2 are halogen.
Under the suitable temp (for example room temperature or reflux temperature); In suitable solvent (for example methyl-sulphoxide or N-Methyl pyrrolidone); Add or when not adding alkali (for example pyridine, trialkylamine, salt of wormwood, Natural manganese dioxide); Making R1 and R2 is compound and the morpholine reaction of the general formula X II of halogen, preparation general formula X IV compound (flow process 7), and wherein R1 and R2 are halogen.
Under the suitable temp (for example room temperature or reflux temperature); In suitable solvent (for example methyl-sulphoxide or N-Methyl pyrrolidone); Add or when not adding alkali (for example pyridine, trialkylamine, salt of wormwood, Natural manganese dioxide), make the reaction of general formula X III compound and morpholine, prepare general formula X V compound.In addition, can be through the known nitration reaction of this area chemist described in the flow process 1 of preparation general formula I V compound, by general formula X IV compound general formula X V compound.
In addition, can use above-mentioned cyanogenation, by general formula X V compound general formula I V compound, wherein R 1Or R 2Be cyanic acid, perhaps R 1And R 2Two all is cyanic acid (flow process 7).Can use above-mentioned cyanogenation, by general formula X IV compound compound of formula III, wherein R 1Or R 2Be cyanic acid, perhaps R 1And R 2Two all is cyanic acid.
Can be through above-mentioned cross-coupling reaction (flow process 6), by general formula X IV compound compound of formula III, wherein R 1Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
Can be through above-mentioned cross-coupling reaction (flow process 6), by general formula X IV compound compound of formula III, wherein R 2Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
Can be through above-mentioned cross-coupling reaction (flow process 6), by general formula X V compound general formula I V compound, wherein R 1Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
Can be through above-mentioned cross-coupling reaction (flow process 6), by general formula X V compound general formula I V compound, wherein R 2Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base or halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base (flow process 6).
Under the suitable temp (for example room temperature or reflux temperature), at suitable solvent (for example two
Figure BSA00000591788100321
Alkane) in; In the presence of alkali (for example Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, lithium hydride, sodium hydride or potassium hydride KH), add or when not adding catalyzer (for example copper sulfate), general formula X V compound and suitable lithium alkoxide, sodium alkoxide, potassium alcoholate or alcohol are reacted; Preparation general formula I V compound, wherein R 1Or R 2Be C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) or C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), perhaps R 1And R 2Two all is C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) or C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).Under the suitable temp (for example room temperature or reflux temperature), at suitable solvent (for example two
Figure BSA00000591788100331
Alkane) in; In the presence of alkali (for example Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, lithium hydride, sodium hydride or potassium hydride KH); Add or when not adding catalyzer (for example copper sulfate); Can make general formula X IV compound and suitable lithium alkoxide, sodium alkoxide, potassium alcoholate or alcohol reaction, preparation compound of formula III, wherein R 1Or R 2Be C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) or C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), perhaps R 1And R 2Two all is C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) or C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).
In addition, for R 1And R 2Other variation, under suitable temp (for example 0 ℃ or room temperature), in suitable solvent (for example methylene dichloride),, for example handle with boron tribromide through the known method of this area chemist, can make the compound demethylating that contains methoxyl group.Gained phenol can pass through the known method alkylation of this area chemist.These methods comprise: (a) under the suitable temperature (for example room temperature or reflux temperature); At suitable solvent (for example THF, N; Dinethylformamide or 1; The 2-ethylene dichloride) in, when existing, reacts with electrophilic reagent (for example alkyl chloride, alkyl bromide, alkyl iodide, carbonyl chloride, carbonyl bromide or carbonic anhydride) at suitable alkali (for example salt of wormwood); (b) under the condition of known Mitsunobu reaction (O.Mitsunobu, Synthesis 1981,1), react with alkyl alcohol.
The compound that contains functional group (for example hydroxyl); When incompatible with the reaction conditions of being advised, the known method of available this area chemist is protected or is gone protection, for example referring to T.W.Greene and P.G.M.Wuts; Protective groups in organic synthesis; Second edition, Wiley Interscience, 1991.Specifically, hydroxyl can with but be not limited to following group and protect: methyl-, the tertiary butyl-, trialkylsilkl-, diarye silyl-, allyl group-or trityl ether.
Under the suitable temp; At suitable solvent for example in methyl alcohol, ethanol or the THF, at suitable hydrogenation catalyst (for example palladium/activated carbon or platinum/activated carbon) when existing, be reduced into alkene or alkane through the alkynes available hydrogen or the ammonium formiate of Sonogashira prepared in reaction; For example referring to S.Siegel; " Heterogeneous catalytic hydrogenation of C=C and alkynes " Comprehensive Organic Synthesis, the 8th volume, 417-442 page or leaf; Pergamon Press, 1991.
The preparation of The compounds of this invention
Embodiment
PE Sciex API 150EX instrument and ShimadzuLC-8A/SLC-10A LC system with being equipped with the normal atmosphere photo-ionisation obtain analysis mode LC-MS data.Post: 30X 4.6mmWaters Symmetry C18 post, particle diameter is 3.5 μ m; Solvent systems: A=water/trifluoroacetic acid (100: 0.05), B=water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); Method: with 90%A-100%B linearity degree of passing wash-out 4 minutes, flow velocity 2ml/ minute.Follow the trail of integration with UV (254nm) and ELSD and confirm purity.RT (t R) with minute representing.
On same instrument, prepare type LC-MS purifying with APCI atmospheric pressure chemical ionization.Post: 50X 20mm YMC ODS-A, particle diameter 5 μ m; Method: with 80%A-100%B linearity degree of passing wash-out 7 minutes, flow velocity 22.7ml/ minute.Detect (split-flow MSdetection) through shunting MS and collect flow point.
Micromass LCT4-ways MUX with being equipped with Waters 2488/Sedex 754 detector systems obtains analysis mode LC-MS-TOF (TOF=flight time) data.Post: 30X 4.6mm Waters Symmetry C18 post, particle diameter 3.5 μ m; Solvent systems: A=water/trifluoroacetic acid (100: 0.05), B=water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); Method: with 90%A-100%B linearity degree of passing wash-out 4 minutes, flow velocity 2ml/ minute.Purity is followed the trail of integration through UV (254nm) and ELSD and is confirmed.RT (t R) with minute representing.
Obtain the GC-MS data with Varian CP 3800 gas chromatographs, this chromatographic instrument be furnished with the Phenomenex post that is connected with Varian Saturn 2000 ion trap mass spectrometers (ZebronZB-5, long: 15 meters, internal diameter: 0.25mm).Method: in 15 minutes, column flow rate 1.4ml/ minute (carrier gas is a helium), baking oven gradient: 0-1 minute, 60 ℃; 1-13 minute, 60-300 ℃; 13-15 minute, 300 ℃.
With Bruker Avance DRX500 instrument record under 500.13MHz 1H NMR spectrum.Deuterate methyl-sulphoxide (99.8%D) is as solvent.TMS is as interior mark.Chemical displacement value is used the ppm value representation with respect to TMS.Below abbreviation is used for the multiplicity of NMR signal: s=is unimodal, and d=is bimodal, t=triplet, q=quartet, qui=quintet; The h=septet, dd=double doublet, ddd=are bimodal in pairs, the two triplets of dt=; The two quartets of dq=, the triplet of tt=triplet, the m=multiplet, b=is wide unimodal.
The preparation of midbody
4-(4,6-dimethyl--pyridine-2-yl)-morpholine
Under argon atmospher, 2-is amino-4,6-lutidine (50g), two (2-chloroethyl) ethers (57.5ml), Soiodin (6.13g) and triethylamine (137ml) and anhydrous N, dinethylformamide (1L) mixing, be heated to 150 ℃ 16 hours.With water/salt solution/saturated sodium bicarbonate aqueous solution (2: 1: 1,750ml) join in the cold reaction mixture, mixture with ETHYLE ACETATE (5 * 200ml) extraction.The organic phase that vacuum concentration merges is to about 500ml.Add entry (500ml) and concentrated hydrochloric acid aqueous solution (35ml), separate each phase, water washs with ETHYLE ACETATE (200ml).Add dense aqueous sodium hydroxide solution (50ml) and make water be alkalescence, with isopropyl acetate (5 * 200ml) extractions.Organic phase is through dried over mgso, and vacuum concentration obtains 44.0g (yield 56%) title compound, is the dark oil thing.Crude product just need not to be further purified and can directly use.GC-MS(m/z)192(M +)；t R＝5.60。 1H?NMR(500MHz，DMSO-d 6)：2.08(s，3H)，2.26(s，3H)，3.39(m，4H)，3.68(m，4H)，6.05(s，1H)，6.44(s，1H)。
4-(4,6-dimethyl--5-nitro-pyridine-2-yl)-morpholine
In 15 minutes, in the 4-that is dissolved in the trifluoroacetic acid (250ml) that is cooled to 0 ℃ (4,6-dimethyl--pyridine-2-yl)-morpholine (9.4g), add Sodium Nitrite (3.54g), then, reaction mixture was stirred 15 minutes down at 0 ℃.The vacuum concentration reaction mixture is regulated pH to 11 to about 100ml with dense aqueous sodium hydroxide solution (150ml).Add salt solution (200ml), (4 * 150ml) extract mixture, and organic phase is through dried over mgso, vacuum concentration with ether.Crude product is carried out flash chromatography (SiO 2, heptane/ETHYLE ACETATE 4: 1) and purifying, obtain 2.01g (yield 17%) title compound, be yellow solid.GC-MS(m/z)237(M +)；t R＝7.69。 1H?NMR(500MHz，DMSO-d 6)：2.28(s，3H)，2.39(s，3H)，3.60(m，4H)，3.67(m，4H)，6.72(s，1H)。
2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl amine
Glacial acetic acid min. 99.5 (25ml) is dissolved in the zinc powder (2.76g) and 4-(4,6-dimethyl--5-nitro-pyridine-2-yl)-morpholine (2.01g) mixture of the THF (100ml) that is cooled to 0 ℃ slow the adding.Then, reaction mixture was stirred 16 hours down at 25 ℃,, transfer to alkalescence, with THF (3 * 75ml) extractions with 25% ammoniacal liquor through diatomite filtration.The organic phase that merges is through dried over mgso, and vacuum concentration obtains 1.76g (100%) title compound, is the garnet solid.GC-MS(m/z)207(M +)；t R＝7.27。 1H?NMR(500MHz，DMSO-d 6)：2.07(s，3H)，2.20(s，3H)，3.16(m，4H)，3.67(m，4H)，4.10(b，2H)，6.38(s，1H)。
4-(4,6-dichloropyridine-2-yl)-morpholine
Morpholine (5.0g) is added 2,4, in acetonitrile (100ml) suspension-s of 6-trichloropyridine (10.0g) and yellow soda ash (5.9g).Then, reaction mixture was stirred 16 hours down at 70 ℃, be cooled to envrionment temperature, through diatomite filtration, vacuum concentration.Crude product is carried out flash chromatography (SiO 2, heptane/ETHYLE ACETATE 4: 1) and purifying, obtain 3.90g (yield 30%) title compound, be pale solid.LC-MS(m/z)323.8(M +)；t R＝3.10，(UV，ELSD)98.5％，98.9％。 1H?NMR(500MHz，CDCl 3)：3.50(m，4H)，3.80(m，4H)，6.45(s，1H)，6.67(s，1H)。
4-(4,6-chloro-5-nitropyridine-2-yl)-morpholine
In 10 minutes, in the vitriol oil (40ml) solution of 4-(4,6-chloropyridine-2-yl)-morpholine (3.90g), add saltpetre (1.80g).Reaction mixture was stirred 16 hours at ambient temperature, pour into then in the trash ice (500g).Reaction mixture is with dense sodium hydroxide furnishing alkalescence, with ETHYLE ACETATE (2 * 100ml) extractions.The organic phase that merges is through dried over mgso, vacuum concentration.Crude product is carried out flash chromatography (SiO 2, heptane/ETHYLE ACETATE 3: 1) and purifying, obtain 2.26g (yield 49%) title compound, be yellow solid.LC-MS(m/z)278.0(M +)；t R＝3.10，(UV，ELSD)96.5％，98.8％。 1H?NMR(500MHz，CDCl 3)：3.62(m，4H)，3.80(m，4H)，6.50(s，1H)。
4-(4-chloro-6-methoxyl group-5-nitropyridine-2-yl)-morpholine and 4-(6-chloro-4-methoxyl group-5-nitropyridine-2-yl)-morpholine
In methyl alcohol (15ml) solution of 4-(4,6-two chloro-5-nitropyridine-2-yls)-morpholine (2.02g), add sodium methylate (0.98g), mixture was heated 16 hours down at 65 ℃.After being cooled to envrionment temperature, the vacuum concentration reaction mixture.Make crude product carry out flash chromatography (SiO 2Heptane/ETHYLE ACETATE 3: 1) purifying; Obtain 0.89g (yield 45%) 4-(4-chloro-6-methoxyl group-5-nitropyridine-2-yl)-morpholine (fast elution band) and 0.38g (19%) 4-(6-chloro-4-methoxyl group-5-nitropyridine-2-yl)-morpholine (elution band late), two are all yellow solid.
4-(4-chloro-6-methoxyl group-5-nitropyridine-2-yl)-morpholine: LC-MS (m/z) 273 (M +); t R=2.77, (UV, ELSD) 95%, 97%. 1H?NMR(500MHz，CDCl 3)：3.60(m，4H)，3.80(m，4H)，3.96(s，1H)，6.17(s，1H)。
4-(6-chloro-4-methoxyl group-5-nitropyridine-2-yl)-morpholine: LC-MS (m/z) 273 (M +); t R=2.39, (UV, ELSD) 93%, 95%. 1H?NMR(500MHz，CDCl 3)：3.57(m，4H)，3.80(m，4H)，3.95(s，3H)，5.95(s，1H)。
4-chloro-2-methoxyl group-6-morpholine-4-yl pyridines-3-base amine
In concentrated hydrochloric acid (50ml) solution of 4-(4-chloro-6-methoxyl group-5-nitropyridine-2-yl)-morpholine (0.82g), add concentrated hydrochloric acid (80ml) solution of tindichloride (3.38g).With reaction mixture be heated to 75 ℃ 1 hour, pour into then in the trash ice (400g), with ETHYLE ACETATE (2 * 100ml) extraction.The organic phase that merges is through dried over mgso, and vacuum concentration obtains 0.45g (yield 61%) title compound, is pale solid.LC-MS(m/z)244(M +)；t R＝1.48，(UV，ELSD)89％，94％。 1H?NMR(500MHz，CDCl 3)：3.30(m，4H)，3.65(br?s，2H)，3.85(m，4H)，3.97(s，3H)，6.20(s，1H)。
2-chloro-4-methoxyl group-6-morpholine-4-yl pyridines-3-base amine
In concentrated hydrochloric acid (20ml) solution of 4-(6-chloro-4-methoxyl group-5-nitropyridine-2-yl)-morpholine (0.38g), add concentrated hydrochloric acid (60ml) solution of tindichloride (1.57g).With reaction mixture be heated to 75 ℃ 5 minutes, pour into then in the trash ice (100g), with ETHYLE ACETATE (2 * 20ml) extraction.The organic phase that merges is through dried over mgso, and vacuum concentration obtains 0.28g (yield 83%) title compound, is pale solid. 1H?NMR(500MHz，CDCl 3)：3.35(m，4H)，3.65(br?s，2H)，3.80(m，4H)，3.90(s，3H)，6.10(s，1H)。
Compound of the present invention
Known by one of skill in the art method can prepare the acid salt of The compounds of this invention easily.
Embodiment 1
1aa (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-benzyl carbamate
Chloroformic acid benzyl ester (18mg) is added 0.085M 2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl amine and 0.17M N, 1 of N-di-isopropyl-ethylamine is in 2-ethylene dichloride (1ml) solution.To react bottle and under argon atmospher, vibrate 16 hours vacuum concentration.(1M, 1ml), (4: 1,2 * 1ml) extracted crude mixture with isopropyl acetate/THF to add aqueous sodium hydroxide solution.Organic phase is with salt solution (1ml) washing, vacuum concentration, be dissolved in again 1-propyl alcohol/methyl-sulphoxide (1: 1,0.4ml) in, wherein 0.2ml prepares type LC-MS purifying, obtains 4.5mg (yield 31%) title compound, is oily matter.LC-MS(m/z)342(MH +)；t R＝1.58，(UV，ELSD)99％，99％。
Following compounds prepares with similar approach:
1ab (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-carboxylamine 2-chloro-benzyl ester
Yield: 18%.LC-MS(m/z)376(MH +)；t R＝1.78，(UV，ELSD)99％，100％。
1ac 2-(4-chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 4%.LC-MS(m/z)360(MH +)；t R＝1.59，(UV，ELSD)96％，100％。
1ad 2-phenyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-cyclopropane carboxamide
Yield: 24%.LC-MS(m/z)352(MH +)；t R＝1.64，(UV，ELSD)96％，100％。
1ae N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-thiophene-2-base-ethanamide
Yield: 16%.LC-MS(m/z)332(MH +)；t R＝1.20，(UV，ELSD)93％，99％。
1af 3-cyclohexyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide
Yield: 15%.LC-MS(m/z)346(MH +)；t R＝1.81，(UV，ELSD)91％，100％。
1ag (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-isobutyl carbamate
Yield: 29%.LC-MS(m/z)308(MH +)；t R＝1.44，(UV，ELSD)97％，99％。
1ah 3-(3-chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide
(in the 2M methylene dichloride, 1ml) solution stirred 2 hours under 25 ℃, argon atmospher with the oxalyl chloride of 3-(3-chloro-phenyl-) propionic acid (20mg).Solvent removed in vacuo, with 0.085M 2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl amine and 0.17M N, 1 of N-di-isopropyl-ethylamine, 2-ethylene dichloride (1ml) solution joins in the reaction mixture.To react bottle and under argon atmospher, vibrate 16 hours vacuum concentration.(1M, 1ml), (4: 1,2 * 1ml) extracted crude mixture with isopropyl acetate/THF to add aqueous sodium hydroxide solution.Organic phase is with salt solution (1ml) washing, vacuum concentration, be dissolved in again 1-propyl alcohol/methyl-sulphoxide (1: 1,0.4ml) in, wherein 0.2ml prepares type LC-MS purifying, obtains 2.3mg (yield 14%) title compound, is oily matter.LC-MS(m/z)374(MH +)；t R＝1.71，(UV，ELSD)99％，99％。
Following compounds prepares with similar approach::
1ai N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3,5-dimethyl--phenyl)-acetyl Amine
Yield: 19%.LC-MS(m/z)354(MH +)；t R＝1.69，(UV，ELSD)99％，99％。
1aj N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3-p-methylphenyl-propionic acid amide
Yield: 20%.LC-MS(m/z)354(MH +)；t R＝1.64，(UV，ELSD)99％，100％。
1ak 2-(3-chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 14%.LC-MS(m/z)360(MH +)；t R＝1.58，(UV，ELSD)97％，99％。
1al 2-(3,4-two chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 9%.LC-MS(m/z)395(MH +)；t R＝1.84，(UV，ELSD)97％，99％。
1am N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-thiene-3-yl--ethanamide
Yield: 18%.LC-MS(m/z)332(MH +)；t R＝1.18，(UV，ELSD)97％，99％。
1an N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-p-methylphenyl-ethanamide
Yield: 16%.LC-MS(m/z)340(MH +)；t R＝1.50，(UV，ELSD)96％，99％。
1ao 2-(3-bromo-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 12%.LC-MS(m/z)405(MH +)；t R＝1.63，(UV，ELSD)96％，99％。
1ap N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3-trifluoromethyl-phenyl)-acetyl Amine
Yield: 20%.LC-MS(m/z)394(MH +)；t R＝1.77，(UV，ELSD)94％，99％。
1aq N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-phenyl-ethanamide
Yield: 11%.LC-MS(m/z)326(MH +)；t R＝1.29，(UV，ELSD)93％，99％。
1ar 3,5,5-trimethylammonium-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide
Yield: 20%.LC-MS(m/z)348(MH +)；t R＝1.97，(UV，ELSD)93％，99％。
1as N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-decoylamide
Yield: 44%.LC-MS(m/z)334(MH +)；t R＝1.92，(UV，ELSD)92％，99％。
1at N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-naphthalene-2-base-ethanamide
Yield: 4%.LC-MS(m/z)376(MH +)；t R＝1.73，(UV，ELSD)92％，99％。
1au N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-heptamide
Yield: 24%.LC-MS(m/z)320(MH +)；t R＝1.56，(UV，ELSD)90％，99％。
1av N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3,4-dimethyl--phenyl)-acetyl Amine
Yield: 26%.LC-MS(m/z)354(MH +)；t R＝1.65，(UV，ELSD)77％，99％。
1aw 2-hexamethylene-1-thiazolinyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 13%.LC-MS(m/z)330(MH +)；t R＝1.50，(UV，ELSD)72％，99％。
1ax N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-methoxyl group-3-methyl-benzene Base)-ethanamide
Yield: 16%.LC-MS(m/z)370(MH +)；t R＝1.56，(UV，ELSD)94％，99％。
1ay N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-methoxyl group-phenyl)-ethanamide
Yield: 19%.LC-MS(m/z)356(MH +)；t R＝1.35，(UV，ELSD)96％，99％。
1az N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3-(4-methoxyl group-phenyl)-propionic acid amide
Yield: 15%.LC-MS(m/z)370(MH +)；t R＝1.48，(UV，ELSD)76％，99％。
Tolyl-ethanamide between 1ba N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-
Tolyl-acetic acid (0.33g), N between inciting somebody to action; N-di-isopropyl-ethylamine (0.90ml) and phosphofluoric acid N-[(dimethylamino)-1H-1; 2,3-triazolo-[4,5-b] pyridine-1-base-methylene radical]-N-methyl-first ammonium N-oxide compound (1.00g) and anhydrous N; Dinethylformamide (3ml) mixes, and under argon atmospher, stirs 2 minutes.To be dissolved in anhydrous N, 2 of dinethylformamide (2ml), 4-dimethyl--6-morpholine-4-base-pyridin-3-yl amine (0.30g) joins in the reaction mixture, and mixture was stirred 16 hours under 25 ℃, argon atmospher.Add ETHYLE ACETATE (20ml), organic phase with saturated aqueous ammonium chloride/water (1: 1,20ml), water (20ml), brine/(1: 1,20ml) wash, through dried over sodium sulfate, vacuum concentration is with flash chromatography (SiO 2, heptane/ETHYLE ACETATE 3: 1) and purifying, obtain 0.069g (yield 14%) title compound, be white solid.LC-MS(m/z)340(MH +)；t R＝1.42，(UV，ELSD)96％，100％。 1H?NMR(500MHz，DMSO-d 6)：2.00(s，3H)，2.11(s，3H)，2.29(s，3H)，3.37(m，4H)，3.56(s，2H)，3.67(m，4H)，6.52(s，1H)，7.06(d，1H)，7.15(m，2H)，7.21(t，1H)，9.30(s，1H)。
Following compounds prepares with similar approach:
1bb N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-fluoro-phenyl)-ethanamide
Yield: 14%.LC-MS(m/z)344(MH +)；t R＝1.34，(UV，ELSD)99％，99％。 1H?NMR(500MHz，DMSO-d 6)：1.99(s，3H)，2.10(s，3H)，3.37(m，4H)，3.60(s，2H)，3.66(m，4H)，6.52(s，1H)，7.16(dd，2H)，7.38(dd，2H)，9.33(s，1H)。
1bc N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3,3-dimethyl--yulocrotine
Yield: 53%.LC-MS(m/z)306(MH +)；t R＝1.26，(UV，ELSD)99％，98％。 1H?NMR(500MHz，DMSO-d 6)：1.05(s，9H)，2.07(s，3H)，2.18(s，2H)，2.19(s，3H)，3.37(m，4H)，3.67(m，4H)，6.54(s，1H)，9.01(s，1H)。
1bd N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3-fluoro-phenyl)-ethanamide
Yield: 15%.LC-MS(m/z)344(MH +)；t R＝1.54，(UV，ELSD)100％，100％。 1H?NMR(500MHz，DMSO-d 6)：2.00(s，3H)，2.11(s，3H)，3.37(m，4H)，3.64(s，2H)，3.66(m，4H)，6.52(s，1H)，7.08(dt，1H)，7.18(m，2H)，7.38(m，1H)，9.34(s，1H)。
1be 2-two ring [2.2.1] heptan-2-base-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-acetyl Amine
Yield: 62%.LC-MS(m/z)344(MH +)；t R＝1.58，(UV，ELSD)99％，99％。 1H?NMR(500MHz，DMSO-d 6)：1.14(m，4H)，1.42(m，4H)，1.90(m，1H)，2.01(m，1H)，2.04(s，3H)，2.10(m，1H)，2.16(s，3H)，2.21(m，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.04(s，1H)。
1bf 2-(3,4-two fluoro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 9%.LC-MS(m/z)362(MH +)；t R＝1.52，(UV，ELSD)95％，99％。 1H?NMR(500MHz，DMSO-d 6)：2.00(s，3H)，2.11(s，3H)，3.37(m，4H)，3.63(s，2H)，3.66(m，4H)，6.52(s，1H)，7.19(m，1H)，7.39(m，2H)，9.32(s，1H)。
1bg 4-methyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-valeramide
Yield: 34%.LC-MS(m/z)306(MH +)；t R＝1.33，(UV，ELSD)100％，99％。 1H?NMR(500MHz，DMSO-d 6)：0.91(d，6H)，1.49(dt，2H)，1.58(m，1H)，2.04(s，3H)，2.16(s，3H)，2.28(t，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.07(s，1H)。
1bh 2-encircles penta-2-thiazolinyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 13%.LC-MS(m/z)316(MH +)；t R＝1.25，(UV，ELSD)97％，94％。 1H?NMR(500MHz，DMSO-d 6)：1.51(m，1H)，2.05(m，1H)，2.06(s，3H)，2.17(s，3H)，2.26(m，2H)，2.35(m，2H)，3.07(m，1H)，3.38(m，4H)，3.68(m，4H)，5.73(m，1H)，5.77(m，1H)，6.54(s，1H)，9.09(s，1H)。
1bi 2-cyclohexyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
Yield: 12%.LC-MS(m/z)332(MH +)；t R＝1.50，(UV，ELSD)99％，95％。 1H?NMR(500MHz，DMSO-d 6)：0.98(m，2H)，1.20(m，3H)，1.71(m，6H)，2.05(s，3H)，2.15(d，2H)，2.16(s，3H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.05(s，1H)。
1bj 5-methyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide
Yield: 40%.LC-MS-TOF(m/z)320(MH +)；t R＝1.51，(UV，ELSD)97％，100％。 1H?NMR(500MHz，DMSO-d 6)：0.87(d，6H)，1.21(m，2H)，1.60(m，3H)，2.05(s，3H)，2.16(s，3H)，2.25(t，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.05(s，1H)。
1bk 2-cyclopentyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide
With 2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl amine (0.22g) and cyclopentyl Acetyl Chloride 98Min. (0.19ml) are dissolved in the acetonitrile (5ml), the sealing microwave reaction bottle (process vial) in be heated to 150 ℃ 10 minutes.The vacuum concentration reaction mixture is with flash chromatography (SiO 2, heptane/ETHYLE ACETATE 3: 1) and purifying, obtain 0.17g (yield 49%) title compound, be white solid.LC-MS(m/z)318(MH +)；t R＝1.40，(UV，ELSD)97％，99％。 1H?NMR(500MHz，DMSO-d 6)：1.21(m，2H)，1.52(m，2H)，1.61(m，2H)，1.77(m，2H)，2.05(s，3H)，2.17(s，3H)，2.24(m，1H)，2.26(m，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.05(s，1H)。
From ETHYLE ACETATE the recrystallize, following compounds prepares with similar approach after 1bl and 1bm are purified by flash chromatography:
1bl 3-cyclopentyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide
Yield: 34%.LC-MS(m/z)332(MH +)；t R＝1.57，(UV，ELSD)99％，99％。 1H?NMR(500MHz，DMSO-d 6)：1.11(m，2H)，1.49(m，2H)，1.60(m，4H)，1.77(m，3H)，2.04(s，3H)，2.16(s，3H)，2.28(t，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.06(s，1H)。
1bm N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide
Yield: 51%.LC-MS(m/z)306(MH +)；t R＝1.39，(UV，ELSD)99％，99％。 1H?NMR(500MHz，DMSO-d 6)：0.88(t，3H)，1.31(m，4H)，1.60(m，2H)，2.05(s，3H)，2.16(s，3H)，2.27(t，2H)，3.37(m，4H)，3.67(m，4H)，6.53(s，1H)，9.03(s，1H)。
1bn N-(4-chloro-2-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-2-cyclopentyl ethanamide
Yield: 53%.LC-MS(m/z)354(MH +)；t R＝2.68，(UV，ELSD)98％，99％。 1H?NMR(500MHz，CDCl 3)：1.25(m，2H)，1.50-1.65(m，4H)，1.90(m，2H)，2.45(m，3H)，3.45(m，4H)，3.77(m，4H)，3.90(s，3H)，6.20(s，1H)，6.50(s，1H)。
1bo N-(2-chloro-4-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-2-cyclopentyl ethanamide
Yield: 69%.LC-MS(m/z)354(MH +)；t R＝2.39，(UV，ELSD)99％，99％。 1H?NMR(500MHz，CDCl 3)：1.25(m，2H)，1.50-1.70(m，4H)，1.90(m，2H)，2.35(m，3H)，3.50(m，4H)，3.80(m，4H)，3.85(s，3H)，6.00(s，1H)，6.45(s，1H)。
1bp N-(2-chloro-4-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-3, the 3-amide dimethyl butyrate
Yield: 56%.LC-MS(m/z)342(MH +)；t R＝2.31，(UV，ELSD)99％，99％。 1H?NMR(500MHz，CDCl 3)：1.10(s，9H)，2.25(s，2H)，3.50(m，4H)，3.77(m，4H)，3.85(s，3H)，6.00(s，1H)，6.45(s，1H)。
1bq N-(4-chloro-2-first hydrogen base-6-morpholine-4-base-pyridin-3-yl)-3, the 3-amide dimethyl butyrate
Yield: 68%.LC-MS(m/z)342(MH +)；t R＝1.39，(UV，ELSD)99％，99％。 1HNMR(500MHz，DMSO-d 6)：1.10(s，9H)，2.15(s，2H)，3.45(m，4H)，3.70(m，4H)，3.80(s，3H)，6.45(s，1H)，8.95(s，1H)。
1br N-(4-chloro-2-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-propionic acid amide
Yield: 71%.LC-MS(m/z)300(MH +)；t R＝0.97，(UV，ELSD)98％，98％。 1H?NMR(500MHz，DMSO-d 6)：1.05(t，3H)，2.25(q，2H)，3.45(m，4H)，3.70(m，4H)，3.80(s，3H)，6.45(s，1H)，9.00(s，1H)。
Table 1. is used to prepare the reagent of embodiment 1 compound
Figure BSA00000591788100461
Figure BSA00000591788100471
Figure BSA00000591788100481
Interior and the body build-in test of body
Compound of the present invention is tested, is presented at least a with the effect in the drag:
Relative discharge through the KCNQ2 passage
This description of test be used to estimate the KCNQ2 screening scheme of The compounds of this invention.The relative discharge of experiment measuring through the KCNQ2 passage, according to Tang etc. (Tang, W. etc., J.Biomol.Screen.2001,6, the method for 325-331) introducing that is used for people ERG potassium channel is undertaken by following modification.
With the Chinese hamster ovary celI of the valtage-gated KCNQ2 passage of the stably express of proper amt, be seeded on the flat board by being enough to obtain the density that individual layer converges previous day in experiment.Adding 1 μ Ci/ml in cell [ 86Rb] spend the night.Test the same day, (the Hanks balanced salt solution, Invitrogen provides cell, cat#14025-050) washing with the damping fluid that contains HBSS.Cell and medicine preincubate 30 minutes are in 30 fens clock times that medicine exists in addition, with the 15mM Repone K stimulation of second largest concentration 86Rb +Flow out.Suitably after incubation period, take out supernatant, count with liquid scintillation counter (Tricarb).Cell is with the cracking of 2mM sodium hydroxide, and is right 86Rb +Amount counting.By ((CPM Supernatant/ (CPM Supernatant+ CPM Cell)) Compound/ (CPM Supernatant/ (CPM Supernatant+ CPM Cell)) 15mMKC1) * 100-100 calculating relative current output.
The EC of The compounds of this invention 50＜20000nM, in most cases＜2000nM, under many situation＜200nM.Therefore think that compound of the present invention can be used for treating and the relevant disease of KCNQ family potassium channel.
The electric physiology patch clamp record of Chinese hamster ovary celI
Use patch clamp recording (Hamill OP etc., the Pfl ü gers Arch 1981 of conventional full cell patch pincers pattern; 391:85-100), the KCNQ2 electric current of voltage-activated in the record Mammals Chinese hamster ovary celI.Let the Chinese hamster ovary celI of KCNQ2 passage of stably express voltage-activated at CO 2In the growth down of normal cell culture condition, be used to inoculate the back and carried out electrophysiological recording in 1-7 days in the incubator.-100mV to the film command potential (holding potential) the between-40mV through when increasing 5-20mV, reaching+voltage step (or use the ramp scheme) of 80mV activation KCNQ2 potassium channel (Tatulian L etc., J Neuroscience 2001; 21 (15): 5535-5545).According to the different parameters of the KCNQ2 electric current of voltage-activated, assessing compound inductive electricity physiological action.Particularly the effect of current activation threshold value and maximum induced current is studied.
In the present invention's test part of compounds of the present invention is tested.Estimate that the left side displacement of activation threshold value or the increase of maximum induction potassium current will reduce the activity of neural network, so make compound can be used for the disease that neuronal activity increases, like epilepsy.
The electrophysiological recording of KCNQ2, KCNQ2/KCNQ3 or KCNQ5 passage in the ovocyte
KCNQ2, KCNQ2/KCNQ3 or the KCNQ5 electric current of record Xenopus laevis (Xenopus) ovocyte voltage-activated, this injection cell the mRNA of encoded K CNQ2, KCNQ2+KCNQ3 or KCNQ5 ionic channel (Wang etc., Science 1998,282,1890-1893; Lerche etc., J Biol Chem 2000,275,22395-400).Reach through increasing 5-20mV+voltage step (or through ramp scheme) of 40mV, activate KCNQ2, KCNQ2/KCNQ3 or KCNQ5 potassium channel from film command potential (between-100mV between-the 40mV).According to the different parameters of KCNQ2, KCNQ2/KCNQ3 or the KCNQ5 electric current of voltage-activated, assessing compound inductive electricity physiological action.Particularly the effect of current activation threshold value and maximum induced current is studied.
Also directly tested part of compounds to current clamp during the hyperpolarizing action of membrane potential.Maximal electroshock
This test is undertaken by following method: use Corneal electrode in each group in male mice, gave the 26mA rectangular wave current 0.4 second, induce with the THE be characteristic convulsions (Wlaz etc., Epilepsy Research 1998,30,219-229).
The epileptic seizures that pilocarpine brings out
Each organizes male mice through peritoneal injection pilocarpine 250mg/kg, brings out the epileptic seizures that pilocarpine brings out, in 30 minutes; Observe the disorderly (Starr etc. of gait that seizure activity causes; Pharmacology Biochemistry and Behavior 1993,45,321-325).
The test of electricity irritation epileptic seizures threshold value
(Kimball etc., Radiation Research 1957 1-12), in each group male mice, measure the meta threshold value of the THE of induced response cornea electroshock with improved changing method.Each organize first mouse accept the electroshock of 14mA (0.4 second, 50Hz), observe seizure activity.If observe epileptic seizures, next mouse is reduced 1mA, yet if do not observe epileptic seizures, then electric current increases 1mA.15 mouse of all of treatment group are all repeated this step.
Pharmaceutical chemicals stimulates the test of epileptic seizures threshold value
Regularly pentetrazole (5mg/ml, 0.5ml/ minute) infusion is respectively organized the tail lateral vein of male mice, measure the threshold dose of bringing out the required pentetrazole of clonism (Nutt etc., J Pharmacy and Pharmacology 1986,38,697-698).
Amygdala are lighted
Rat is implemented operation three-pole electrode (tri-polar electrode) is implanted back of the body outside amygdala.Make after the operation after the animal recovery, give respectively to organize the test compound or the medicine solvent of rat various dose.Animal stimulates 3-5 week altogether with its initial ADT value+25 μ A every day; Write down severity, epileptic seizures time length and back discharge period (the Racine.Electroencephalography and Clinical Neurophysiology 1972 of each epileptic seizures; 32,281-294).
Spinoff
Rest on time on the bull stick device (Capacio etc., Drug and Chemical Toxicology 1992,15,177-201)) through measuring mouse; (Watson etc., Neuropharmacology 1997,36,1369-1375), measure the spinoff to cns with the autonomic activities ability of weighing mouse for the number of perhaps crossing the experimental cage infrared beam through record.Survey embedded type radio-telemeter transmitter (radiotelemetry the transmitter) (Keeney etc. that maybe can survey body temperature through rectum; Physiology and Behaviour 2001; 74,177-184), measure the hypothermia effect of compound to the animal core temperature.
The pharmacokinetics characteristic
Through intravenously and orally give Spraque Dawley rat above-claimed cpd, then, take a blood sample in 20 hours, measure the pharmacokinetics characteristic of compound.Measure plasma concns with LC/MS/MS.

Claims (21)

1. compound with following general formula I, said compound is free alkali or its salt:
Figure FSA00000591788000011
Wherein:
Q is 0 or 1;
R 1And R 2Be selected from halogen, cyanic acid, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base and halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 4And R 5Be selected from hydrogen, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
2. the compound of claim 1, wherein q is 0.
3. the compound of claim 1, wherein q is 1.
4. each compound, wherein R among the claim 1-3 1And R 2Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6Basic oxygen base of-alkane (alkene/alkynes) and halogen.
5. the compound of claim 4, wherein R 1And R 2Two all is C 1-6-alkane (alkene/alkynes) base.
6. the compound of claim 4, wherein R 1Be C 1-6The basic oxygen base of-alkane (alkene/alkynes), R 2Be halogen, or R wherein 1Be halogen, R 2Be C 1-6The basic oxygen base of-alkane (alkene/alkynes).
7. each compound, wherein R among the claim 1-6 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
8. the compound of claim 7, wherein R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base and heteroaryl-C 1-6-alkane (alkene/alkynes) base.
9. each compound in the claim 1,7 and 8, wherein optional substituted aryl can independently be selected from following substituting group and replace by one or more: halogen, cyanic acid, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes).
10. the compound of claim 9, wherein optional substituted aryl can independently be selected from following substituting group and replace by one or more: halogen, C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base and C 1-6The basic oxygen base of-alkane (alkene/alkynes).
11. each compound among the claim 1-10, said compound is selected from following compound, and said compound is free alkali or its salt:
(1) (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-benzyl carbamate;
(2) (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-carboxylamine 2-chloro-benzyl ester;
(3) 2-(4-chloro-phenyl)-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(4) 2-phenyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-cyclopropane carboxamide;
(5) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-thiophene-2-base-ethanamide;
(6) 3-cyclohexyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide;
(7) (2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-isobutyl carbamate;
(8) 3-(3-chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide;
(9) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3,5-dimethyl--phenyl)-ethanamide;
(10) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3-p-methylphenyl-propionic acid amide;
(11) 2-(3-chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(12) 2-(3,4-two chloro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(13) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-thiene-3-yl--ethanamide;
(14) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-p-methylphenyl-ethanamide;
(15) 2-(3-bromo-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(16) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3-trifluoromethyl-phenyl)-ethanamide;
(17) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-phenyl-ethanamide;
(18) 3,5,5-trimethylammonium-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide;
(19) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-decoylamide;
(20) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-naphthalene-2-base-ethanamide;
(21) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-heptamide;
(22) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3,4-dimethyl--phenyl)-ethanamide;
(23) 2-hexamethylene-1-thiazolinyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(24) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-methoxyl group-3-methyl-phenyl)-ethanamide;
(25) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-methoxyl group-phenyl)-ethanamide;
(26) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3-(4-methoxyl group-phenyl)-propionic acid amide;
(27) tolyl-ethanamide between N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-;
(28) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(4-fluoro-phenyl)-ethanamide;
(29) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-3,3-dimethyl--yulocrotine;
(30) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-2-(3-fluoro-phenyl)-ethanamide;
(31) 2-two ring [2.2.1] heptan-2-base-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(32) 2-(3,4-two fluoro-phenyl)-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(33) 4-methyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-valeramide;
(34) 2-ring penta-2-thiazolinyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(35) 2-cyclohexyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(36) 5-methyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide;
(37) 2-cyclopentyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-ethanamide;
(38) 3-cyclopentyl-N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-propionic acid amide; With
(39) N-(2,4-dimethyl--6-morpholine-4-base-pyridin-3-yl)-hexanamide
(40) N-(4-chloro-2-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-2-cyclopentyl ethanamide
(41) N-(2-chloro-4-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-2-cyclopentyl ethanamide
(42) N-(2-chloro-4-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-3, the 3-amide dimethyl butyrate
(43) N-(4-chloro-2-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-3, the 3-amide dimethyl butyrate
(44) N-(4-chloro-2-methoxyl group-6-morpholine-4-base-pyridin-3-yl)-propionic acid amide.
12. a pharmaceutical composition, said compsn comprise one or more pharmaceutically acceptable carriers or thinner and as the compound of the general formula I of free alkali or its salt:
Figure FSA00000591788000051
Wherein:
Q is 0 or 1;
R 1And R 2Be selected from halogen, cyanic acid, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base, halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8Basic oxygen base of-cycloalkanes (alkene) and C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes);
R 3Be selected from C 1-8-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 1-6-alkane (alkene/alkynes) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base, optional substituted aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 1-6-alkane (alkene/alkynes) base, heteroaryl-C 3-8-cycloalkanes (alkene) base, heteroaryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 1-6-alkane (alkene/alkynes) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base, NR 4R 5-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halogen-C 1-6-alkane (alkene/alkynes) base, halogen-C 3-8-cycloalkanes (alkene) base and halogen-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 4And R 5Be selected from hydrogen, C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
13. the medicine of claim 12 is increasing the for example purposes in people's the potassium channel ionic current of Mammals.
14. the purposes of claim 13, being used to treat increases responsive disease to the potassium channel ionic current, and said disease is preferably central nervous system disease.
15. the purposes of claim 14, wherein said subject disease is selected from epileptic seizures disease, anxiety disorder, neuropathic pain and migraine property pain disease, neurodegenerative disease, apoplexy, cocaine abuse, nicotine withdrawal, alcohol and gives up and tinnitus.
16. the purposes of claim 15, wherein said epileptic seizures disease are selected from acute epileptic seizures, convulsions, epileptic state, epilepsy for example epilepsy syndrome and epileptic seizures.
17. the purposes of claim 15, wherein said anxiety disorder are selected from anxiety and illness and the disease relevant with following disease: anxiety disorder and other anxiety disorder of not enumerating that panic attack, agoraphobia, the anxiety disorder that causes with stress disorder after the agoraphobia of the panic disorder of the panic disorder of agoraphobia, no agoraphobia, no panic disorder history, simple terrified, social phobia and other simple terror, obsession, the wound, acute stress sexual dysfunction, generalized anxiety disorder, because of the general medical science illness, anxiety disorder that material brings out, separation anxiety diaorder, adjustment disorder, behavior anxiety, hypochondria, the anxiety disorder that causes because of the general medical science illness and material bring out.
18. the purposes of claim 15, wherein said neuropathic pain is selected from allodynia, hyperpathia property pain, phantom pain, the neuropathic pain relevant with diabetic neuropathy, the neuropathic pain of being correlated with trigeminal neuralgia and the neuropathic pain relevant with migraine with migraine property pain disease.
19. the neurodegenerative disease that the purposes of claim 15, wherein said neurodegenerative disease are selected from for example drug withdrawal or the poisoning of the encephalopathic of bringing out behind encephalopathic that alzheimer's disease, Huntington Chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutz Fil spy-jacob's syndrome, Parkinson's disease, AIDS bring out or rubella virus, simplexvirus, burgdorferi or the unknown pathogenic infection, the ultra state of excitation of neurodegeneration, neurone that wound is brought out, peripheral nervous system is polyneuropathy and polyneuritis for example.
20. the purposes of claim 14, wherein said subject disease is selected from bipolar disorder.
21. the purposes of claim 14, wherein said subject disease is selected from somnopathy, for example insomnia.
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