CN101242836A - Method of improving wakefulness - Google Patents
Method of improving wakefulness Download PDFInfo
- Publication number
- CN101242836A CN101242836A CNA2006800303879A CN200680030387A CN101242836A CN 101242836 A CN101242836 A CN 101242836A CN A2006800303879 A CNA2006800303879 A CN A2006800303879A CN 200680030387 A CN200680030387 A CN 200680030387A CN 101242836 A CN101242836 A CN 101242836A
- Authority
- CN
- China
- Prior art keywords
- sleep
- alkyl group
- low alkyl
- disorder
- effective dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the use of certain imidazolylalkyl-pyridines as wakefulness compounds.
Description
The cross reference of related application
The application advocates jointly-waits to examine the interests of U.S. Provisional Application number 60/703,604 and 60/732,536, and its applying date is respectively on July 29th, 2005 and on February 11st, 2005, incorporates these two pieces of applications into this paper by the mode of reference thus.
Background of invention
(1) technical field
The present invention relates in general to the treatment to excessive sleep.The present invention totally also relates to following treatment of diseases, and wherein excessively sleep is the factor that work or the concurrent disease relevant with other disease or following anesthesia.
(2) description of association area
Known or the doubtful wakefulness that can improve individuality of multiple chemical compound is arranged.For example, U.S. Patent Application Publication No. 20040143021 has been put down in writing modafinil improves wakefulness after anaesthetizing sb. generally application.U.S. Patent Application Publication No. 20010034373 has been put down in writing similarly and has been given modafinil to improve cognitive function.
The invention summation
The present invention relates to particularly use in the human patients specific imidazole radicals alkyl-pyridine to follow excessive sleep in following disease: sleeping sickness as wakefulness compounds for treating or prevention in mammalian subject, occlusive sleep apnea/breathing diminuendo syndrome, the shiftwork sleep disorder, obstacle desynchronizes, ovulation failure, seasonal melancholia, jet lag (time zone syndrome) or as the wakefulness disorder of jet lag consequence, or nervous system disease, and help, separately or with specific sleep derivation agent, regulate because shiftwork, old and feeble, blind, jet lag, day and night be exposed to the subarctiv, or the circadian rhythm rhythmicity parasthenia that is produced under other environment.
More particularly, the present invention relates to this application of formula I chemical compound,
R wherein
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen or optional by low alkyl group list-or dibasic amino, R
2And R
3Independently of one another and be hydrogen or low alkyl group, R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen, chemical compound exists with the form of free alkali or acid-addition salts, and the bridge between pyridine and the imidazoles is methylene or ethylidene, is illustrated as methylene.
Special aspect of the present invention provides the method that changes wakefulness and sleep, and it comprises the imidazolyl methyl-pyridine that gives patient's effective dose.Imidazolyl methyl-pyridine can give separately or give jointly with the sleep inducing agent of effective dose, or, give jointly with other wakefulness promoter of effective dose.The example of sleep derivation agent comprises melatonin agonists.
Another aspect of the present invention provides treatment or prevention to follow the method for the excessive sleep in following disease: sleeping sickness, occlusive sleep apnea/breathing diminuendo syndrome, jet lag or as the wakefulness disorder of jet lag consequence, or nervous system disease, it comprises the imidazolyl methyl-pyridine that gives patient's effective dose.
Above-mentioned and further feature of the present invention will be shown in the embodiment of the present invention of following more special record.
Detailed Description Of The Invention
" rudimentary " as used herein, in contextual alkyl and alkoxyl, expression has nearly 7 carbon atoms, preferably nearly 4 carbon atoms and the more preferably group of 2 carbon atoms nearly.Therefore, low alkyl group has nearly 7 carbon atoms especially, preferably reaches 4 carbon atoms, particularly reaches 2 carbon atoms, for example is methyl, ethyl, propyl group, isopropyl, butyl, tert-butyl, amyl group or hexyl.Therefore, lower alkoxy has nearly 7 carbon atoms, preferably reaches 4 carbon atoms, particularly reaches 2 carbon atoms, for example is methoxyl group, ethyoxyl, propoxyl group, uncle-butoxy or hexyloxy.
In the scope of above definition, in low alkyl group or lower alkoxy existence and formula (I) chemical compound, preferably have one or two carbon atom, especially represent methyl or methoxy.Imidazolyl methyl is preferably 2 of pyridine.R
1Be preferably methyl or ethyl, more preferably methyl.R
2And R
3Be preferably separately is hydrogen.R
4Be preferably methyl, ethyl or hydrogen, more preferably methyl or hydrogen, particularly hydrogen.The compd A of embodiment 1 is preferred.
In a special group of formula (I) chemical compound, R
1Be low alkyl group, R
2And R
3Be hydrogen or low alkyl group independently of one another, R
4Be that hydrogen, low alkyl group or atomic number are 9 to 35 halogen.
In another special group of formula (I) chemical compound, R
1Be methyl, R
2And R
3Be hydrogen or methyl independently of one another, R
4Be that hydrogen, methyl or atomic number are 9 to 35 halogen.
Atomic number is that 9 to 35 halogen refers specifically to fluorine and chlorine residue, more refers in particular to the chlorine residue.
Formula (I) chemical compound can exist with the form of free alkali or with the form of its acid-addition salts, and it comprises, for example, and difumarate (hydrogen fumarate) and fumarate form.Acid-addition salts can be formed by known methods by free alkali, and vice versa.
Formula (I) chemical compound is known, for example from U.S. Patent number 5,856, and 343 and 5,635,521,, maybe can promptly be similar to known method and generate by with reference to introducing at this by known method.
U.S. Patent number 5,856,343 have put down in writing the synthetic, as follows of compd A [2-(glyoxal ethyline-1-yl) methyl] pyridine:
9.7g (75mM) 2-(chloromethyl) pyridine and 42g (512mM) 2-methyl-imidazoles are suspended in the 40ml dimethyl formamide, stirred 3 hours down at 105 ℃ then.Distillate dimethyl formamide and with the crystallization residue with ethyl acetate and some hexane wash.Subsequent filtration, mother solution is through evaporation and concentration and distillate dimethyl formamide, shakes out several times between water and dichloromethane then.Obtain 10.3g oily title compound.
The wakefulness that formula (I) chemical compound and physiology thereof go up acceptable salt pair experimenter has interesting effect, therefore can be used on this respect.So can be used for the treatment of excessive sleep, the occlusive sleep apnea/breathing diminuendo syndrome of following sleeping sickness according to chemical compound of the present invention, or nervous system disease, and help to regulate owing to shiftwork, aging, blind, jet lag, day and night be exposed to subarctiv or the circadian rhythm rhythmicity parasthenia that is produced under other environment situation with specific sleep derivation agent.
" melatonin agonists or melatonin agonists class " refers to bioactive molecule as used herein, its be given the back can be in mammal in conjunction with one or more melatonin receptors, preferred MT1 and MT2, and sleep and physiological rhythm had effect.They comprise acidity, alkalescence, amphion, or the neutrophilous organism bioactive molecule, its salt and derivant, its be given the back in mammal can in conjunction with one or more melatonin receptors and to the sleep and physiological rhythm effect is arranged.Derivant comprises the prodrug or the metabolite of melatonin agonists, or the salt of melatonin agonists, solvate, hydrate, biological activity stereoisomer, or crystal or amorphous form, for example, MA-1 is (referring to Vachharajani etc., J.Pharmaceutical Sci., 92 (4): 760-772 (19) and hydroxylating, dehydrogenation, glucosiduronic acid and diol, derivatives.The example of melatonin agonists compounds is a melatonin agonists-1, (1R-is trans)-N-[[2-(2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] the propane amide, (N-[1-(2 for melatonin agonists-2,3-Dihydrobenzofuranes-4-yl) pyrrolidine-3-yl]-the N-ethyl urea)), and ramelteon, (S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furan-8-yl) ethyl] propionic acid amide., its compositions and structure are disclosed among the PCT patent publication us WO 97/32871.Other example of this compounds is LY156735, (R)-N-(2-(6-chloro-5-methoxyl group-1H-indole-3 base) propyl group) acetamide, GR196429, N-[2,3,7,8-tetrahydrochysene-1H-furan (2,3-g) indole-1-yl] ethyl) acetamide is (referring to Beresford etc., J.Pharmacol, and Exp.Therapeutics, 285:1239-45 (1998), be used for structure and feature), S-20098 (agomelatine; Referring to Yous etc., J.Med.Chem., 35:21484-86 (1992), be used for structure, synthetic and feature) and 2-bromine melatonin, (N-[2-(2-bromo-5-methoxyl group-1H-indol-3-yl) ethyl]-acetamide is (referring to Duranti etc., Life Sci., 51:479-85 (1992) is used for synthetic and feature).Other comprise the melatonin agonists class that is recorded in the following document: Spadoni etc.; J.Med.Chem.; 36:4069-74 (1993) (5-methoxyl group-N-acyl-trypamine); Langlois etc., J.Med.Chem., 38:2050-60 (1995) (N-[2-(2-methoxyl group-naphthyl) ethyl] propionic acid amide.; H-[2-(2; 7-dimethoxy naphthyl) ethyl] cyclopropyl carboxamide) and Copinga etc., J.Med.Chem., 36:2891-98 (1993) (2-acetylaminohydroxyphenylarsonic acid 8-methoxyl group naphthane).
Term " common-as to give ", " by giving jointly " and " giving jointly " refer to one or more other active pharmaceutical ingredients are combined with a kind of wakefulness derivant of the present invention as used herein, give mammal in one way, it can produce desired therapeutic effect.For example, in 24 hours, give sleep derivation agent and give the wakefulness derivant and be considered to " common-give ".
Term " treatment (treatment) " or " treatment (treat) " refer to prevention or defensive treatment and cure or revise treatment of diseases as used herein, comprise that treatment has the disease risks of infection or the suspicious patient who has caught and ill or be diagnosed as the patient who suffers from disease or medical conditions.
Can give by the approach of any routine according to chemical compound of the present invention, enteral, oral or local particularly is for example with the form of tablet, capsule or eye drop, or the parenteral route approach, for example with the form of injectable solution or suspension.
Can be controlled the activating agent of the present invention of animal (typically be the people, but also can treat other animals for example farm-animals, house pet and contest animal) effective dose, for example, imidazolyl methyl-pyridine such as compd A.Effective dose is to prevent, suppress or stop amount in the following disease: the hyperarousal state (ES) of following sleeping sickness, occlusive sleep apnea/breathing diminuendo syndrome (OSAHS), jet lag or as the wakefulness disorder of jet lag consequence, or other disease (comprising nervous system disease), for example hypersomnia, the REM dystropy, forehead dystonia at night, restless legs syndrome, wakefulness, parasomnia, epilepsy outbreak at night, the night movement imbalance, the difficult diagnosis relevant with sleep, the sleep apnea relevant with neurological disorder, shiftwork person's sleep disorder (SWSD), Kleine-Levin syndrome, sleep among the blind patient/clear-headed disease and parkinson (family name) syndrome.Effective dose is to prevent, suppress or to stop residual sedation, fatigue, amount sleepy and that lacked by the energy that anesthesia causes, or can prevent, suppresses or stop the sleep disordered amount by nerve injury, abnormal conditions, damage or the generation of performing the operation.
Sleep disorder and special REM are sleep disordered, and known also is to follow in different psychosiss to comprise in depression, mania, seasonal affective disorder, bipolar disorder and the schizophrenia.Compd A has demonstrated usually has effect and effective especially to reducing the REM sleep to clear-headed-sleep cycle.Therefore, in special embodiment, the present invention is directed to be that treatment or prevention are followed at depression, manicly levied, the method for the sleep disorder in seasonal affective disorder, bipolar disorder or the schizophrenia.
For for the indication of this record, appropriate dosage will change with for example compound used therefor, host, administering mode and character and the seriousness of being controlled disease certainly.Yet gratifying result refers to and obtains about 0.05 daily dose to about 50mg/kg the weight of animals in animal usually.In bigger animal, for example human, the daily dose of indication can typically be about 0.1mg to about 1600mg, and more typical is that about 1mg arrives about 800mg, or about 10mg arrives about 200mg, gives more easily, and for example the broken dose with four times a day gives.Activating agent can be before sleep disorder (with prevention or its influence is minimized) or back (stopping or to reduce its influence, and improve and quicken and restore) gives.
Wakefulness promoter of the present invention can give with the effective dose of effective dose and sleep derivation agent jointly so that regulate amount and/or time clear-headed and sleep, for example owing to shiftwork, aging, blind, jet lag, day and night be exposed in subarctiv or other environment under the parafunctional situation of caused circadian rhythm rhythmicity.In this article, will give the sleep derivation agent with at the reasonable time hypnotic, and will give wakefulness promoter, regulate patient's the sleep-wake cycle thus to promote wakefulness at reasonable time.For this application, sleep derivation agent and wakefulness promoter can be packaged in together, for example " day and night " packing so that the patient knows which medicine of when using at a day.Other example of sleep derivation agent comprises that other melatonin agonists class, eszopiclone, pyrazoles is smooth, zopiclone, brotizolam and triazolam.
Wakefulness promoter of the present invention also can give with the effective dose of effective dose and other wakefulness promoter to promote wakefulness or other effect so that strengthen jointly.For example, wakefulness promoter of the present invention can give so that strengthen or replenish the effect of these two kinds of medicaments jointly with modafinil or armodafinil or beta stimulant.
When sleep derivation agent and wakefulness promoter of the present invention give jointly so that when regulating with the amount of clear-headed and sleep and/or time, the suitable effective dose of sleep derivation agent is the amount that can produce the expection sleeper effect in the patient, certainly, it will change with for example compound used therefor, host, administering mode and character and the seriousness of being controlled disease.In animal, obtaining gratifying result can be about 1 daily dose to about 500mg/kg the weight of animals.In bigger animal, for example human, the daily dose of indication can typically be about 1mg to about 300mg, and more typical is that about 10mg arrives about 200mg, or about 10mg is to about 150mg.For best result, the sleep derivation agent should give in 1 hour in the precontract of sleeping, and wakefulness promoter about 8 gave by about 10 hours in about 1 hour of wakefulness or after giving the sleep derivation agent.
We can understand, and actual administered compound amount is controlled disease with being comprised according to relevant situation by the doctor, to selection to drug compound, and the selection of route of administration, at the age, the seriousness of the reaction of body weight and individual patient and patient's symptom is determined.
Concerning treatment or prophylactic use, imidazolyl methyl-pyridine generally will give as pharmaceutical composition, wherein compositions comprises at least a such chemical compound as (or a kind of) necessary active component, itself and solid-state or liquid pharmaceutically acceptable carrier optionally use standard and conventional technical combinations with pharmaceutically acceptable excipient and adjuvant.
Pharmaceutical composition comprises and is used for oral, the parenteral (suitable dosage forms that comprises subcutaneous, intramuscular, Intradermal, intravenous, percutaneous (for example by skin patch, gel, micropin, ionotherapy, phonophoresis or phonophoresis), bronchus or intranasal administration.Like this, if use is solid-state carrier, preparation can be a tablet so, with powder or piller form, or with tablet or lozenge form, places hard gelatin capsule.Solid-state carrier can comprise conventional adjuvant, for example binding agent, filler, tabletting lubricant, disintegrating agent, wetting agent etc.If desired, tablet can be through conventional technology by film coating.If what use is liquid carrier, preparation can be the form of syrup, Emulsion, Perle, the sterile carrier that is used to inject, aqueous or non-aqueous liquid suspension so, perhaps can be the dry products that is used for the suitable carrier reconstruct before use of water or other.Liquid formulation can comprise conventional additive, for example suspensoid, emulsifying agent, wetting agent, non--aqueous carrier (comprising edible oil), antiseptic, and flavoring and/or coloring agent.For parenteral introduction, although can use saline solution, glucose solution etc., carrier will comprise sterilized water usually, and major part is at least.Injectable suspension also can be used, and can use conventional suspensoid this moment.Conventional antiseptic, buffer agent etc. also be introduced in the parenteral dosage form.Special application is the form giving construction I chemical compound with oral formulations.Pharmaceutical composition is by being suitable for expecting that the routine techniques of preparation prepares, and wherein preparation comprises the active component of Sq, just according to formula I chemical compound of the present invention.For example referring to Remington ' s pharmaceutical science, Mack publishing company, Easton, Pa., the 17th edition, 1985.
Comprise in the pharmaceutical composition of The compounds of this invention in preparation, active component will mix with carrier usually, or by the carrier dilution, or be included in the carrier, it can be the form of capsule, sachet, paper or other shell.When carrier was used as diluent, it can be solid-state, semisolid or liquid, as carrier, excipient or the medium of active component.Like this, compositions just can be tablet, pill, powder, lozenge, sachet, cachet, elixir, suspensoid, Emulsion, solution, syrup, aerosol (as solid-state or liquid medium), for example comprise the form up to the ointment of 10% weight active compound, soft hard gelatin capsule, suppository, sterile injectable solution and aseptic packaging powder.
The example of some appropriate carrier and diluent comprises lactose, dextrose, sucrose, sorbitol, mannitol, starch, arabic gum, calcium phosphate, alginate, tragakanta, gelatin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate and propyl ester, Pulvis Talci, magnesium stearate and mineral oil.Can additionally comprise lubricant, wetting agent, emulsifying and suspensoid, antiseptic, sweeting agent or correctives in the preparation.Compositions of the present invention can be through preparation so that after giving the patient, can provide quick, lasting or the release of the active component that delays.
Compositions preferably is made into unit dosage form, and each dosage form comprises about 0.1 to 800mg active component.Term " unit dosage form " refers to and is suitable for as the discontinuous unit of the physics of unit dose administration of human patient or other animal, each unit all comprises the active substance of scheduled volume, it can produce desired therapeutic effect as calculated, and with the combination of required pharmaceutical carrier.For co-administered, the unit dose type of sleep derivation agent will comprise about 10 to about 200mg active component.
Below Ji Zai some embodiment have proved the Imidazolylmethyl-pyridines for example various salt forms and the ability of various dosage aspect change sleep cycle and wakefulness of compd A.
1. material and method
1.1 chemical compound
In first group of test, estimated compd A oral (p.o.) and subcutaneous (s.c.) and given effect rat Sleep-Wake period of state.For this purpose, we have used the form of many fumarates (mfu) or fumarate (fu).
In second group of test, estimated the effect of oral administration of compound A in the rat Sleep-Wake period of state of Mai Neite (family name) basal nuclei (NBM) and locus coeruleus (LC) damage.For this purpose, we have used the form of many fumarates (mfu).
1.2 zoopery
1.2.1 not-damage rat
Test is not being carried out in the not limited male Wistar rat of anesthesia, has long-term embedded electrode in the rat with record electrocorticogram (ECoG).Animal is closed into the room, keep 22 ℃ of steady temperatures and artificial lighting every day 12 hours.Before beginning test, give 1 to 3 day temporal adaptation of animal record cage and carry out freely-movable fully, even when linking recording electrode.ECoG is recorded in administration to carry out after 15 minutes 22 to 23 hours continuously.Each animal is the contrast of conduct oneself all.In a test, after giving distilled water (carrier that compd A uses), also obtained ECoG and write down the contrast that conduct does not have administration or gives compd A.
1.2.2 the rat of damage
Use male rat.They are by pentobarbital anesthesia (50mg/kg i.p.) and place stereotaxic apparatus, on it dens in dente point of contact connecting rod be lower than line 5mm between ear (locus coeruleus, LC) or 3.3mm (Mai Neite (family name) basal nuclei, NBM).Damage was carried out for 10 seconds with the rf injury generator and is produced under 60 ℃.Corresponding false injury rats group also is formed.After damage forms, animal was put into independent cage respectively 6 months.After damage forms 5 months, implant cortical electrode.Animal is closed in the room, keep 22 ℃ of steady temperatures and artificial lighting every day 12 hours.Before beginning test, give 1 day temporal adaptation of animal record cage.These cages are high plastic cylinders, and animal is freely-movable fully therein, even when linking recording electrode.ECoG is recorded in to animal and installed back 15 minutes or administration was carried out 22 hours/day after 15 minutes continuously.
Four treated animals are studied (A1-4), and between different groups, carry out statistical analysis (T-check, p＜0.05).
A1:5 only damages animal, carries out 35 days record after damage, wherein gives 3mg/kg p.o. compd A in 5 days.Embedded electrode after 5 months.The 22nd day and 23 days record ECoG after implantation.
A2: identical with A1, but replace compd A with excipient.
A3: identical with A1, but replace injury rats with false rat.
A4: identical with A3, but replace compd A with excipient.
2 results
2.1 injury rats not
3,10 and 30mg/kg (mfu) p.o., 3 and 10mg/kg (fu) p.o., and 1,3 and 10mg/kg (mfu) s.c. in the rhythm and pace of moving things that rat changes with daily variations, produced significant variation in dose-dependent mode really.
Under 3mg/kg p.o. dosage, compd A is in a persistent period of reducing the REM sleep in 4 hours.Orthodoxsleep has also reduced.During this, observed the increase of wakefulness.Compd A has significantly delayed the beginning of S sleep (SWS).Effectively regain consciousness and tend to increase to some extent at 0-4 with between 7-11 hour, and intra-record slack byte in the end, significantly increase in 18.75-23 hour.
Under 10mg/kg p.o. dosage, compd A tended to increase the clear-headed time at 6 hours, reduced orthodoxsleep in 3 hours, and can significantly reduce the REM sleep time in several hours.During 7-11 after the administration hour, compd A still can significantly increase recovery time and reduce the persistent period of SWS.For same interval, the REM sleep is also tended to increase.Effectively regain consciousness remarkable increase is arranged in 0-4 hour after administration.In addition, compd A has delayed the beginning of REM sleep forcefully, and also tends to delay the beginning of SWS.Under 30mg/kg p.o. dosage, compd A has delayed the beginning of SWS and REM sleep forcefully.In addition, it has increased the clear-headed time and reduced the persistent period that has reduced the REM sleep in persistent period and the 4-7 after administration hour of SWS and REM sleep in 4 hour of record.All effects are all very strong; The minimizing of REM sleep has continued about 11 hours, and the increase of wakefulness has continued about 9 hours.
Under 1mg/kg s.c. dosage, compd A has reduced the persistent period of REM sleep in 2 hours, and has strengthened wakefulness in 4 hours.
3 and 10mg/kg s.c. dosage under, compd A has produced and by oral administration effect much at one.
3 dosage that tried p.o fu salt form with 10mg/kg are identical to the effect in rat sleep wakefulness cycle and the effect of mfu form.
2.2 injury rats
Damage after 5 months, compare with false rat, the sleep wakefulness cycle of rat has been upset fully.The animal of damage occurs more clear-headed and less orthodoxsleep is arranged.
In injury rats, the treatment of carrying out with compd A has reduced the change that is caused by damage in a large number; By two kinds of effects that damage produces, i.e. wakefulness increase and orthodoxsleep reduce all partly combined thing A have been prevented, and this appears at during the whole record.
3. discuss
The result of the test explanation compd A that does not damage animal has delayed REM sleep and SWS, has reduced the REM sleep, has reduced conventional sleep, and has increased wakefulness.In this experiment, the effectiveness of effect is well, because compd A is very similar by s.c. with the effect that the p.o. administration produces.
The result of the test of injury rats explanation compd A can reduce that to damage the cycle that changes with daily variations that is produced by for example simultaneous LC+NBM of neuronal damage unusual, and shows that compd A can produce rectification effect in the some months after it carries out last administration.
Although invention has been described in conjunction with above-mentioned specific embodiment, it is apparent that many changes, modification and variation all will be conspicuous for a person skilled in the art or be included in wherein in addition.Therefore, above-mentioned embodiment of the present invention is illustrative rather than definitive thereof.Various changes can be made and do not deviated from defined the spirit and scope of the present invention in following claim.All incorporate this paper at these all patents of quoting, patent application, scientific paper and other publication document thus into the full content of its disclosed essence.
Claims (according to the modification of the 19th of treaty)
The modification right requirement that international office was received on January 10th, 2007
1-16 (deletion)
17. the method for treatment or the parahypnosis of prevention mammal, it comprises: the chemical compound with following structure that mammal inside is given effective dose:
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene.
18. the method for claim 17, wherein R
1Be that low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino, and the bridge between pyridine and the imidazoles is a methylene.
19. the method for claim 18, wherein R
1It is methyl.
20. the method for claim 17, wherein institute's administered compound is the form of free alkali, difumarate or fumarate.
21. the method for claim 17, wherein institute's administered compound is [2-(glyoxal ethyline base-1-base-) methyl] pyridine, gives with the form of free alkali or physiologically acceptable acid-addition salts.
22. the method for claim 21, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine, gives with the form of free alkali, difumarate or fumarate.
23. the method for claim 21, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine fumarate salt.
24. the method for claim 17, wherein mammal is the people.
25. the method for claim 24, wherein sleep disorder is at least a following disease: follow the excessive sleep (ES) of sleeping sickness, occlusive sleep apnea/hypopnea syndrome (OSAHS), jet lag or as the wakefulness disease of jet lag consequence, nervous system disease, hypersomnia, REM behavior disease, forehead dystonia at night, restless legs syndrome, wakefulness, parasomnia, Nocturnal seizures, the night movement imbalance, the difficult diagnosis relevant with sleep, the sleep apnea relevant with neurological disorder, shiftwork person's sleep disorder (SWSD), Kleine-Levin syndrome, sleep/wake disorders among the blind patient, parkinson (family name) syndrome, residual sedation, tired, sleepy, the energy that is caused by anesthesia lacks, and by nerve injury, abnormal conditions, the sleep disorder that damage or operation produce.
26. the method for claim 24, wherein sleep disorder is followed at least a following nervous system disease, and it is selected from: parkinson, Alzheimer's disease, multiple sclerosis and post-traumatic stress disorder.
27. the method for claim 24, wherein sleep disorder is followed at least a following mental sickness, and it is selected from: depression, mania, seasonal affective disorder, bipolar disorder and schizophrenia.
28. the method for claim 17, wherein chemical compound oral administration, suction, part, through mucous membrane, parenteral, intravenous or ophthalmic give.
29. the method for claim 17, wherein chemical compound gives at least a following mode: rapid release form, controlled release forms and slow release form.
30. the method for claim 17, wherein effective dose is about 0.1 to about 1600mg/kg/ days.
31. the method for claim 30, wherein effective dose is about 1 to about 800mg/kg/ days.
32. the method for claim 31, wherein effective dose is about 10 to about 200mg/kg/ days.
33. the method for claim 17, wherein institute's administered compound has following structure:
R wherein
1It is methyl.
34. the method for claim 33, wherein institute's administered compound is the form of free alkali or physiologically acceptable acid-addition salts.
35. the method for claim 33, wherein institute's administered compound is the form of free alkali, difumarate or fumarate.
36. the method for claim 33, wherein chemical compound oral administration, suction, part, through mucous membrane, parenteral, intravenous or ophthalmic give.
37. the method for claim 33, wherein chemical compound gives at least a following mode: rapid release form, controlled release forms and slow release form.
38. the method for claim 33, wherein effective dose is about 0.1 to about 1600mg/kg/ days.
39. the method for claim 38, wherein effective dose is about 1 to about 800mg/kg/ days.
40. the method for claim 39, wherein effective dose is about 10 to about 200mg/kg/ days.
41. the method for claim 33, wherein mammal is the people.
42. the method for claim 41, wherein sleep disorder is at least a following disease: follow the excessive sleep (ES) of lethargy disease, occlusive sleep apnea/hypopnea syndrome (OSAHS), jet lag or as the wakefulness disease of jet lag consequence, nervous system disease, hypersomnia, REM behavior disease, forehead dystonia at night, restless legs syndrome, wakefulness, parasomnia, Nocturnal seizures, the night movement imbalance, the difficult diagnosis relevant with sleep, the sleep apnea relevant with neurological disorder, shiftwork person's sleep disorder (SWSD), Kleine-Levin syndrome, sleep/wake disorders among the blind patient, parkinson (family name) syndrome, residual sedation, tired, sleepy, the energy that is caused by anesthesia lacks, and by nerve injury, abnormal conditions, the sleep disorder that damage or operation produce.
43. the method for claim 41, wherein sleep disorder is followed at least a following nervous system disease, and it is selected from: parkinson, Alzheimer's disease, multiple sclerosis and post-traumatic stress disorder.
44. the method for claim 41, wherein sleep disorder is followed at least a following mental sickness, and it is selected from: depression, mania, seasonal affective disorder, bipolar disorder and schizophrenia.
45. regulate the amount and/or the time method of the clear-headed and sleep of mammal, it comprises at least a following chemical compound that gives effective dose jointly and the sleep derivation agent of effective dose:
Chemical compound with following structure:
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene;
Chemical compound with following structure:
R wherein
1It is methyl;
Chemical compound with following structure,
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene; And
Chemical compound with following structure:
R wherein
1It is methyl.
46. the method for claim 45, wherein the sleep derivation agent is a melatonin agonists.
47. the method for claim 46, wherein melatonin agonists is MA-1.
Claims (47)
1. promote the method for mammal wakefulness, it comprises: the chemical compound with following structural formula that mammal inside is given effective dose:
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene.
2. the process of claim 1 wherein R
1Be that low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino, and the bridge between pyridine and the imidazoles is a methylene.
3. the method for claim 2, wherein R
1It is methyl.
4. the process of claim 1 wherein that institute's administered compound is the form of free alkali, difumarate or fumarate.
5. the process of claim 1 wherein that institute's administered compound is [2-(glyoxal ethyline base-1-base-) methyl] pyridine, give with the form of free alkali or physiologically acceptable acid-addition salts.
6. the method for claim 5, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine, gives with the form of free alkali, difumarate or fumarate.
7. the method for claim 5, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine fumarate salt.
8. the process of claim 1 wherein that mammal is the people.
9. the process of claim 1 wherein that institute's administered compound has following structure:
R wherein
1It is methyl.
10. the method for claim 9, wherein institute's administered compound is the form of free alkali or physiologically acceptable acid-addition salts.
11. the method for claim 9, wherein institute's administered compound is the form of free alkali, difumarate or fumarate.
12. the process of claim 1 wherein that chemical compound oral administration, suction, part, through mucous membrane, parenteral, intravenous or ophthalmic give.
13. the process of claim 1 wherein that chemical compound gives at least a following mode: rapid release form, controlled release forms and slow release form.
14. the process of claim 1 wherein that effective dose is about 0.1 to about 1600mg/kg/ days.
15. the method for claim 14, wherein effective dose is about 1 to about 800mg/kg/ days.
16. the method for claim 15, wherein effective dose is about 10 to about 200mg/kg/ days.
17. the method for treatment or the parahypnosis of prevention mammal, it comprises: the chemical compound with following structure that mammal inside is given effective dose:
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene.
18. the method for claim 17, wherein R
1Be that low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino, and the bridge between pyridine and the imidazoles is a methylene.
19. the method for claim 18, wherein R
1It is methyl.
20. the method for claim 17, wherein institute's administered compound is the form of free alkali, difumarate or fumarate.
21. the method for claim 17, wherein institute's administered compound is [2-(glyoxal ethyline base-1-base-) methyl] pyridine, gives with the form of free alkali or physiologically acceptable acid-addition salts.
22. the method for claim 21, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine, gives with the form of free alkali, difumarate or fumarate.
23. the method for claim 21, wherein institute's administered compound is [2-(glyoxal ethyline base-1-yl) methyl] pyridine fumarate salt.
24. the method for claim 17, wherein mammal is the people.
25. the method for claim 24, wherein sleep disorder is at least a following disease: follow the excessive sleep (ES) of sleeping sickness, occlusive sleep apnea/hypopnea syndrome (OSAHS), jet lag or as the wakefulness disease of jet lag consequence, nervous system disease, hypersomnia, REM behavior disease, forehead dystonia at night, restless legs syndrome, wakefulness, parasomnia, Nocturnal seizures, the night movement imbalance, the difficult diagnosis relevant with sleep, the sleep apnea relevant with neurological disorder, shiftwork person's sleep disorder (SWSD), Kleine-Levin syndrome, sleep/wake disorders among the blind patient, parkinson (family name) syndrome, residual sedation, tired, sleepy, the energy that is caused by anesthesia lacks, and by nerve injury, abnormal conditions, the sleep disorder that damage or operation produce.
26. the method for claim 24, wherein sleep disorder is followed at least a following nervous system disease, and it is selected from: parkinson, Alzheimer's disease, multiple sclerosis and post-traumatic stress disorder.
27. the method for claim 24, wherein sleep disorder is followed at least a following mental sickness, and it is selected from: depression, mania, seasonal affective disorder, bipolar disorder and schizophrenia.
28. the method for claim 17, wherein chemical compound oral administration, suction, part, through mucous membrane, parenteral, intravenous or ophthalmic give.
29. the method for claim 17, wherein chemical compound gives at least a following mode: rapid release form, controlled release forms and slow release form.
30. the method for claim 17, wherein effective dose is about 0.1 to about 1600mg/kg/ days.
31. the method for claim 30, wherein effective dose is about 1 to about 800mg/kg/ days.
32. the method for claim 31, wherein effective dose is about 10 to about 200mg/kg/ days.
33. the method for claim 17, wherein institute's administered compound has following structure:
R wherein
1It is methyl.
34. the method for claim 33, wherein institute's administered compound is the form of free alkali or physiologically acceptable acid-addition salts.
35. the method for claim 33, wherein institute's administered compound is the form of free alkali, difumarate or fumarate.
36. the method for claim 33, wherein chemical compound oral administration, suction, part, through mucous membrane, parenteral, intravenous or ophthalmic give.
37. the method for claim 33, wherein chemical compound gives at least a following mode: rapid release form, controlled release forms and slow release form.
38. the method for claim 33, wherein effective dose is about 0.1 to about 1600mg/kg/ days.
39. the method for claim 38, wherein effective dose is about 1 to about 800mg/kg/ days.
40. the method for claim 39, wherein effective dose is about 10 to about 200mg/kg/ days.
41. the method for claim 33, wherein mammal is the people.
42. the method for claim 41, wherein sleep disorder is at least a following disease: follow the excessive sleep (ES) of lethargy disease, occlusive sleep apnea/hypopnea syndrome (OSAHS), jet lag or as the wakefulness disease of jet lag consequence, nervous system disease, hypersomnia, REM behavior disease, forehead dystonia at night, restless legs syndrome, wakefulness, parasomnia, Nocturnal seizures, the night movement imbalance, the difficult diagnosis relevant with sleep, the sleep apnea relevant with neurological disorder, shiftwork person's sleep disorder (SWSD), Kleine-Levin syndrome, sleep/wake disorders among the blind patient, parkinson (family name) syndrome, residual sedation, tired, sleepy, the energy that is caused by anesthesia lacks, and by nerve injury, abnormal conditions, the sleep disorder that damage or operation produce.
43. the method for claim 41, wherein sleep disorder is followed at least a following nervous system disease, and it is selected from: parkinson, Alzheimer's disease, multiple sclerosis and post-traumatic stress disorder.
44. the method for claim 41, wherein sleep disorder is followed at least a following mental sickness, and it is selected from: depression, mania, seasonal affective disorder, bipolar disorder and schizophrenia.
45. regulate the amount and/or the time method of the clear-headed and sleep of mammal, it comprises at least a following chemical compound that gives effective dose jointly and the sleep derivation agent of effective dose:
Chemical compound with following structure:
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene;
Chemical compound with following structure:
R wherein
1It is methyl;
Chemical compound with following structure,
Wherein
R
1Be that hydrogen, low alkyl group, atomic number are 9 to 35 halogen, or optional by low alkyl group list-or dibasic amino;
R
2And R
3Independently of one another and be hydrogen or low alkyl group;
R
4Be that hydrogen, hydroxyl, low alkyl group, lower alkoxy or atomic number are 9 to 35 halogen; And
Bridge between pyridine and the imidazoles is methylene or ethylidene, is exemplified as methylene; And
Chemical compound with following structure:
R wherein
1It is methyl.
46. the method for claim 45, wherein the sleep derivation agent is a melatonin agonists.
47. the method for claim 46, wherein melatonin agonists is MA-1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70360405P | 2005-07-29 | 2005-07-29 | |
| US60/703,604 | 2005-07-29 | ||
| US60/732,536 | 2005-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101242836A true CN101242836A (en) | 2008-08-13 |
Family
ID=39933855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800303879A Pending CN101242836A (en) | 2005-07-29 | 2006-07-26 | Method of improving wakefulness |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101242836A (en) |
| ZA (1) | ZA200800590B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022206985A1 (en) * | 2021-04-02 | 2022-10-06 | 四川大学华西医院 | Novel use of cyclic ketone compound |
-
2006
- 2006-07-26 CN CNA2006800303879A patent/CN101242836A/en active Pending
-
2008
- 2008-01-21 ZA ZA200800590A patent/ZA200800590B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022206985A1 (en) * | 2021-04-02 | 2022-10-06 | 四川大学华西医院 | Novel use of cyclic ketone compound |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200800590B (en) | 2009-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI419681B (en) | Use of carbamate compounds for the manufacturing of a medicament for treating excessive daytime sleeping(eds) | |
| CA2616177C (en) | Imidazolylalkyl-pyridines for the treatment of a sleep disorder | |
| NZ582942A (en) | Use of kncq potassium channel openers for treating attention deficit hyperactivity disorder (adhd) or aggression | |
| Barletta et al. | Evaluation of dexmedetomidine and ketamine in combination with opioids as injectable anesthesia for castration in dogs | |
| JP2008519847A (en) | How to treat movement disorders | |
| JP2008531714A (en) | Pharmaceutical composition for the treatment and / or prevention of anxiety disorders | |
| KR20230003503A (en) | (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine for the treatment of neurological and psychiatric disorders | |
| NO333610B1 (en) | Use of alpha-aminamide derivatives in the manufacture of a medicament for the treatment of headache conditions | |
| TWI453013B (en) | Use of n-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3,3-dimethyl-butyramide and medicament comprising said compound | |
| EP1832286A1 (en) | Preventive or therapeutic agent for sleep disorder | |
| Akanmu et al. | A novel melatonin derivative modulates sleep–wake cycle in rats | |
| KR20120103557A (en) | Compositions and methods for treating parkinson's disease | |
| CN101242836A (en) | Method of improving wakefulness | |
| TW544311B (en) | Therapeutic or preventive agent for intractable epilepsies | |
| JP5557243B2 (en) | Sleep improver | |
| CN1717235A (en) | Method of treating movement disorders using barbituric acid derivatives | |
| de Andrés et al. | The disconnected brain stem does not support rapid eye movement sleep rebound following selective deprivation | |
| CN108079305A (en) | The medical composition and its use of cannabidiol and tricyclic antidepressant | |
| Georgiev | NEUROPHYSIOLOGICAL CONTROL OF SLEEP WITH SPECIAL EMPHASIS ON MELATONIN | |
| CN114948975A (en) | Application of monophosphoryl lipid A in preparation of medicine for treating adult amblyopia | |
| WO2024052880A1 (en) | Use of mdma for treatment of stress-related disorders | |
| WO2000056292A2 (en) | Use of 1,2,4-triazolo[1,5-a]pyrimidine derivatives for treating migraine | |
| Balzamo et al. | Effects of tianeptine on sleep-wakefulness cycles in the rhesus monkey | |
| TW200524920A (en) | Treatment of circadian rhythm disorders with NPY Y5 receptor antagonist | |
| MX2008001249A (en) | Method of improving wakefulness |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080813 |