CN104292126B - Naphthalene derivatives and the application on medicine thereof - Google Patents

Abstract

The present invention provides some naphthaline derivatives or its stereoisomer, dynamic isomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug, for exciting melatonin receptors.The invention also discloses the pharmaceutical composition containing such compound and use the purposes in the compounds of this invention or its medicine composite for curing mammal, particularly mankind's central nervous system dysfunction.

Description

Naphthalene derivatives and the application on medicine thereof

Technical field

The invention belongs to drug world, be specifically related to a class and can be used for treating the new chemical combination of central nervous system dysfunction Thing, the method preparing them, the pharmaceutical composition comprising described compound and described compound and pharmaceutical composition thereof are being controlled Treat the application in central nervous system dysfunction.More specifically, the melatonin receptors that can serve as of the present invention is exciting The naphthalene compounds of agent.

Background technology

Epiphysin (melatonin) is a kind of neuro-endocrinology hormone secreted by pineal body, and its major physiological effect has: 1. antitumor action, epiphysin can suppress breast cancer, melanoma, prostate cancer, the growth of the multiple cancer cells such as liver cancer, is important Physiological tumor inhibitor；2. antioxidation, body can produce free radical by enzymatic reaction and non-enzymatic reaction, as Oxygen radical, hydroxyl radical free radical etc., epiphysin is mainly by providing electronics to carry out Scavenger of ROS (ROS)；3. immunoregulation effect, Epiphysin is contact one of organism nervous system and immune important factor, for maintaining body normal function to have important Effect；4. anti-inflammatory and stress, epiphysin can be obviously promoted the increasing of rheumatoid arthritis human peripheral lymphocyte Growing reaction, to low temperature, anoxic, noise, light is upset stress all antagonism；5. glycolipid metabolism regulation effect, epiphysin can Reduce blood sugar and blood fat, increasing high density lipoprotein；6. antidepression and the antianxiety effect 7. impact on Sleep latency, take off black Element can also be mediated by specific melatonin receptors, play regulation sleep-waking cycle unique effect (Malpaux B, Migaud M, et a1.Biology of mam malian photoperiodism and the critical role of The pineal gland and melatonin.J Biol Rhythms, 2001,16 (4): 336-347).Epiphysin need to lead to Crossing activated receptor and play biological agent, melatonin receptors belongs to G-protein coupling receptor superfamily member, is widely present in nerveous system The SCN of system, hippocampus, cerebellar cortex, prefrontal lobe, Basal ganglia, black substance ventral tegmental area, volt core etc., and retina, blood vessel, breast Gland, liver, kidney, in the cell membrane of the other system such as intestines and stomach and sexual gland and nucleus.Mankind's melatonin receptors has MT₁, MT₂And MT₃ Three hypotypes.MT₁, high aggregation is in the parts such as SCN, nervus thalamicus core, regulation sleep；MT₂, relate to circadian rhythm；MT₃Effect Not clear.(Charlotte von Gal1, Jorg H, et al., Mammalian melatonin receptors: Molecular biology and signal transduction.Cell TissueRPs, 2002,309 (1): 151- 162)。

In the disease relevant to melatonin receptors, insomnia is very important one.Insomnia refers to the beginning of sleep Send out and sleep maintains and obstacle occurs, cause sleep quality can not meet individual physiological requirements and to significantly affect patient diurnal A kind of sleep-disorder syndrome.Insomnia is a kind of common disease, makes people show dejected, impatient, can weaken immunization machine simultaneously System, hinders antisecosis, and along with the modern life rhythm and pace of moving things is accelerated, insomnia has increasing trend, in real life because of sleep not The contingency that foot causes also more generation.At present, the whole world has the people of nearly 1/4 to be perplexed by insomnia, and China's sleep-disorder is ill Rate reaches 42.7%, there are about 300,000,000 a middle-aged persons and suffers from sleep-disorder.Within 2009, global somnifacient market value is 4,000,000,000 dollars, Nian Zeng Long rate is 11%.

At present, drug therapy is one of main method for the treatment of of insomnia patients, and the hypnotic sedative agent applied clinically has: bar ratio Appropriate class medicine, benzodiazepine medicine, non-benzodiazepine medicine, antidepression class medicine, epiphysin and Chinese medicine etc..Barbiturate It is the derivative of barbiturates (malonyl urea), by optionally suppressing thalamus ascending reticular activing system, thus blocks emerging Put forth energy to corticocerebral conduction.This type of drug main phenobarbital to be had, amytal and quinalbarbitone etc..Such medicine poison Side effect is relatively big, the most serious liver, and renal toxicity can be produced after long-time use tolerance and dependence, accumulates poisoning, now clinical The most less for tranquilizing soporific.Benzodiazepine medicine has calmness, and flesh is loose, antianxiety and anticonvulsant action, clinical commonly used drug: Mainly there are midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), Flurazepam (flurazepam), Clonazepam (clonazepam) etc..These medicines Though thing can extend total sleep time, shorten Sleep latency, reduce slow wave sleep and quickly with dynamic (rapid eye Movement, REM) sleep, the most really improves sleep quality.Its bad reaction and complication are more apparent, and prolonged application can be drawn Play drug tolerance, dependence and withrawal symptom.(Krystal AD.The changing perspective on chronic Insomnia management.J Clin Psychiatry, 2004,65Suppl 8:20-25).Non-benzodiazepine, approved The medicine of listing has zolpidem (zolpidem), Zaleplon (zalepbn) and zopiclone (zopielone), this type of medicine Do not affect ortho structure, the most do not produce rebound insomnia and abstinence reaction.Common bad reaction has incoordination, head Bitterly, drowsiness, memory difficulty, (Rotht, Soubranec, Titeuxl, et al., the Efficacy and such as abalienation Safety of zolpidem-MR:a double-blind.placehe-controll study in adults with Primary insomniam.Sleep Med, 2006,7 (5): 397-406).Antidepressant does not has special hypnosis and makees With, but it is by treatment is depressed and anxiety is to improve insomnia, and what clinic was conventional has Paxil (paroxetine), sertraline Woods (sertraline), Mirtazapine (mirtazapine), Trazodone (trazodone) and amitriptyline etc., individuals patients makes When using SSRIs, sleep, without improving, even deteriorates (Uhlenhutheh, EH, Balter MB, et al., Trends in recommendations for the pharmacotherapy of anxiety disorders by an Intemationa expert panel, 1992-1997.Eur Neuropsyehopharmacol, 1999.9Suppl 6: 393-398).Therefore, exploitation efficiently, high selectivity, the study hotspot that the little sedative hypnotic drug of side effect becomes.

The good effect of epiphysin class medicine, side effect is little, has good application prospect.2005 in U.S.'s Initial Public Offering Melatonin receptors activator Ramelteon (ramelteon), for treatment of insomnia patients, can shorten Sleep latency, improve sleep Efficiency and sleep maintain, and compared with conventional medicament, this medicine does not damage cognitive activities next day, without withdrawal symptoms；But this medicine has Slight side effect, as having a headache, tired, drowsiness grade (Arendt J, Van Someren E J, Appleton R, et a1., Clinical update:melatonin and sleep disorders.Clin Med, 2008,8 (4): 381-383).

The invention provides some noval chemical compounds with melatonin receptors agonist activity, possess preferable clinical practice Prospect.Compared with existing similar compound, the compound of the present invention has more preferable drug effect, and medicine is special for character and/or toxicity Property.

Summary of the invention

The invention provides a class and there is the compound of melatonin receptors agonist activity, may be used for the preparation treatment mankind Central nervous system dysfunction, such as sleep-disorder, stress reaction, SAD, insomnia that the time difference causes and tired Labor and the medicine of insomnia.Present invention provides the method preparing these compounds, use these compounds for treating lactations to move The method of the above-mentioned disease of thing, the especially mankind and comprise the pharmaceutical composition of these compounds.

Specifically:

On the one hand, the present invention relates to a kind of compound, it is the solid of structure shown in the structure shown in formula (I) or formula (I) Isomers, dynamic isomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug,

On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound disclosed by the invention.

In one embodiment, pharmaceutical composition of the present invention comprises pharmaceutically acceptable excipient further, Carrier, adjuvant, solvent or combinations thereof.

On the other hand, the present invention relates to compound disclosed by the invention or the composition purposes in preparing medicine, described Medicine is used for preventing, and treats or alleviates mammal, including the central nervous system dysfunction of the mankind: refer to sleep-disorder, and should Swash reaction, depression, anxiety disorder, SAD, insomnia that the time difference causes and fatigue, schizophrenia, faint from fear, in terror Outbreak, melancholia, insomnia, psychotic disorder, epilepsy, Parkinson's, senile dementia, with normal or pathological seaility Relevant various obstacles, antimigraine, the loss of memory or Alzheimer disease.

On the other hand, the present invention relates to compound disclosed by the invention or the composition purposes in preparing medicine, described Medicine is for melatonin receptors the most exciting in biological sample.

On the other hand, the present invention relates to the preparation of the compound that formula (I) is comprised, the method separating and purifying.

Biological results shows, the compound that the present invention provides can be as preferable melatonin receptors activator.

Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and Content in terms of him will make more specific complete description below.

Detailed description of the invention

Definition and general terms

Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.

It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.

Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.

It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.

" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.

" enantiomter " refer to two of a compound can not be overlapping but be mutually the isomers of mirror.

" diastereoisomer " refers to two or more chiral centres and the alloisomerism of its molecule mirror image the most each other Body.Diastereoisomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatogram, such as HPLC.

Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Many organic compounds exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hand The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity time, May occur in which this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with racemic or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.

According to starting material and the selection of method, the compounds of this invention can with in possible isomers or they Mixture, the such as form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomers can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomter, diastereoisomer, such as, by chromatography and/or fractional crystallization Method.

By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

What term " dynamic isomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach Chemical balance to dynamic isomer.Such as, proton tautomer (protontautomer) (also referred to as proton translocation change Isomers (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization And imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes the restructuring by some bonding electrons The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone The change of dynamic isomer.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one dynamic isomer.Unless otherwise noted, the institute of the compounds of this invention Tautomeric forms is had to be within the scope of the present invention.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituents, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.It is said that in general, art Language " substituted " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent.Unless other aspect tables Bright, an optional substituted radical can replace in each commutable position of group.When in given structural formula not One or more substituents that only position can be selected from concrete group are replaced, then substituent can identical or differently Replace in each position.Wherein said substituent is it may be that but be not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyanogen Base, azido, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, virtue Epoxide, heteroaryloxy, oxo, carboxyl, haloalkyl, the substituted alkyl of hydroxyl, the substituted alkoxyl of hydroxyl, the substituted alkane of hydroxyl Base-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)₂-, hydroxyl substituted alkyl-S (=O), hydroxyl takes Alkyl-the S (=O) in generation₂, Carboxyalkoxy etc..

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.With R^aAs a example by, structural formula "-N (R^a)C (=O) NR^aR^b" and structural formula "-(C₁-C₆Alkyl)-NR^aR^b" R between the two^aConcrete option the most unaffected, with Time, at same chemical formula "-N (R^a) C (=O) NR^aR^bIn ", multiple R^aConcrete option the most unaffected.

At each several part of this specification, the come into the open substituent of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C₁-C₆Alkyl " refer in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituent.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent institute that described alkyl group can optionally be described by one or more present invention Replacing, wherein said substituent is, hydroxyl, amino, fluorine, cyano group, azido, heteroaryl, alkoxyl, alkylamino, alkylthio group, Alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo, carboxyl, haloalkyl, hydroxyl is substituted Alkyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (= O)₂-, hydroxyl substituted alkyl-S (=O), hydroxyl substituted alkyl-S (=O)₂, Carboxyalkoxy etc..Unless it is the most detailed Illustrating, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；At another In embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom； The most in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-pro-pyl (n- Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), etc..

Term " alkylidene " represents remove obtained by two hydrogen atoms from saturated straight or branched alkyl saturated Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；Another embodiment party In case, alkylidene group contains 1-3 carbon atom；The most in one embodiment, alkylidene group contains 1-2 carbon atom.This The example of sample includes methylene (-CH₂-), ethylidene (-CH₂CH₂-), isopropylidene (-CH (CH₃)CH₂-) etc..

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is a carbon-to-carbon sp²Double bond, wherein, described alkenyl group can optionally be retouched by one or more present invention The substituent stated is replaced, and it includes " cis " and the location of " tans ", or the location of " E " and " Z ".In one embodiment, Alkenyl group comprises 2-8 carbon atom；In another embodiment, alkenyl group comprises 2-6 carbon atom；Another embodiment party In case, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (-CH=CH₂), Pi-allyl (-CH₂CH=CH₂) etc..

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is carbon-to-carbon sp tri-key, wherein, described alkynyl group can optionally be retouched by one or more present invention The substituent stated is replaced.In one embodiment, alkynyl group comprises 2-8 carbon atom；In another embodiment, alkynyl Group comprises 2-6 carbon atom；In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example bag of alkynyl group Include, but be not limited to, acetenyl (-C ≡ CH), propargyl (-CH₂C ≡ CH), 1-propinyl (-C ≡ C-CH₃) etc..

Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as with oxygen atom phase Even, oh group is formed.

The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.

Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N is (as 3, in 4-dihydro-2 h-pyrrole base N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " the substituted alkyl of hydroxyl " represents that alkyl group is replaced by one or more oh groups, wherein alkyl base Group has implication of the present invention.Such example comprises, but is not limited to methylol, ethoxy, 1,2-dihydroxy ethyl Deng.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and thiazolinyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent that the present invention describes is replaced.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH₂CH₂CH₃), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH₃)₂), 1-butoxy (n-BuO, n-butoxy ,-OCH₂CH₂CH₂CH₃), etc..

Term " p former molecular ", wherein p is integer, typically describes the number of ring member nitrogen atoms in molecule, described In molecule, the number of ring member nitrogen atoms is p.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is 10 former molecular groups of naphthene base.

Term " carbocylic radical " or " carbocyclic ring " expression contain the nonaromatic saturated of 3-12 carbon atom, unit price or multivalence Or the unsaturated monocycle of part, dicyclo or three-ring system.In one embodiment, carbocyclic ring comprises 3-8 carbon atom；Real at another Executing in scheme, carbocyclic ring comprises 3 carbon atoms；In yet another embodiment, carbocyclic ring comprises 5-8 carbon atom.Carbon bicyclic group includes Spiral shell carbon bicyclic group and condense carbon bicyclic group, suitable carbocylic radical group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkyne Base.The example of carbocylic radical group farther includes, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-thiazolinyl, and 1-cyclopenta- 2-thiazolinyl, 1-cyclopenta-3-thiazolinyl, cyclohexyl, etc..

Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies System.In one embodiment, cycloalkyl comprises 3-12 carbon atom；In another embodiment, to comprise 3-8 carbon former for cycloalkyl Son；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can the most unsubstituted or Replaced by one or more substituents described in the invention.

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Dividing undersaturated monocycle, dicyclo or three rings, at least one of which annular atoms is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, miscellaneous Ring group can be carbon back or nitrogen base, and-CH₂-group can be optionally by-C (O)-replacement.The sulphur atom of ring can optionally by It is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but does not limits In: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolin Base, pyrazolinyl, pyrazolidinyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, 2-oxa--5-azepine Dicyclo [2.2.1] hept-5-base.-CH in heterocyclic radical₂-group is included, but not limited to 2-oxo pyrrole by-C (O)-substituted example Cough up alkyl, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyls and hybar X base.In heterocyclic radical, sulphur is former The oxidized example of son includes, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can Optionally to be replaced by one or more substituents described in the invention.

In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, refers to comprise the full of 4-7 annular atoms With or the undersaturated monocycle of part, at least one of which annular atoms be selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 4-7 is individual former Molecular heterocyclic radical can be carbon back or nitrogen base, and-CH₂-group can be optionally by-C (O)-replacement.The sulphur atom of ring can To be optionally oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.4-7 atom composition The example of heterocyclic radical include, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrroles Quinoline base, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, four Hydrogen thienyl, dihydro-thiophene base.-CH in heterocyclic radical₂-group is included, but not limited to 2-oxo pyrrole by-C (O)-substituted example Cough up alkyl, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyls and hybar X base.In heterocyclic radical, sulphur is former The oxidized example of son includes, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.4-7 described atom composition Heterocyclyl groups can optionally be replaced by one or more substituents described in the invention.

In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to comprise the saturated of 4 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, and sulphur and oxygen atom are replaced.Unless otherwise indicated, 4 Former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH₂-group can be optionally by-C (O)-replacement.The sulphur atom of ring Can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.4 atom compositions The example of heterocyclic radical include, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.4 described atom groups The heterocyclyl groups become can optionally be replaced by one or more substituents described in the invention.

In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, refers to comprise the saturated of 5 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 5 atom groups The heterocyclic radical become can be carbon back or nitrogen base, and-CH₂-group can be optionally by-C (O)-replacement.The sulphur atom of ring can be appointed Selection of land is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.5 former molecular heterocycles The example of base includes, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulphur rings Amyl group.-CH in heterocyclic radical₂-group is included, but not limited to 2-oxo-pyrrolidine base by-C (O)-substituted example, oxo-1, 3-thiazolidinyl.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base.5 described atom compositions Heterocyclyl groups can optionally be replaced by one or more substituents described in the invention.

In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, refers to comprise the saturated of 6 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 6 atom groups The heterocyclic radical become can be carbon back or nitrogen base, and-CH₂-group can be optionally by-C (O)-replacement.The sulphur atom of ring can be appointed Selection of land is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.6 former molecular heterocycles The example of base includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperazine Piperidinyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl.-CH in heterocyclic radical₂-group quilt- C (O)-substituted example includes, but not limited to 2-piperidone base, 3,5-dioxy piperazine piperidinyls and hybar X base.In heterocyclic radical The oxidized example of sulphur atom includes, but not limited to 1,1-dioxothiomorpholinyl.6 described former molecular heterocycles Base group can optionally be replaced by one or more substituents described in the invention.

The most in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to comprise 7-12 annular atoms Saturated or part undersaturated spiral shell dicyclo or condensed-bicyclic, at least one of which annular atoms be selected from nitrogen, sulphur and oxygen atom.Unless Additionally illustrating, 7-12 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH₂-group can optionally by-C (O)- Substitute.The sulphur atom of ring can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxidation Compound.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-benzodioxole base, 2-oxa--5-azabicyclo [2.2.1] hept-5-base.Described 7-12 former molecular heterocyclic radical Group can optionally be replaced by one or more substituents described in the invention.

Term " aromatic radical " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, Dicyclo and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and each of which member ring systems comprises 3-7 Former molecular ring, and have one or more attachment point to be connected with the remainder of molecule.Term " aryl " can be with term " virtue Fragrant ring " exchange use.The example of aromatic yl group can include phenyl, naphthyl and anthracene.Described aromatic yl group can individually optionally Replaced by one or more substituents described in the invention.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, Dicyclo and three-ring system, at least one of which member ring systems is aromatic, and at least one member ring systems comprises one or more miscellaneous Atom, each of which member ring systems comprises 5-7 former molecular ring, and has one or more attachment point and molecule remainder It is connected.Term " heteroaryl " can be with term " hetero-aromatic ring ", and " heteroaromatic " or " heteroaromatics " exchange uses.Described heteroaryl Base group is optionally replaced by one or more substituents described in the invention.In one embodiment, 5-10 atom The heteroaryl of composition comprises 1,2,3 or 4 hetero atom being independently selected from O, S and N.

The example of heteroaryl groups includes, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-azoles Base, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals etc..

As described in the invention, substituent draws the member ring systems (as follows) formed on a ring being bonded the center of receiving Represent substituent any commutable position on ring can replace.Such as, formula e represents substituent any possibility on A ring The position being replaced, such as formula f¹-f⁴Shown in:

Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright pro-drug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as pro-drug (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate, if these phosphate compounds are that the di on parent obtains.About complete the begging for of pro-drug Discuss and be referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salts of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., Described in J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed Including, but is not limited to, reacting, with amino group, the inorganic acid salt formed has a hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or obtain these salt by additive method such as ion-exchange described on books document.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3-phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..The salt obtained by suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄ Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water-soluble or oil-soluble or Dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt farther includes the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenation Thing, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

The description of the compounds of this invention

The invention discloses a class naphthalene derivatives, its pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof thing, can conduct Melatonin receptors activator, to mankind's central nervous system dysfunction, such as sleep-disorder, stress reaction, Seasonal Affective Insomnia and tired and insomnia treatment that obstacle, the time difference cause have potential purposes.

On the one hand, the present invention relates to a kind of compound, it is the solid of structure shown in the structure shown in formula (I) or formula (I) Isomers, dynamic isomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein:

Ring A is cyclopropyl, or the ring of 5-6 carbon atom composition or 3-12 former molecular heterocycle；

R¹For H, OH, C₁-C₆Alkyl, C₂-C₆Thiazolinyl or C₂-C₆Alkynyl；

R³For H, F, Cl, Br, OH, CN, NO₂, C₁-C₆Alkyl, C₁-C₆Alkoxyl ,-C (=O)-(C₁-C₆Alkyl) ,-C (= O)NR^aR^b,-O-(3-8 former molecular carbocyclic ring) ,-(C₁-C₆Alkyl)-(3-8 former molecular carbocyclic ring) ,-(C₁-C₆Alkane Base)-NR^aR^b, 5-12 former molecular heteroaryl or C₆-C₁₀Aryl；

Each R²And R⁴It is separately H, D, F, Cl, Br, I, CN, OH, NO₂,-NR^aR^b,-C (=O) R^c, C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl ,-C (=O)-(C₁-C₆Alkyl) ,-C (=O) NR^aR^b,- (C₁-C₆Alkyl)-C (=O) OR^c,-O-(3-8 former molecular carbocyclic ring) ,-(C₁-C₆Alkyl)-(3-8 former molecular carbon Ring) ,-(C₁-C₆Alkyl)-NR^aR^b, 3-12 former molecular heterocyclic radical, the substituted C of hydroxyl₁-C₆Alkyl ,-NR^a-(C₁-C₆Alkane Base)-(C₆-C₁₀Aryl) ,-(C₁-C₆Alkyl)-(C₆-C₁₀Aryl) ,-(C₁-C₆Alkyl)-(5-12 former molecular heteroaryl) Or 5-12 former molecular heteroaryl；

Each R^aAnd R^bIt is separately H, C₁-C₆Alkyl ,-(C₁-C₆Alkyl)-(C₆-C₁₀Aryl) ,-C (=O) Rc or-S (=O)₂-(C₁-C₆Alkyl)；With

Each R^cIndependently be as H, C₁-C₆Alkyl, C₆-C₁₀Aryl or C₃-C₈Cycloalkyl.

Wherein in some embodiments, R¹For H, OH, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group or The tert-butyl group.

In other embodiments, R³For H, F, Cl, Br, OH, CN, NO₂, methyl, ethyl, n-pro-pyl, isopropyl, Normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide, normal-butyl epoxide, isobutyl group oxygen Base or tert-butyl group epoxide.

In other embodiments, each R²And R⁴It is separately H, D, F, Cl, Br, I, CN, OH, NO₂, methyl, Ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, epoxide, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide, just Butyl epoxide, isobutyl group epoxide or tert-butyl group epoxide.

In other embodiments, the present invention comprises the structure of one below:

Or its stereoisomer, dynamic isomer, nitrogen oxides, metabolite, pharmaceutically can connect The salt being subject to or prodrug.

Present invention compound of coming into the open can contain asymmetric or chiral centre, therefore can deposit by different stereoisomer forms ?.It is contemplated that all stereoisomer forms of compound shown in formula (I), include but not limited to diastereoisomer, Enantiomter, atropisomer and geometry (or conformation) isomers, and their mixture such as racemic mixture, become The part of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicates, then this structure All stereoisomers all consider within the present invention, and be included in the invention as present invention compound of coming into the open.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or time dotted line indicates, then the alloisomerism of this structure Body clearly and defines with regard to this.

Compound shown in formula (I) can exist with different tautomeric forms, and all these dynamic isomer, As is described in the claims, it is included within the scope of the present invention.

Compound shown in formula (I) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or composition must be with other compositions comprising preparation and/or use it The mammal for the treatment of is chemically and/or compatible in toxicology.In another embodiment, described salt is not necessarily and pharmaceutically may be used The salt accepted, could be for compound shown in preparation and/or purification formula (I) and/or is used for separating compound shown in this formula (I) The intermediate of enantiomer.

Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly-half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc. can be included by its derivative inorganic acid obtaining salt.

Such as acetic acid can be included by its derivative organic acid obtaining salt, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic table to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt includes ammonium, potassium, Sodium, calcium and magnesium salts.

Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (such as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: character selects and applies (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

It addition, compound disclosed by the invention, including their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that include solvation And unsolvated form.

Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).

On the other hand, the present invention relates to the preparation of compound, the method separating and purifying shown in formula (I).

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semi-solid, gel or spray Type.

The compounds of this invention and pharmaceutical composition, preparation and administration

When can be used for treatment, formula (I) compound of therapeutically effective amount and pharmaceutically acceptable salt thereof can be as not adding The chemicals of work gives, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, present disclosure also provides for medicine group Compound, this pharmaceutical composition include formula (I) compound of therapeutically effective amount or its pharmaceutically acceptable salt and one or more Pharmaceutically acceptable carrier, diluent or excipient.

Term as used herein " therapeutically effective amount " refers to be enough to demonstrate each activity group of significant patient benefit The total amount divided.When using single active component individually dosed, this term only refers to this composition.When combination application, this term No matter then referring to combination, when being sequentially or simultaneously administered, all cause the combined amount of the active component of result for the treatment of.Formula (I) compound And pharmaceutically acceptable salt is described above.From compatible with other compositions of preparation and to its recipient harmless in the sense that come Saying, carrier, diluent or excipient must be acceptable.According to the another aspect of present disclosure, also provide for for preparing The method of pharmaceutical preparation, the method includes by formula (I) compound or its pharmaceutically acceptable salt with one or more pharmaceutically Acceptable carrier, diluent or excipient mixing.Term used in the present invention " pharmaceutically acceptable " refers to such Compound, raw material, composition and/or formulation, they rational medicine judge in the range of, it is adaptable to patient tissue contacts and Without excessive toxicity, excitant, allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and have Effectiveness is in given application.

It will also be appreciated that some compound of the present invention can exist in a free form for treating, if or suitably Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Compound of the present invention or its metabolite or any other adduct of residue or derivative are provided indirectly.

Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) in bulk form, wherein can extract safety The compound shown in formula (I) of effective dose, then gives patient with powder or syrup form.Or, medicine disclosed by the invention Composition can be prepared and be packaged as unit dosage forms, and the most discrete the most each unit contains formula (I) institute of safe and effective amount The compound shown.When preparing with unit dosage forms, pharmaceutical composition disclosed by the invention generally can contain, such as, and 0.5mg to 1g, Or 1mg to 700mg, or the compound disclosed by the invention of 5mg to 100mg.

The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition uniformity Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing Split-phase is held, and can be substantially reduced the present invention and come into the open the interaction of effect of compound and causing during to avoid being administered patient It it not the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As, there is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected concrete formulation.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.Such as, optional can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Optional some pharmaceutically acceptable figuration that can help to produce stabilizer type Agent.Optional contribute to time patient is administered carrying or transport the present invention come into the open compound from health organ or part to Another organ of health or some pharmaceutically acceptable excipient of part.Optional some medicine strengthening patient compliance Acceptable excipient on.

Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stable Agent, surfactant and buffer.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends on existing in preparation and has those other in how many these excipient and preparation Excipient.

Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and be used for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

At Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams &Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker, New York discloses the various carriers for configuring pharmaceutically acceptable composition, and is used for what it was prepared Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable life Thing effect, or so that other composition any in harmful way and pharmaceutically acceptable composition occurs to interact and the present invention Outside any commonly employed carrier that compound of coming into the open is incompatible, pay close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。

Therefore, on the other hand, the present invention relates to prepare the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Come into the open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, and this technique includes that mixing is each Plant composition.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as environment temperature and atmospheric pressure and make Standby.

Compound disclosed by the invention is usually formulated as being adapted to pass through the formulation that patient is administered by required approach.Example As, formulation includes that those are suitable for the formulation of following method of administration: (1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and the powder that redissolves；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) topical, such as cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.

In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention is permissible It is configured to nose administration formulation.In yet another embodiment, compound disclosed by the invention can be configured to cutaneous penetration agent Type.The most in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.

The present invention provide pharmaceutical composition can with compressed tablets, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet, or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the material bag being resistant to hydrochloric acid in gastric juice effect but dissolve in intestines or be disintegrated The compressed tablets of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Sheet, it can be beneficial to cover taste beastly or smell and can prevent tablet from aoxidizing.Thin membrane coated tablet is for water-soluble The compressed tablets that the thin layer of material or film cover.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethylcellulose calcium Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple Compressing tablet is the compressed tablets through preparing more than a press cycles, including multilayer tablet, and pressed coated or dry coating tablet.

Tabules can be crystallized or granular active component one that is single or that describe with the present invention by powder Or prepared by variety carrier or excipient composition, described carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.

The pharmaceutical composition that the present invention provides can provide with soft capsule or hard shell capsules, and it can be by gelatin, and methyl is fine Dimension element, prepared by starch or calcium alginate.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, enclose active component the most completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It is by adding glycerine, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell can comprise the pre-preventing microorganism of preservative Long.Suitably preservative be as described in the present invention those, including methyl hydroxybenzoate and nipalgin and refer to, and sorbic acid.This The liquid that invention provides, semi-solid and solid dosage forms can be encapsulated in capsule.Suitably liquid and semisolid dosage form is included in Solution in propene carbonate, vegetable oil or triglycerides and supensoid agent.The capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.Described capsule can also be adopted Use coating as is known to persons skilled in the art, thus improve or maintain the dissolution of active component.

The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including emulsion, solution, suspendible Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal accepted, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there is one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, the water-alcohol solution of sweet taste.Syrup is dense The aqueous solution of sugar such as sucrose, and also preservative can be comprised.For liquid dosage form, such as, the solution in polyethylene glycol Can be with enough pharmaceutically acceptable liquid-carrier such as water dilutions, to be accurately, conveniently administered.

Other useful liquid and semisolid dosage form include, but are not limited to comprise the active component and two grades that the present invention provides Change list-or those formulations of poly-alkylene glycol, described list-or poly-alkylene glycol include: 1,2-dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, poly-second Glycol-750-dimethyl ether, wherein the approximation mean molecule quantity of 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, burnt Sodium sulfite, thio-2 acid and ester thereof and dithiocarbamate.

Time suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or dimension Hold the composition of release, such as by being coated by microparticle material or being embedded in polymer, in wax or the like.

The combination of oral medication that the present invention provides can also be with liposome, and micella, the form of microballoon or nanometer system carries Supply.Micella formulation can be prepared by the method that U.S.Pat.No.6,350,458 describes.

The pharmaceutical composition that the present invention provides can provide with non-effervesce or the granule of effervesce and pulvis, to reconstruct Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent or pulvis and excipient can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and the excipient that use in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.

Colouring agent and flavor enhancement can be used in all above-mentioned formulations.

Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the substituted oxide polylysine of palmitoyl residues.Additionally, compound disclosed in this invention can with in reality The class Biodegradable polymeric controlling to use in release of existing medicine combines, such as, PLA, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are altogether Polymers.

The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutic action Preparation, or with supplement the material co-formulation of intended effect.

The pharmaceutical composition that the present invention provides can be by injection, and infusion or implantation parenteral, for local or complete Body is administered.The parenteral used such as the present invention includes intravenous, intra-arterial, intraperitoneal, in sheath, in ventricle, in urethra, and chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical composition that the present invention provides can be configured to be suitable to any formulation of parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid Bodily form formula.Such formulation can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees Remington:The Science and Practice of Pharmacy, ibid).

Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or anti-micro-life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersion Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.

Suitably include, but are not limited to containing transporter: water, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solution, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solution.Non-transporter includes, but not limited to the fixed oil of plant origin, castor oil, corn oil, cottonseed The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides, and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3-BDO, the poly-second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propane diols, glycerine, METHYLPYRROLIDONE, N, N-dimethylacetamide Amine and dimethyl sulfoxide.

Suitably antimicrobial or preservative includes, but not limited to phenol, cresols, mercurial, phenmethylol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitably isotonic agent includes, but not limited to sodium chloride, glycerine and glucose.Suitably buffer Include, but not limited to phosphate and citrate.Suitably antioxidant is as the present invention describes, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitably local anesthetic includes, but are not limited to procaine hydrochloride.Suitably suspending agent and point Powder is as the present invention describes, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitably emulsifying agent includes those that the present invention describes, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitably sequestering agent or chelating agent includes, but are not limited to EDTA. Suitably pH adjusting agent includes, but are not limited to NaOH, hydrochloric acid, citric acid and lactic acid.Suitably complexing agent includes, but does not limits In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, HP-β-CD, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7-beta-schardinger dextrin (CyDex,Lenexa,KS)。

The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations is wrapped It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro-of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.

In one embodiment, pharmaceutical composition provides with instant sterile solution.In another embodiment, medicine Composition provides with aseptic dried soluble product, and including freeze-dried powder and hypodermic tablet, it uses carrier before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine The aseptic dry insolubility product that compositions reconstructs with carrier before being formulated into use.The most in one embodiment, Pharmaceutical composition is formulated into the aseptic emulsion of instant.

Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including postpone-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.

Pharmaceutical composition can be configured to supensoid agent, solid, semi-solid or thixotropic liquid, and the reservoir being used as to implant is administered. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, its be insoluble to body fluid but The outside polymeric membrane allowing the active component in pharmaceutical composition to diffuse through is surrounded.

The internal matrix being suitable for includes polymethyl methacrylate, and poly-butyl methacrylate is plasticising or unplasticizied Polyvinyl chloride, the nylon of plasticising, the PET of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly-diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.

The outside polymeric membrane being suitable for includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene and propylene, ionomer is poly-to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.

The pharmaceutical composition being suitable for cutaneous penetration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).

It is suitable for the pharmaceutical composition of topical and can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.Such as, ointment, cream and gel can be with water or oil Matrix, and the thickener and/or gel and/or the solvent that are suitable for configure.Such matrix can include, water, and/or oil example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Make according to medium property Thickener and gel include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly-carboxylic second Alkene and cellulose derivative, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

Lotion can be prepared with water or oil matrix, and generally also contains one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.

Externally-applied powder can be molded in the presence of lactose or starch at the powder matrix such as talcum powder being arbitrarily suitable for.Drops Can be formulated with the water or non-aqueous matrix comprising one or more dispersants, solubilizer, suspending agent or preservative.

Topical formulations can be by applying one or many to be administered every day in affected part；The impermeable plastic wound dressing covering skin is preferential Used.The administration that adhesiveness store system can realize continuously or extend.

The compounds of this invention and the purposes of composition

The present invention provides use compound disclosed in this invention and medicine composite for curing, prevention, or it is dynamic to alleviate lactation Thing, including the medicine of the central nervous system dysfunction of the mankind, it is also possible to be used for the medicine of exciting melatonin receptors for preparation Product.

Specifically, in the composition of the present invention, the amount of compound can the most optionally excitement take off black Element acceptor, the compound of the present invention can be as treatment mankind's central nervous system (CNS) dysfunction such as sleep-disorder, should Swash reaction, SAD, insomnia that the time difference causes and fatigue, insomnia, depression, anxiety disorder, psychotic The medicine of obstacle, epilepsy, Parkinson's, senile dementia, to normal or that pathological seaility is relevant various obstacles, antimigraine, note Recall forfeiture or Alzheimer disease.

The compound of the present invention can apply to, but is not limited to, and uses the compound of the present invention or the effective of composition Patient is administered by amount to be prevented, and treats or alleviates mammal, including the central nervous system dysfunction disease of the mankind.Institute The central nervous system dysfunction disease of the mankind stated, farther includes but is not limited to, sleep-disorder, stress reaction, Depression, anxiety disorder, SAD, insomnia that the time difference causes and fatigue, schizophrenia, faint from fear, panic attack, sorrow Strongly fragrant disease, insomnia, psychotic disorder, epilepsy, Parkinson's, senile dementia, to normal or pathological seaility is relevant Various obstacles, antimigraine, the loss of memory or Alzheimer disease etc..

The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in thing, the animal of introduced variety and the animal on farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.

Therapeutic alliance

The compounds of this invention can be administered as single active agent, or can be administered with other therapeutic agent, Including there is same or similar therapeutic activity and being defined as other compound safe and efficient for this type of administering drug combinations.

On the one hand, the present invention provides treatment, the method preventing or improving disease or illness, including giving safe and effective amount Comprise the present invention to come into the open the combination medicine of compound and one or more therapeutically active agents.In one embodiment, combination medicine Comprise the medicine of one or more other treatment central nervous system dysfunction.

In another embodiment, the medicine of other treatment central nervous system dysfunction includes but not limited to: calm Hypnotic drug, antipsychotics, antiepileptic, antidepressant, antihistamine drug, anti-parkinson class medicine, GABA Receptor stimulating agent and/or GABA reuptaking inhibitor class medicine, as the medicine of iron ion channel blocker, aoxidize as monoamine The medicine of enzyme inhibitor, as adenosine A₁/A₂The medicine of receptor stimulating agent and the medicine as melatonin receptors activator.

In another embodiment, the medicine of the treatment central nervous system dysfunction of described other is midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), Flurazepam (flurazepam), nitrazepam (nitrazepam), Clonazepam (clonazepam), for Ma Xi Dissolve (temazepam), Flunitrazepam (flunitrazepam), Oxazepam (oxazepam), zolpidem (zolpidem), prick Coming general grand (zaleplon), zopiclone (zopielone), eszopiclone (eszopiclone), English ground is general grand (indiplon) Tiagabine (tiagabine), Gaboxadol (gaboxadol), clomipramine (clomipramine), fill in more Flat (doxepin) Paxil (paroxetine), Sertraline (sertraline), Mirtazapine (mirtazapine), it is hydrated chlorine Aldehyde (chloral hydrate), haloperole (haloperidol), chlorpromazine (chlorpromazine), carbamazepine (carbamazepine), fenazil (promethazine), Lorazepam (lorazepam), hydroxyzine (hydroxyzine), Ah A department woods (aspirin), diphenhydramine (diphenhydramine), chlorpheniramine (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Prozac (fluoxetine), Trazodone (trazodone), Du Luoxi Spit of fland (duloxetine), Fluvoxamine (fluvoxamine), vilazodone (vilazodone), Dapoxetine hydrochloride (dapoxetine), method Mack Xi Ting (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), Quetiapine (quetiapine), Clozapine (clozapine), imipramine (imipramine), nabilone (nabilone), doxepin (doxepin), Gabapentin (gabapentin), Pramipexole (pramipexole), melatonin (circadin), profit is slept Rather (chlordiazepoxide), perphenazine (perphenazine), suvorexant, Xuezang Guben or they appoint Meaning combination.

On the other hand, the present invention provides the product including the compounds of this invention and at least one other therapeutic agent, can prepare Become in the treatment simultaneously, the combination separately or sequentially used.In one embodiment, treatment is for relevant to melatonin receptors Disease or the treatment of symptom.The product that combining preparation provides includes being present in same pharmaceutical composition and comprises disclosed hereinization Compound and the composition of other therapeutic agents, or the compound disclosed herein that exists in different forms and other therapeutic agents, such as, Medicine box.

On the other hand, the present invention provides a kind of and comprises compound disclosed herein and another or the medicine of multiple therapeutic agent Composition.In one embodiment, pharmaceutical composition can comprise pharmaceutically acceptable excipient as above, carrier, Adjuvant or solvent.

On the other hand, the present invention provides and comprises two kinds or the medicine box of above drug alone composition, at least one of which The present invention that comprises pharmaceutical composition comes into the open compound.In one embodiment, medicine box includes the work individually keeping described composition Tool, such as container, separate bottle or separate paper tinsel box.The example of this kind of medicine box is blister package, is commonly used for package troche, Capsule etc..

Present invention also offers the purposes in the compounds of this invention pivot nervous system dysfunction in the treatment, wherein patient Previously treated by other therapeutic agents (such as in 24 hours).Present invention also offers other therapeutic agents in treatment Purposes in central nervous system dysfunction, wherein patient previously (such as in 24 hours) enters with the compounds of this invention Go treatment.

Compound disclosed herein can be used as single-activity component or as such as adjuvant, jointly execute with other medicines With.Described other medicines include, sedative hypnotic drug, antipsychotics, antiepileptic, antidepressant, antihistamine Thing, anti-parkinson class medicine, GABA receptor stimulating agent and/or GABA reuptaking inhibitor class medicine, as iron ion passage The medicine of blocking agent, as the medicine of MAOI, as adenosine A₁/A₂The medicine of receptor stimulating agent and conduct The medicine of melatonin receptors activator.

Above-described associating can be prepared as pharmaceutical composition easily and use, therefore, including defined above group Close the pharmaceutical composition with pharmaceutically acceptable excipient or carrier and represent another aspect of the present invention.

These united each compounds can be with alone or in combination pharmaceutical dosage forms order of administration or be administered simultaneously. In one embodiment, each compound component is to be administered simultaneously with the pharmaceutical dosage forms of combination.Being suitable for of known treatment agent Dosage is prone to be understood by the person skilled in the art.

Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, comprises compound disclosed by the invention and controls with other Treat the associating of activating agent.

Above-described, can come into the open the compound that compound is applied in combination with the present invention, can be by people in the art Member, prepares according to the method described in above-mentioned document and is administered.

Methods for the treatment of

In one embodiment, methods for the treatment of disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or comprise the pharmaceutical composition of the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the present invention of safe and effective amount and comes into the open compound or comprise the present invention and come into the open the pharmaceutical composition of compound, The method treating disease mentioned above.

In one embodiment, the present invention comes into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention permissible It is administered by any applicable method of administration, including Formulations for systemic administration and topical.Formulations for systemic administration includes oral administration, stomach and intestine External administration, cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, Intramuscular and hypodermic injection or administered by infusion.Topical includes being applied to skin and intraocular, ear, vagina, sucks and intranasal It is administered.In one embodiment, the present invention comes into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention permissible It it is oral administration.In another embodiment, the present invention comes into the open compound or comprise the present invention and come into the open the drug regimen of compound Thing can be inhalation.In a further embodiment, the present invention comes into the open compound or comprise present invention compound of coming into the open and can be Intranasal administration.

In one embodiment, the present invention comes into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention permissible Once daily, or according to dosage regimen, at the appointed time in section, be administered several times in different time intervals.Such as, often It is administered once, twice, three time or four times.In one embodiment, it is administered once a day.In yet another embodiment, every day It is administered twice.Can be administered until reaching the result for the treatment of wanted or maintaining the result for the treatment of wanted indefinitely.The present invention is public Become civilized compound or comprise the come into the open appropriate dosage regimen of pharmaceutical composition of compound of the present invention and depend on medicine generation of this compound Kinetic property, such as, dilute, and distribution and half-life, these can be by determination of technical staff.The compound additionally, the present invention comes into the open Or comprise the present invention and come into the open the appropriate dosage regimen of pharmaceutical composition of compound, including implementing duration of the program, take Certainly in treated disease, the order of severity of disease being treated, the age of patient under consideration and health, patient under consideration's Medical history, the simultaneously character of therapy, it is desirable to the factor in the range of technical staff's knowledge and experience such as result for the treatment of.Such Technical staff be also to be understood that for the individual patient reaction to dosage regimen, or passage individual patient needs to become over time During change, in order to be sufficiently accurate it may be desired to adjust the dosage regimen of matters.

Present invention compound of coming into the open can, or be administered before it or afterwards with one or more other therapeutic agents simultaneously. The compounds of this invention can be administered by identical or different method of administration respectively with other therapeutic agents, or therewith with medicine group Solvate form is administered.

For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be containing about 1-1000mg, Or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or the unit dose of about 1-50mg active component Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individuality species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinician or animal doctor can easily determine prevention, treat or suppress disease (disorder) or disease (disease) development The effective dose of each active component needed for during.

Dose Characteristics cited above use favourable mammal (such as mouse, rat, dog, monkey) or its from Body organ, confirms in the external and in vivo studies of tissue and sample.Present invention compound of coming into the open with solution, such as aqueous solution form Using in vitro, it is also possible to such as suspension or aqueous solution form enteral in vivo, parenteral, especially intravenous uses.

In one embodiment, the come into the open treatment effective dose of compound of the present invention is about 0.1mg to about 2 every day, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg this compound of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation is provided that about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about The combination of each main component in 500mg, or the main active of about 25mg to about 250mg or every dosage unit form.One In particular, the pharmaceutical dosage unit forms of preparation is provided that about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.

Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention comes into the open compound " prodrug " when being that patient is administered, finally can discharge the present invention in vivo and come into the open the functional derivatives of compound.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement the one in following manner and more than: (a) The internal onset time of modification compound；The internal acting duration of (b) modification compound；(c) modification compound internal Conveying or distribution；The internal solubility of (d) modification compound；And (e) overcomes the side effect or other difficult points that compound faced. For preparing the typical functional derivatives of prodrug, be included in internal chemically or the mode of the enzyme compound that cracks Variant.Comprising and prepare phosphate, acid amides, ester, monothioester, these variants of carbonate and carbaminate are to people in the art It is well-known from the point of view of Yuan.

The general synthetic method of the compounds of this invention

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen Dragon chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao is commercially available.

Anhydrous tetrahydro furan is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride and chloroform are to return through calcium hydride Fluidized drying obtains.Ethyl acetate, DMA and petroleum ether are to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber stopper, substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃Or DMSO-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).

The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-M (pillar model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% in flowing The CH of formic acid₃CN) at (H containing 0.1% formic acid₂O) ratio in), use electron spray ionisation (ESI), under 210nm/254nm, Detect with UV.

Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (the pillar type of pure compound Number: NOVASEP 50/80mm DAC), detect at 210nm/254nm UV.

The use of brief word below runs through the present invention:

HOAc acetic acid

MeCN,CH₃CN acetonitrile

Cl₃C₂OCl trichloro-acetic chloride

CHCl₃Chloroform

CDCl₃Deuterochloroform

DMSO dimethyl sulfoxide (DMSO)

DMSO-d₆Deuterated dimethyl sulfoxide

DMF N,N-dimethylformamide

POCl₃POCl3

C₄H₁₀F₃NS diethylin sulfur trifluoride

ClSO₂OH chlorosulfonic acid

EtOAc/EA ethyl acetate

Et- CH₃CH₂-/ethyl

HCl hydrochloric acid

MgSO₄Magnesium sulfate

MgCl₂Magnesium chloride

MeOH,CH₃OH methyl alcohol

HCHO formaldehyde

CH₂Cl₂, DCM dichloromethane

ML, m milliliter

PE petroleum ether (60-90 DEG C)

Na₂CO₃Sodium carbonate

NaHCO₃Sodium acid carbonate

KOH potassium hydroxide

RT room temperature

Rt retention time

NaBH₃CN sodium cyanoborohydride

NaCl sodium chloride

NaH sodium hydride

Na₂SO₄Sodium sulphate

THF oxolane

DDQ DDQ

Following synthetic schemes describes the preparation present invention and comes into the open the step of compound.

Synthetic method 1

Formula (6Compound shown in) can be prepared by following process:

Formula (1Compound shown in) and cyanoacetic acid react obtain formula (2Compound shown in).Formula (2Chemical combination shown in) Thing formula dehydroaromatizationof under the effect of oxidant (DDQ) obtain formula (3Compound shown in), formula (3Compound shown in) exists Obtain under the effect of alkali formula (4Compound shown in), formula (4Compound shown in) reduces under the effect of reducing agent (such as borine) Obtain formula (5Compound shown in), formula (5Compound shown in) and excess acetyl chloride obtain formula (6) product.Course of reaction is such as Shown in lower:

Embodiment

Embodiment 1N-((1-(naphthalene-1-base) cyclopropyl) methyl) acetamide

Step 1) synthesis of 1-(naphthalene-1-base) cyclopropanecarbonitrile

At-30 DEG C, by 2-(naphthalene-1-base) acetonitrile (500mg, 2.99mmol) and sodium hydride (60%, 598mg, 14.95mmol) join in 10mL dry DMF, after stirring reaction 1h, be slowly added dropwise into 1,2-Bromofume (0.52mL, 5.98mmol, is dissolved in 10mL DMF), it is to slowly warm up to 25 DEG C, reacts 1 hour.Stop reaction, add 30mL saturated common salt shrend Go out, be extracted with ethyl acetate (30mL × 3), merge organic phase anhydrous sodium sulfate and be dried.Filtering, filtrate decompression is spin-dried for, post layer Analysis purifies (petrol ether/ethyl acetate (v/v)=50/1), and obtaining title compound is white solid (325mg, 56.2%).

MS(ESI,pos.ion)m/z:194.2[M+1]⁺；

¹H NMR(400MHz,CDCl₃) δ 8.41 (d, J=8.4Hz, 1H), 7.91 (d, J=8.4Hz, 1H), 7.86 (d, J =8.0Hz, 1H), 7.69-7.65 (m, 1H), 7.60-7.54 (m, 1H), 7.50 (dd, J=7.2,1.2Hz, 1H), 7.46- 7.39 (m, 1H), 1.86 (q, J=4.8Hz, 2H), 1.45 (q, J=4.8Hz, 2H).

Step 2) synthesis of (1-(naphthalene-1-base) cyclopropyl) methylamine

At 0 DEG C, 1-(naphthalene-1-base) cyclopropanecarbonitrile (325mg, 1.68mol) is joined oxolane (10.0mL) In, it is then slowly added into borine-oxolane (1.0M, 9.3mL, 9.3mmol).After reacting ten minutes, it is warming up to 80 DEG C, stirring Reaction 24h.Methyl alcohol (5mL) cancellation is reacted, and filtrate decompression is spin-dried for, and column chromatography purifies (methylene chloride/methanol (v/v)=20/1) and obtains It is white solid (165mg, 49.7%) to title compound.

MS(ESI,pos.ion)m/z:198.2[M+1]⁺；

1H NMR (600MHz, CDCl3) δ 8.35 (d, J=7.8Hz, 1H), 7.87 (d, J=7.8Hz, 1H), 7.75 (t, J =7.8Hz, 1H), 7.54 (t, J=7.8Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.40 (t, J=7.8Hz, 1H), 2.88 (brs, 2H), 0.98-0.97 (m, 4H).

Step 3) synthesis of N-((1-(naphthalene-1-base) cyclopropyl) methyl) acetamide

(1-(naphthalene-1-base) cyclopropyl) methylamine (165mg, 836 μm ol) and triethylamine (230 μ L, 1.67mmol) are added In dichloromethane (15mL), it is slowly added dropwise chloroacetic chloride (88 μ L, 1.25mmol) under 0 DEG C of low temperature bath, after dripping, is transferred to 25 React 3 hours at DEG C, stop reaction.Add 30mL dichloromethane, wash with saturated nacl aqueous solution (60mL), organic after separatory It is dried with anhydrous sodium sulfate.Filtering, filtrate decompression is spin-dried for, and column chromatography purifies (petrol ether/ethyl acetate (v/v)=2/1) and obtains It is white solid (180mg, 89.9%) to title compound.

MS(ESI,pos.ion)m/z:240.2[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 8.37 (d, J=7.8Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.77 (d, J =7.8Hz, 1H), 7.55 (t, J=7.2Hz, 1H), 7.50 (t, J=7.2Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.41 (t, J=7.8Hz, 1H), 3.51 (brs, 2H), 1.85 (s, 3H), 1.13 (s, 2H), 0.96 (s, 2H)；

¹³C NMR(150MHz,CDCl₃)δ170.3,138.6,134.1,132.5,128.9,128.2,128.0,126.2, 125.9,125.4,124.7,48.1,24.7,23.4,12.2(br)。

Embodiment 2N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) acetamide

Step 1) synthesis of 1-(7-methoxynaphthalene-1-base) cyclopropanecarbonitrile

This step title compound prepares with reference to the method described by embodiment 1 step 1, will 2-(7-methoxy naphthalene- 1-yl) acetonitrile (1.0g, 5.07mmol), sodium hydride (60%, 1.01g, 25.35mmol) and 1,2-Bromofume (0.88mL, 10.14mmol, is dissolved in 10mL DMF) reaction preparation, crude on silica gel column chromatography (petroleum ether/second in dry DMF (10mL) Acetoacetic ester (v/v)=50/1), it is white solid (615mg, 54.4%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:224.1[M+1]⁺；

¹H NMR(400MHz,CDCl₃) δ 7.79 (t, J=9.2Hz, 2H), 7.64 (d, J=2.0Hz, 1H), 7.46 (dd, J =6.8,0.8Hz, 1H), 7.28 (dd, J=7.2,8.0Hz, 1H), 7.24 (dd, J=8.8,2.4Hz, 1H), 4.02 (s, 3H), 1.84 (q, J=4.8Hz, 2H), 1.43 (q, J=4.4Hz, 2H).

Step 2) synthesis of (1-(7-methoxynaphthalene-1-base) cyclopropyl) methylamine

This step title compound prepares with reference to the method described by embodiment 1 step 2, will 1-(7-methoxyl group Naphthalene-1-base) cyclopropanecarbonitrile (300mg, 1.34mol) and borine-oxolane (1.0M, 7.4mL, 7.4mmol) reaction preparation, Crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colorless oil that concentrate drying obtains title compound Liquid solid (150mg, 49.2%).MS(ESI,pos.ion)m/z:228.1[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.76 (d, J=9.0Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.62 (d, J =2.4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.26 (t, J=8.4Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 3.95(s,3H),2.87(brs,2H),0.95(s,4H)。

Step 3) synthesis of N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) acetamide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-methoxyl group Naphthalene-1-base) cyclopropyl) methylamine (150mg, 660 μm ol), triethylamine (180 μ L, 1.32mmol) and chloroacetic chloride (70 μ L, 990 μ Mol) reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), It is white solid (160mg, 90.0%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:270.1[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.77 (d, J=8.4Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.68 (d, J =2.4Hz, 1H), 7.43 (d, J=6.6Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 3.96(s,3H),3.53(brs,2H),1.87(s,3H),1.26(s,2H),0.95(s,2H)；

¹³C NMR(150MHz,CDCl₃)δ170.1,157.7,137.1,133.7,130.4,129.5,128.5,127.6, 123.1,118.3,103.2,55.4,47.4,24.5,23.3,12.0。

Embodiment 3N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) acetamide

Step 1) synthesis of 1-(7-fluoronaphthalene-1-base) cyclopropanecarbonitrile

This step title compound prepares with reference to the method described by embodiment 1 step 1, will 2-(7-fluoronaphthalene-1- Base) acetonitrile (700mg, 3.78mmol), sodium hydride (60%, 756mg, 18.90mmol) and 1,2-Bromofume (0.65mL, 7.56mmol, is dissolved in 10mL DMF) reaction preparation, crude on silica gel column chromatography (petroleum ether/second in dry DMF (10mL) Acetoacetic ester (v/v)=50/1), it is white solid (520mg, 65.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:212.1[M+1]⁺；

¹H NMR(400MHz,CDCl₃) δ 7.98 (dd, J=10.4,1.2Hz, 1H), 7.90 (dd, J=8.8,5.6Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.53 (d, J=7.2Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.34 (td, J= 8.8,2.0Hz, 1H), 1.87 (q, J=4.8Hz, 2H), 1.43 (q, J=4.8Hz, 2H).

Step 2) synthesis of (1-(7-fluoronaphthalene-1-base) cyclopropyl) methylamine

This step title compound prepares with reference to the method described by embodiment 1 step 2, will 1-(7-fluoronaphthalene-1- Base) cyclopropanecarbonitrile (537mg, 2.54mol) and borine-oxolane (1.0M, 14mL, 14mmol) reaction preparation, crude product Through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is colourless oil liquid that concentrate drying obtains title compound (416mg, 76.0%).MS(ESI,pos.ion)m/z:216.2[M+1]⁺；¹H NMR(600MHz,CDCl₃)δ7.96(dd,J =11.4,2.4Hz, 1H), 7.87 (dd, J=9.0,6.0Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 7.50 (d, J= 7.2Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.28 (td, J=9.0,2.4Hz, 1H), 2.88 (brs, 2H), 0.99-0.94 (m,4H)。

Step 3) synthesis of N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) acetamide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-fluoronaphthalene- 1-yl) cyclopropyl) methylamine (200mg, 929 μm ol), triethylamine (260 μ L, 1.86mmol) and chloroacetic chloride (99 μ L, 1.39mmol) Reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate Being dried to obtain title compound is white solid (140mg, 58.6%).

MS(ESI,pos.ion)m/z:258.2[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.96 (dd, J=11.4,1.8Hz, 1H), 7.85 (dd, J=9.0,6.0Hz, 1H), 7.76 (d, J=7.8Hz, 1H), 7.48 (d, J=7.2Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.28 (dd, J= 8.4,24Hz,1H),3.49(brs,2H),1.86(s,3H),1.13(s,2H),0.93(s,2H)；

¹³C NMR(150MHz,CDCl₃) δ 170.2,160.7 (d, J=244.5Hz), 138.1 (d, J=5.6Hz), 133.5 (d, J=8.7Hz), 131.3 (d, J=9.0Hz), 131.0,129.1,127.8,124.6 (d, J=2.4Hz), 116.2 (d, J=25.2Hz), 108.2 (d, J=21.2Hz), 47.6,24.7,23.2,12.1.

Embodiment 4N-((1-(naphthalene-1-base) cyclopropyl) methyl) propionamide

Step 1) synthesis of N-((1-(naphthalene-1-base) cyclopropyl) methyl) propionamide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(naphthalene-1-base) Cyclopropyl) methylamine (165mg, 836 μm ol), triethylamine (230 μ L, 1.67mmol) and propionyl chloride (88 μ L, 1.25mmol) are two Reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying in chloromethanes (15mL) Obtaining title compound is white solid (148mg, 69.8%).MS(ESI,pos.ion)m/z:254.2[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 8.37 (d, J=7.8Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.77 (d, J =7.8Hz, 1H), 7.55 (t, J=7.2Hz, 1H), 7.50 (t, J=7.2Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.41 (t, J=7.8Hz, 1H), 3.51 (brs, 2H), 2.28 (q, J=5.4Hz, 2H), 1.13 (s, 2H), 1.02 (t, J=5.4Hz, 3H),0.96(s,2H)。

Embodiment 5N-((1-(naphthalene-1-base) cyclopropyl) methyl) butyramide

Step 1) synthesis of N-((1-(naphthalene-1-base) cyclopropyl) methyl) butyramide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(naphthalene-1-base) Cyclopropyl) methylamine (165mg, 836 μm ol), triethylamine (230 μ L, 1.67mmol) and n-butyryl chloride (88 μ L, 1.25mmol) exist Reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate dry The dry title compound that obtains is white solid (146mg, 65.2%).MS(ESI,pos.ion)m/z:268.4[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 8.39 (d, J=7.8Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.76 (d, J =7.8Hz, 1H), 7.53 (t, J=7.2Hz, 1H), 7.50 (t, J=7.2Hz, 1H), 7.47 (d, J=6.6Hz, 1H), 7.41 (t, J=7.8Hz, 1H), 3.53 (brs, 2H), 2.37 (t, J=5.4Hz, 2H), 1.17 (m, 2H), 1.13 (s, 2H), 0.96 (s, 2H), 0.89 (t, J=5.4Hz, 3H).

Embodiment 6N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) propionamide

Step 1) synthesis of N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) propionamide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-methoxyl group Naphthalene-1-base) cyclopropyl) methylamine (150mg, 660 μm ol), triethylamine (180 μ L, 1.32mmol) and propionyl chloride (70 μ L, 990 μ Mol) reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), It is white solid (149mg, 80.0%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:285.3[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.79 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.64 (d, J =2.4Hz, 1H), 7.43 (d, J=6.6Hz, 1H), 7.30 (t, J=7.8Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 3.98 (s, 3H), 3.53 (brs, 2H), 2.27 (q, J=5.4Hz, 2H), 1.15 (s, 2H), 1.02 (t, J=5.4Hz, 3H), 0.98(s,2H)。

Embodiment 7N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) butyramide

Step 1) synthesis of N-((1-(7-methoxynaphthalene-1-base) cyclopropyl) methyl) butyramide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-methoxyl group Naphthalene-1-base) cyclopropyl) methylamine (150mg, 660 μm ol), triethylamine (180 μ L, 1.32mmol) and n-butyryl chloride (70 μ L, 990 μ Mol) reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), It is white solid (167mg, 85.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:298.3[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.77 (d, J=8.4Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.62 (d, J =2.4Hz, 1H), 7.43 (d, J=6.6Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 3.98 (s, 3H), 3.53 (brs, 2H), 2.39 (t, J=5.4Hz, 2H), 1.15 (m, 2H), 1.09 (s, 2H), 0.96 (s, 2H), 0.89 (t, J=5.4Hz, 3H).

Embodiment 8N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) propionamide

Step 1) synthesis of N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) propionamide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-fluoronaphthalene- 1-yl) cyclopropyl) methylamine (200mg, 929 μm ol), triethylamine (260 μ L, 1.86mmol) and propionyl chloride (99 μ L, 1.39mmol) Reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate Being dried to obtain title compound is white solid (186mg, 73.8%).

MS(ESI,pos.ion)m/z:272.1[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.95 (dd, J=11.4,1.8Hz, 1H), 7.81 (dd, J=9.0,6.0Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.48 (d, J=7.2Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.30 (dd, J= 8.4,24Hz, 1H), 3.49 (brs, 2H), 2.25 (q, J=5.4Hz, 2H), 1.14 (s, 2H), 1.02 (t, J=5.4Hz, 3H), 0.98(s,2H)。

Embodiment 9N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) butyramide

Step 1) synthesis of N-((1-(7-fluoronaphthalene-1-base) cyclopropyl) methyl) butyramide

This step title compound prepares with reference to the method described by embodiment 1 step 3, will (1-(7-fluoronaphthalene- 1-yl) cyclopropyl) methylamine (200mg, 929 μm ol), triethylamine (260 μ L, 1.86mmol) and n-butyryl chloride (99 μ L, 1.39mmol) reaction preparation in dichloromethane (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1), concentrate drying obtains title compound is white solid (155mg, 57.8%).

MS(ESI,pos.ion)m/z:286.4[M+1]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.96 (dd, J=11.4,1.8Hz, 1H), 7.81 (dd, J=9.0,6.0Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.45 (d, J=7.2Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.31 (dd, J= 8.4,24Hz, 1H), 3.53 (brs, 2H), 2.36 (t, J=5.4Hz, 2H), 1.15 (m, 2H), 1.09 (s, 2H), 0.96 (s, 2H), 0.90 (t, J=5.4Hz, 3H).

Compound 4-8,10-14 obtain according to the synthetic method side of embodiment 1-9:

Biologic test

The LC/MS/MS system analyzed includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, and orifice plate is certainly Dynamic sampler, post insulating box, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis Carry out under MRM pattern, MRM conversion parameter as in Table A:

Table A

Many reaction detection scan	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	40psi
		Drier flow velocity	10L/min

Analyze and use Agilent XDB-C18,2.1x 30mm, 3.5 μMs of posts, inject 5 μ L sample.Analysis condition: flowing phase It is aqueous formic acid (A) and the formic acid methanol solution (B) of 0.1% of 0.1%.Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B:

Table B

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%

2.3min	5%
		5.0min	stop

Additionally, also have Agilent 6330 series LC/MS/MS spectrometer for analyze, note equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Each analyte is carried out suitable cation model treatment and MRM conversion carries out optimal analysis.Use during analyzing Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μMs (Phenomenex, Torrance, California, USA).Flowing is 5mM ammonium acetate mutually, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L sample.

Embodiment A epiphysin MT ₁ Acceptor binding affinity is tested

Test method

Use radioligand associated methods, evaluate the affine of compound humanization MT1 acceptor that Chinese hamster ovary celI is transfected Power.Under the conditions of 22 DEG C, to cell membrane homogenate albumen (64 μ g), 0.01nM [¹²⁵I] iodomelatonin and buffer solution (50mM Tris-HCl (pH 7.4), 5mM MgCl₂And 1%BSA) in the mixed system that formed, add or be added without testization Compound, hatches 60 minutes altogether.Standard reference compound is melatonin, in the mixed system of above-mentioned condition, adds 1 μM Melatonin, is used for recording non-specific binding value.

Sample after hatching passes through pre-dipped under vacuum with 96 like cell collectors (Unifilter, Packard) The glass fiber filter (GF/B, Packard) of 0.3%PEI, and use ice-cold 50mM Tris-HCl repeatedly to rinse several times.Dry Dry filter membrane, in scintillation counter (Topcount, Packard), calculates residual with scintillation solution (Microscint 0, Packard) The radioactivity stayed.Experimental result represents with the suppression percentage specific binding relative to control group radioligand.

Standard reference compound is melatonin, by the experimental data of the melatonin of series concentration, it is thus achieved that competition Linearity curve.

Data analysis

Use radioligand associated methods, evaluate the humanization MT that Chinese hamster ovary celI is transfected by compound₁Acceptor affine Power.Test-compound at least tests three times, and data pass through competition curve nonlinear regression analysis through Hill equation curve fitting process Measure IC₅₀Value and Hill coefficient, then calculated by ChengPrusoff equation, calculate Ki value.

Experimental result shows, the compounds of this invention is to MT₁Acceptor demonstrates stronger binding affinity.

The humanization MT that Chinese hamster ovary celI is transfected by the compound that table 1 embodiment of the present invention provides₁The binding affinity of acceptor is real Test result

Embodiment number	Ki(nM)	Embodiment number	Ki(nM)
				Embodiment 1	C	Embodiment 2	A
Embodiment 3	A	Embodiment 4	C
				Embodiment 5	C	Embodiment 6	A
Embodiment 7	A	Embodiment 8	B
				Embodiment 9	B

A:0.1～1nM, B:1～10nM, C: > 10nM

In the description of this specification, reference term " embodiment ", " some embodiments ", and " example ", " specifically show Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature It is contained at least one embodiment or the example of the present invention.In this manual, need not to the schematic representation of above-mentioned term Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be arbitrary Individual or multiple embodiment or example combine in an appropriate manner.Additionally, in the case of the most conflicting, the technology of this area The feature of the different embodiments described in this specification or example and different embodiment or example can be combined by personnel And combination.

Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, amendment, replaces and modification.

Claims (7)

1. a compound, it is the stereoisomer of structure shown in the structure shown in formula (I) or formula (I), dynamic isomer or Pharmaceutically acceptable salt,

Wherein:

Ring A is cyclopropyl；

R¹For H, OH or C₁-C₆Alkyl；

R³For H, F, Cl, Br, OH, CN, NO₂, C₁-C₆Alkyl or C₁-C₆Alkoxyl；With

Each R²And R⁴It is separately H.

Compound the most according to claim 1, wherein, R¹For H, OH, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, Isobutyl group or the tert-butyl group.

Compound the most according to claim 1, wherein, R³For H, F, Cl, Br, OH, CN, NO₂, methyl, ethyl, n-pro-pyl, Isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide, normal-butyl epoxide, different Butyl epoxide or tert-butyl group epoxide.

Compound the most according to claim 1, it has a structure of one below:

Or its stereoisomer, dynamic isomer or pharmaceutically acceptable salt.

5. a pharmaceutical composition, it comprises the compound described in claim 1-4 any one, and pharmaceutically acceptable load Body, excipient, diluent or combinations thereof.

6. compound described in claim 1-4 any one or the pharmaceutical composition described in claim 5 are in preparing medicine Purposes, described medicine is for preventing, treat or alleviate the central nervous system dysfunction of the mankind, wherein said central nervous system System dysfunction is sleep-disorder, stress reaction, depression, anxiety disorder, SAD, and schizophrenia is sent out in terror Make, epilepsy, Parkinson's, antimigraine, the loss of memory or Alzheimer disease.

7. the compound described in claim 1-4 any one or the pharmaceutical composition described in claim 5 are in preparing medicine Purposes, described medicine is for selective exciting melatonin receptors in biological sample.