CN104292125B - Naphthalene derivatives and the application on medicine thereof - Google Patents

Abstract

The present invention provides some naphthaline derivatives or its steric isomer, tautomer, oxynitride, meta-bolites, pharmacy acceptable salt or front medicine, 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 Mammals, particularly mankind's central nervous system dysfunction.

Description

Naphthalene derivatives and the application on medicine thereof

Technical field

The invention belongs to pharmaceutical field, it is specifically related to the new compound that a class can be used for treating central nervous system dysfunction, prepare their method, comprise the application in pivot nervous system dysfunction in the treatment of the pharmaceutical composition of described compound and described compound and pharmaceutical composition thereof. More specifically, of the present invention is the naphthalene compounds that can be used as melatonin receptors agonist.

Background technology

Melatonin (melatonin) is a kind of neuro-endocrinology hormone secreted by pineal gland, and its major physiological effect has: 1. antitumor action, and melatonin can suppress mammary cancer, melanoma, prostate cancer, the growth of the multiple cancer cells such as liver cancer is important physiological tumor inhibitor; 2. antioxygenation, body can produce free radical by enzymatic reaction and non-enzymatic reaction, and such as oxyradical, hydroxyl radical free radical etc., mainly through providing, electronics carrys out Scavenger of ROS (ROS) to melatonin; 3. immunoregulation effect, melatonin is one of important factor of contact organism nervous system and immunity system, has vital role for maintenance body normal function; 4. anti-inflammatory and stress, melatonin can obviously promote the proliferative response of rheumatoid arthritis human peripheral lymphocyte, and to low temperature, anoxic, noise, light is upset stress all antagonistic action; 5. glycolipid metabolism regulating effect, melatonin can reduce blood sugar and blood fat, high density lipoprotein increasing; 6. antidepressant and anxiety effect 7. are on the impact of Sleep latency, melatonin also mediates by specificity melatonin receptors, play the unique effect (MalpauxB regulating the sleep wakefulness cycle, MigaudM, eta1.Biologyofmammalianphotoperiodismandthecriticalroleo fthepinealglandandmelatonin.JBiolRhythms, 2001,16 (4): 336-347). Melatonin need to play biological action by activated receptor, and melatonin receptors belongs to G-protein coupling receptor superfamily member, is extensively present in the SCN of neural system, hippocampus, cerebellar cortex, prefrontal lobe, Basal ganglia, black matter ventral tegmental area, volt core etc., and retina, blood vessel, mammary gland, liver, in kidney, the cytolemma of other systems such as gi tract and sexual gland and nucleus. Mankind's melatonin receptors has MT₁, MT₂And MT₃Three hypotypes. MT₁, highly it is gathered in SCN, the parts such as thalamus nucleus, regulates sleep; MT₂, it relates to diel rhythm; MT₃Effect is not clear. (CharlottevonGal1, JorgH, etal., Mammalianmelatoninreceptors:molecularbiologyandsignaltra nsduction.CellTissueRPs, 2002,309 (1): 151-162).

In the disease relevant to melatonin receptors, insomnia is extremely important one. Insomnia refers to starting and sleep to maintain obstacle occurring of sleep, causes sleep quality can not meet individual physiological requirements and obviously affect a kind of somnopathy syndrome of patient's activity on daytime. Insomnia is a kind of common disease, people is shown dejected, impatient, immunologic mechanism can be weakened simultaneously, hinder antisecosis, along with the modern life rhythm and pace of moving things is accelerated, having a sleepless night to have and increase progressively trend, the mishap caused because not having enough sleep in real life also more generation. At present, the whole world has the people of nearly 1/4 to be subject to insomnia puzzlement, and China's somnopathy morbidity reaches 42.7%, about has 300,000,000 middle-aged peoples to suffer from somnopathy. Within 2009, global soporific marketable value is 4,000,000,000 dollars, and annual growth is 11%.

At present, pharmacological agent is one of main method of Cure for insomnia disease, and the sedative hypnotic of clinical upper application has: barbiturate, benzene two nitrogen class medicine, non-benzene two nitrogen class medicine, antidepressant class medicine, melatonin and Chinese medicine etc. Barbiturate is the derivative of barbituric acid (malonyl urea), by optionally suppressing thalamus ascending reticular activing system, thus blocks excited to corticocerebral conduction. This type of medicine mainly contains phenylethyl barbituric acid, Amobarbital and secobarbital etc. Such poisonous side effect of medicine is relatively big, particularly serious liver, and renal toxicity, for a long time with producing tolerance and dependency, has accumulate poisoning, now clinical less for tranquilizing soporific. Benzene two nitrogen class medicine has calmness, flesh pine, anxiety and anticonvulsant action, clinical commonly used drug: mainly contain midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), clonazepam (clonazepam) etc. Though these medicines can extend total length of one's sleep, shorten Sleep latency, reduce slow wave sleep and follow dynamic (rapideyemovement, REM) sleep fast, real improving water flood quality. Its untoward reaction and complication are relatively obvious, and prolonged application can cause drug tolerance, dependency and Withrawal symptom.

(KrystalAD.Thechangingperspectiveonchronicinsomniamanagem ent.JClinPsychiatry, 2004,65Suppl8:20-25). non-benzene two nitrogen class, the medicine having ratified listing has zolpidem (zolpidem), Zaleplone (zalepbn) and Zopiclone (zopielone), this type of medicine does not affect normal Sleep architecture, does not usually produce rebound insomnia and withdrawal symptom. common untoward reaction has ataxia, headache, drowsiness, the memory difficulty, (Rotht such as abalienation, Soubranec, Titeuxl, etal., Efficacyandsafetyofzolpidem-MR:adouble-blind.placehe-con trollstudyinadultswithprimaryinsomniam.SleepMed, 2006,7 (5): 397-406). the syngignoscism that antidepressant drug is not special, but it is by treating depression with anxiety to improve insomnia, clinical conventional have paroxetine (paroxetine), Sertraline (sertraline), mirtazapine (mirtazapine), trazodone (trazodone) and amitriptyline etc., indivedual patient is when using SSRIs, sleep is without improving, even worsen (Uhlenhutheh, EH, BalterMB, etal., Trendsinrecommendationsforthepharmacotherapyofanxietydis ordersbyanintemationaexpertpanel, 1992-1997.EurNeuropsyehopharmacol, 1999.9Suppl6:393-398). therefore, exploitation is efficient, highly selective, the research focus that the little sedative hypnotic drug of side effect becomes.

The good effect of melatonin class medicine, side effect is little, has good application prospect. Within 2005, at melatonin receptors agonist Ramelteon (ramelteon) of U.S.'s Initial Public Offering, it is used for the treatment of insomnia, Sleep latency can be shortened, improving water flood efficiency and sleep maintain, compared with conventional medicament, this medicine does not damage cognitive activities next day, without withdrawal symptoms; But this medicine has slight side effect, such as headache, tired, drowsiness (ArendtJ such as grade, VanSomerenEJ, AppletonR, eta1., Clinicalupdate:melatoninandsleepdisorders.ClinMed, 2008,8 (4): 381-383).

Summary of the invention

The present invention provides some new compounds with melatonin receptors agonist activity, possesses good potential applicability in clinical practice. Compared with existing similar compound, the compound of the present invention has better drug effect, and medicine is for character and/or toxicological characteristics.

The present invention provides the compound that a class has melatonin receptors agonist activity, may be used for preparation treatment mankind's central nervous system dysfunction, such as somnopathy, stress reaction, seasonal affective disorder, the insomnia that the time difference causes and medicine that is tired and insomnia. Present invention provides the method for these compounds of preparation, it may also be useful to these compounds for treating Mammalss, especially the method for the above-mentioned disease of the 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 steric isomer of the structure shown in formula I or structure shown in formula I, tautomer, oxynitride, meta-bolites, pharmacy acceptable salt or front medicine,

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 vehicle further, carrier, adjuvant, solvent or their combination.

On the other hand, the present invention relates to compound disclosed by the invention or composition in the purposes preparing in medicine, described medicine is used for prevention, treat or alleviate Mammals, comprise the central nervous system dysfunction of the mankind: refer to somnopathy, stress reaction, strongly fragrant disease, anxiety disorder, seasonal affective disorder, the insomnia that the time difference causes and fatigue, schizophrenia, faint from fear, panic attack, melancholia, insomnia, psychotic disease mental disorder, epilepsy, Parkinson's disease, senile dementia, to normal or that pathological seaility is relevant various obstacles, migraine, the loss of memory or alzheimer's disease.

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

On the other hand, the present invention relates to the preparation of the compound that formula (I) comprises, the method for abstraction and purification.

Biological results shows, compound provided by the invention can be used as good melatonin receptors agonist.

Any embodiment of the either side of the present invention, it is possible to combine with other embodiment, as long as they there will not be contradiction. In addition, in any embodiment of either side of the present invention, any technology feature goes for this technology feature in other embodiment, as long as they there will not be contradiction.

Embodiment

Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects. The content of these aspects and other aspects will do more specifically complete description below.

Definition and general term

Describing certain embodiments of the present invention in detail now, the example is by the structural formula enclosed and chemical formula explanation. The invention is intended to contain all replacements, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition. Those skilled in the art will recognize that, many similar with described herein or that be equal to method and material can be used in practice. The present invention is never limited to method as herein described and material. One or more of the document combined, patent and analogous material are different from the application or when contradicting (include but not limited to the term defined, term application, described technology, etc.), are as the criterion with the application.

It is further recognized that some feature of the present invention, for clearly visible, should be described in multiple independent embodiment, but can also provide in combination in single embodiment. Otherwise, the various features of the present invention, for brevity, are described in single embodiment, but can also provide separately or with the sub-portfolio being applicable to arbitrarily.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention. The all patents that the present invention relates to and public publication by reference entirety be incorporated to the present invention.

Unless otherwise indicated, it should application is used to obtain following definition herein. For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent. In addition, organic chemistry General Principle can with reference to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley&Sons, description in NewYork:2007, its whole content is incorporated to herein by reference.

Unless otherwise illustrating or have obvious conflict, article used herein " " in context, " one (kind) " and " described " are intended to comprise " at least one " or " one or more ". Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object. Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the enforcement mode of described embodiment and adopt or use.

Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of the content of other aspects.

" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different. Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, 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.

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

" diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other. Diastereomer has different physical propertiess, such as fusing point, boiling point, spectral quality and reactivity. Non-enantiomer mixture operates such as electrophoresis and chromatogram by high resolution analysis, and such as HPLC is separated.

Stereochemistry used in the present invention definition and rule generally follow S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley&Sons, Inc., NewYork, 1994.

Many organic compound exist with optical activity form, and namely they have the ability that the plane of plane polarized light is rotated. When describing optically active compound, it may also be useful to prefix D and L or R and S represents the absolute configuration of molecule about one or more chiral centre. Prefix d and l or (+) and (-) are used to specify the symbol that plane polarized light caused by compound rotates, wherein (-) or l represent that compound is left-handed. Prefix for (+) or the compound of d be dextrorotation. Concrete steric isomer is an enantiomer, and the mixture of this kind of isomer is called enantiomeric mixture. The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, this kind of situation can occurs.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration form exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this quantity depending on unsymmetrical carbon) exists. Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split. If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.

The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.

Optical antipode can be split into, e.g., by being separated by its diastereoisomeric salt obtained by the method that the racemic modification of any gained end product or intermediate is familiar with by known method by those skilled in the art. The product of racemize can also be separated by chiral chromatography, as, it may also be useful to the high performance liquid chromatography (HPLC) of chiral sorbent. Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2ndEd.RobertE.Gawley, JeffreyAub ��, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH&Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomerism form " refer to the constitutional isomer building (lowenergybarrier) mutual conversion by low energy with different-energy. If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer. Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, such as keto-enol isomerization and imine-enamine isomerizations. Valency key tautomer (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss. The specific examples of keto-enol tautomerism is pentane-2,4-diketone and the change of 4-hydroxyl penta-3-alkene-2-keto tautomer. Another example of tautomerism is phenol-keto tautomerism. A specific examples of phenol-keto tautomerism is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer. Unless otherwise noted, all tautomeric forms of the compounds of this invention are all 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 substituting group, such as general formula compound above, or example special inside picture embodiment, subclass, and the compounds that the present invention comprises. Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term. Generally speaking, term " replacement " expression is replaced to the one or more hydrogen atoms in structure by concrete substituting group. Unless other aspects show, an optional substituted radical can replace in each position that can replace of group. Not only one or more substituting groups that position can be selected from concrete group in given structural formula are replaced, and so substituting group can identical or differently replace in each position. Wherein said substituting group it may be that but be not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano group, azido-, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, alkene base, alkynes base, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl that hydroxyl replaces, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)₂-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces₂, Carboxyalkoxy etc.

In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the present invention " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should being interpreted broadly, it both can refer in different group, does not affect mutually between concrete option expressed between same-sign, can also represent in identical group, not affect mutually between concrete option expressed between same-sign. With R^aFor example, structural formula "-N (R^a) C (=O) NR^aR^b" and structural formula "-(C₁-C₆Alkyl)-NR^aR^b" R between the two^aConcrete option mutually between not influenced, meanwhile, at same chemical formula "-N (R^a) C (=O) NR^aR^b" in, multiple R^aConcrete option mutually between not influenced.

At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope. Particularly pointing out, the present invention comprises each independent sub-combinations thereof of each member of these radical species and scope. Such as, term " C₁-C₆Alkyl " refer in particular to independent disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

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

The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replaces, wherein said substituting group is, hydroxyl, amino, fluorine, cyano group, azido-, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, alkene base, alkynes base, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl that hydroxyl replaces, the alkoxyl group that hydroxyl replaces, alkyl-the C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)₂-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces₂, Carboxyalkoxy etc. Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom. In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also 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-propyl (n-Pr ,-CH₂CH₂CH₃), sec.-propyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), etc.

Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms from saturated straight or branched alkyl and obtaining. Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom. In one embodiment, alkylidene group contains 1-6 carbon atom; In another embodiment, alkylidene group contains 1-4 carbon atom; In yet another embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom. Such example comprises methylene radical (-CH₂-), ethylidene (-CH₂CH₂-), isopropylidene (-CH (CH₃)CH₂-) etc.

Term " alkene base " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has at least a unsaturated site, namely has a carbon-carbon sp²Double bond, wherein, described alkenyl group can optionally be replaced by one or more substituting group described in the invention, and it comprises " 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; In yet another embodiment, alkenyl group comprises 2-4 carbon atom. The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH₂), allyl group (-CH₂CH=CH₂) etc.

Term " alkynes base " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has at least a unsaturated site, namely having a carbon-carbon sp triple bond, wherein, described alkynyl group can optionally be replaced by one or more substituting group described in the invention. 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 of alkynyl group comprises, but is not limited to, ethynyl (-C �� CH), propargyl (-CH₂C �� CH), 1-proyl (-C �� C-CH₃) etc.

Term " H " represents single hydrogen atom. Such atomic group can be connected with other groups, such as is connected with Sauerstoffatom, forms oh group.

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

Term " heteroatoms " refers to O, S, N, P and Si, comprises N, the form of any oxidation state of S and P; The primary, secondary, the form of tertiary amine and quaternary ammonium salt; Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).

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

Term " alkyl that hydroxyl replaces " represents that alkyl group is optionally substituted with one or more hydroxyl group and is replaced, and wherein alkyl group has implication of the present invention. Such example comprises, but is not limited to methylol, hydroxyethyl, 1,2-dihydroxy ethyl etc.

Term " alkyl that sulfydryl replaces " represents that alkyl group is replaced by one or more mercapto groups, and wherein alkyl group has implication of the present invention. Such example comprises, but is not limited to mercapto methyl, mercaptoethyl etc.

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

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention. Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom. In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom. The substituting group that described alkoxy base can optionally be described by one or more the present invention replaces.

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

Term " p former molecular ", wherein p is integer, typically describes the number becoming annular atoms in molecule, and the number becoming annular atoms in described molecule 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 " carbocyclic ring base " or " carbocyclic ring " expression contain 3-12 carbon atom, the unsaturated monocycle of saturated or part of the nonaro-maticity of unit price or multivalence, two ring or three-ring system. Carbon bicyclic group comprises spiral shell carbon bicyclic group and thick conjunction carbon bicyclic group, and suitable carbocyclic ring base group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical. The example of carbocyclic ring base group comprises further, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkene base, 1-cyclopentyl-2-alkene base, 1-cyclopentyl-3-alkene base, cyclohexyl, etc.

Term " cycloalkyl " expression contains 3-12 carbon atom, the saturated monocycle of unit price or multivalence, two ring or three-ring system. In one embodiment, cycloalkyl comprises 3-12 carbon atom; In another embodiment, cycloalkyl comprises 3-8 carbon atom; In yet another embodiment, cycloalkyl comprises 3-6 carbon atom. Described group of naphthene base can independently not be replaced or replaced by one or more substituting group described in the invention.

Term " heterocyclic radical " and " heterocycle ", in commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or the unsaturated monocycle of part, and two ring or three rings, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom. Unless otherwise indicated, heterocyclic radical can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of heterocyclic radical comprises, but is not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia cyclobutyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, 2-oxygen is mixed-5-azabicyclo [2.2.1]-5-in heptan base.-CH in heterocyclic radical₂-group is comprised by the example of-C (O)-replacement, but is not limited to, 2-oxo-pyrrolidine base, oxo-1,3-thiazolidyl, 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base. The example that in heterocyclic radical, sulphur atom is oxidized comprises, but is not limited to, tetramethylene sulfone base, 1,1-dioxo thio-morpholinyl. Described heterocyclyl groups can optionally be replaced by one or more substituting group described in the invention.

In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, refers to and comprises the saturated of 4-7 annular atoms or the unsaturated monocycle of part, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom. Unless otherwise indicated, 4-7 former molecular heterocyclic radical can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of 4-7 former molecular heterocyclic radical comprises, but is not limited to: azelidinyl, oxetanylmethoxy, thia cyclobutyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base.-CH in heterocyclic radical₂-group is comprised by the example of-C (O)-replacement, but is not limited to, 2-oxo-pyrrolidine base, oxo-1,3-thiazolidyl, 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base. The example that in heterocyclic radical, sulphur atom is oxidized comprises, but is not limited to, tetramethylene sulfone base, 1,1-dioxo thio-morpholinyl. Described 4-7 former molecular heterocyclyl groups can optionally be replaced by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to and comprises the saturated of 4 annular atomses or the unsaturated monocycle of part, and wherein at least one annular atoms is selected from nitrogen, and sulphur and Sauerstoffatom are replaced. Unless otherwise indicated, 4 former molecular heterocyclic radicals can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of 4 former molecular heterocyclic radicals comprises, but is not limited to: azelidinyl, oxetanylmethoxy, thia cyclobutyl. The former molecular heterocyclyl groups of described 4 can optionally be replaced by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, refers to and comprises the saturated of 5 annular atomses or the unsaturated monocycle of part, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom. Unless otherwise indicated, 5 former molecular heterocyclic radicals can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of 5 former molecular heterocyclic radicals comprises, but is not limited to: pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-bis-oxygen cyclopentyl, two sulphur cyclopentyl.-CH in heterocyclic radical₂-group is comprised by the example of-C (O)-replacement, but is not limited to, 2-oxo-pyrrolidine base, oxo-1,3-thiazolidyl. The example that in heterocyclic radical, sulphur atom is oxidized comprises, but is not limited to, tetramethylene sulfone base. The former molecular heterocyclyl groups of described 5 can optionally be replaced by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, refers to and comprises the saturated of 6 annular atomses or the unsaturated monocycle of part, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom. Unless otherwise indicated, 6 former molecular heterocyclic radicals can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of 6 former molecular heterocyclic radicals comprises, but is not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl.-CH in heterocyclic radical₂-group is comprised by the example of-C (O)-replacement, but is not limited to, 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base. The example that in heterocyclic radical, sulphur atom is oxidized comprises, but is not limited to, 1,1-dioxo thio-morpholinyl. The former molecular heterocyclyl groups of described 6 can optionally be replaced by one or more substituting group described in the invention.

Also in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to and comprises the saturated of 7-12 annular atoms or the unsaturated two rings of spiral shell of part or thick conjunction pair ring, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom. Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon base or nitrogen base, and-CH₂-group can optionally by-C (O)-replacement. The sulphur atom of ring can optionally be oxidized to S-oxide compound. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound. The example of 7-12 former molecular heterocyclic radical comprises, but is not limited to: indoles quinoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-benzodioxole base, and 2-oxygen is mixed-5-azabicyclo [2.2.1]-5-in heptan base. Described 7-12 former molecular heterocyclyl groups can optionally be replaced by one or more substituting group described in the invention.

Term " aromatic base " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, the carbocyclic ring system of two ring and three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 former molecular ring, and has one or more attachment point to be connected with the rest part of molecule. Term " aryl " can exchange with term " aromatic nucleus " and use. The example of aromatic yl group can comprise phenyl, naphthyl and anthracene. Described aromatic yl group can independently be replaced by one or more substituting group described in the invention optionally.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, two ring and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more attachment point to be connected with molecule rest part. Term " heteroaryl " can with term " hetero-aromatic ring ", " virtue heterocycle " or " heteroaromatics " exchanges and uses. Described heteroaryl groups optionally is replaced by one or more substituting group described in the invention. In one embodiment, 5-10 former molecular heteroaryl comprises the heteroatoms that 1,2,3 or 4 are independently selected from O, S and N.

The example of heteroaryl groups comprises, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, the different azoles base of 3-, the different azoles base of 4-, the different azoles base of 5-, 2-azoles base, 4-azoles base, 5-azoles base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl etc.

As described in the invention, substituting group is drawn the member ring systems (as follows) that a key is connected on the ring at center to be formed and is represented substituting group on ring the position in any desirable generation can replace. Such as, formula e represents any position that may be replaced on A ring, such as formula f¹-f⁴Shown in:

Substituent R in formula g, on A ring^xAnd R^y, it is possible to replacing in any position that may be replaced of ring, concrete illustration comprises, but is not limited to formula k¹-k⁴Shown in:

Term used in the present invention " front medicine ", represents a compound and is converted into the compound shown in formula (I) in body. Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure. Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug_1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters. such as, a compound in the present invention comprises hydroxyl, and namely its acidylate can obtain the compound of prodrug form. other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that the di on parent obtains. can with reference to following document about the complete discussion of prodrug: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal, Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal, ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention. pharmacy acceptable salt at art known by us, such as document: S.M.Bergeetal., described in J.PharmaceuticalSciences, 66:1-19,1977. the salt of pharmaceutically acceptable nontoxic acid formation comprises, but is not limited to, and the inorganic acid salt formed with amino group reaction has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is such as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document. other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, dextrocamphoric acid salt, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonic acid salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, flutter acid salt, pectate, persulphate, 3-phenylpropionic acid salt, picrate, trimethylacetic acid salt, propionic salt, stearate, thiocyanate-, tosilate, undeeanoic acid salt, valerate, etc.. the salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt. The present invention also intends contemplating 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. Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc. It is suitable that pharmacy acceptable salt comprises further, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and anti-counterion are formed, such as halogenide, oxyhydroxide, carboxylate, and hydrosulfate, 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 present invention discloses a class naphthaline derivatives, its pharmacy acceptable salt, pharmaceutical preparation and composition thereof, can be used as melatonin receptors agonist, to mankind's central nervous system dysfunction, insomnia and treatment that is tired and insomnia that such as somnopathy, stress reaction, seasonal affective disorder, the time difference cause have potential purposes.

On the one hand, the present invention relates to a kind of compound, it is the steric isomer of the structure shown in formula I or structure shown in formula I, tautomer, oxynitride, meta-bolites, pharmacy acceptable salt or front medicine,

Wherein:

M is 1,2 or 3;

N is 1,2 or 3;

R¹For H, OH, C₁-C₆Alkyl, C₂-C₆Alkene base or C₂-C₆Alkynes base;

Each R²And R³It is separately H, D, F, Cl, Br, I, CN, OH, NO₂,-NR^aR^b,-C (=O) R^c, C₁-C₆Alkyl, C₂-C₆Alkene base, C₂-C₆Alkynes base, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl group ,-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 carbocyclic ring) ,-(C₁-C₆Alkyl)-NR^aR^b, 3-12 former molecular heterocyclic radical, the C that hydroxyl replaces₁-C₆Alkyl ,-NR^a-(C₁-C₆Alkyl)-(C₆-C₁₀Aryl) ,-(C₁-C₆Alkyl)-(C₆-C₁₀Aryl) ,-(C₁-C₆Alkyl)-(5-12 former molecular heteroaryl) or 5-12 former molecular heteroaryl;

R⁴For F, Cl, Br, OH, CN, NO₂, C₁-C₆Alkoxyl group ,-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-C₆Alkyl)-NR^aR^b, 5-12 former molecular heteroaryl or C₆-C₁₀Aryl;

R⁵And R⁶It is F, Cl, Br, I, C independently of one another₁-C₆Alkyl, C₂-C₆Alkene base, C₂-C₆Alkynes base, C₁-C₆Haloalkyl ,-(C₁-C₆Alkyl)-(C₆-C₁₀Aryl), the C that sulfydryl replaces₁-C₆Alkyl ,-(C₁-C₆Alkyl)-N₃,-(C₁-C₆Alkyl)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₆Alkyl)-NR^aR^b,-(C₁-C₆Alkyl)-(C₁-C₆Alkoxyl group) or-(C₁-C₆Alkyl)-O-S (=O)₂-(C₁-C₆Alkyl);

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

Each R^cIndependently for being H, C₁-C₆Alkyl, C₆-C₁₀Aryl or C₃-C₈Cycloalkyl.

Wherein in some embodiments, R¹For H, OH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.

In other embodiments, each R²And R³It is separately H, D, F, Cl, Br, I, CN, NO₂, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base or tertiary butyl oxygen base.

In other embodiments, R⁴For F, Cl, Br, OH, CN, NO₂, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base or tertiary butyl oxygen base.

In other embodiments, R⁵And R⁶It is F, Cl, Br, I, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl independently of one another.

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

Or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or front medicine.

The present invention's compound of coming into the open can contain asymmetric or chiral centre, and stereoisomer form that therefore can be different exists. The present invention is intended to make all stereoisomer forms of compound shown in formula (I), include but not limited to diastereomer, enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture is such as racemic mixture, become the integral part of the present invention.

In structure disclosed by the invention, when the stereochemistry of the chiral atom of any specific does not indicate, then all steric isomers of this structure are all considered within the present invention, and comprise in the present invention as the present invention's compound of coming into the open. When stereochemistry is expressed the real wedge shape line (solidwedge) of particular configuration or dotted line indicates, then the steric isomer of this structure clear and definite and definition with regard to this.

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

Compound shown in formula (I) can exist in a salt form. In one embodiment, described salt refers to pharmacy acceptable salt. Term " pharmaceutically acceptable " refer to material or composition must with comprise preparation other composition and/or with Mammals of its treatment chemically and/or in toxicology compatible. In another embodiment, described salt not necessarily pharmacy acceptable salt, it is possible to be for the preparation of and/or purification formula (I) shown in the intermediate of compound and/or the enantiomorph for separating of compound shown in this formula (I).

Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearic acid salt, oleate, oxalate, palmitate, flutter acid salt, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-galactosonic acid salt, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Such as hydrochloric acid can be comprised, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. by its derivative mineral acid obtaining salt.

Such as acetic acid can be comprised, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. by its derivative organic acid obtaining salt.

Can be formed with mineral alkali and organic bases by acceptable base addition salt.

Can comprise by its derivative mineral alkali obtaining salt, the metal of the I race of such as ammonium salt and periodictable to XII race. In certain embodiments, this salt derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salt.

Can comprising primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine of naturally occurring replacement, cyclic amine, deacidite etc. Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.

The pharmacologically acceptable salt of the present invention can by conventional chemical method by parent compound, and alkalescence or acidic moiety synthesize. Generally speaking, such salt can by the suitable alkali of the free acid form and stoichiometry that make these compounds (such as Na, Ca, the oxyhydroxide of Mg or K, carbonate, supercarbonate etc.) reaction, or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared. Such reaction carries out usually in water or organic solvent or the mixture of the two. Generally, when suitable, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or acetonitrile. At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character; choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germary, 2002) list of the suitable salt of other can be found in.

In addition, compound disclosed by the invention, comprises their salt, it is also possible to obtain with their hydrate forms or the form that comprises its solvent (such as ethanol, DMSO, etc.), for their crystallization. The present invention come into the open compound can with the intrinsic ground of pharmaceutically acceptable solvent (comprising water) or by design forming solvate; Accordingly, it is intended to comprise the form with non-solvation of solvation.

Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment. The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number. The Exemplary isotopes can introduced in the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, the isotropic substance of 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 the intermediate of compound shown in preparation formula (I).

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

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention. In one embodiment, pharmaceutical composition of the present invention, further comprises pharmaceutically acceptable carrier, vehicle, adjuvant, solvent or their combination. In another embodiment, pharmaceutical composition can be liquid, solid, semi-solid, gel or aerosol.

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

When can be used for treatment, the formula I compound for the treatment of significant quantity and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and also can be used as the activeconstituents of pharmaceutical composition provides. Therefore, present disclosure also provides pharmaceutical composition, and this pharmaceutical composition comprises the formula I compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle for the treatment of significant quantity.

Term as used herein " treatment significant quantity " refers to the total amount being enough to demonstrate each active ingredient of meaningful patient's benefit. When using independent activeconstituents individually dosed, this term only refers to this composition. When Combination application, no matter this term then refers to combination, successively or during simultaneously administration, all cause the combined amount of the activeconstituents of result for the treatment of. Formula I compound and pharmacy acceptable salt thereof are described above. From compatible with other compositions of preparation and to, the harmless meaning of its recipient, carrier, thinner or vehicle must be acceptable. Another aspect according to present disclosure, is also provided for the method for useful in preparing drug formulations, and the method comprises formula I compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, and thinner or vehicle mix even. Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope of reasonable medical judgment, be applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and it is effective to set purposes.

Also will be appreciated that, some compound of the present invention can exist in a free form and is used for the treatment of, if or suitably can exist with the form of its pharmaceutically acceptable derivates. Some non-limiting embodiments of pharmaceutically acceptable derivative comprise pharmaceutically acceptable front medicine, salt, ester, the salt of these esters, or to can directly or indirectly provide any other adducts or the derivative of compound of the present invention or its meta-bolites or residue during patient's administration in need.

Drug pharmaceutical compositions disclosed by the invention can be prepared and be packaged as (bulk) in bulk form, wherein can extract the compound shown in formula (I) of safe and effective amount, then give patient with powder or syrup form. Or, pharmaceutical composition disclosed by the invention can be prepared and be packaged as unit dosage, and wherein each physically discrete unit contains the compound shown in formula (I) of safe and effective amount. When preparing with unit dosage, pharmaceutical composition disclosed by the invention can contain usually, 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's " pharmaceutically acceptable vehicle " used means pharmaceutically acceptable material, mixture or the solvent relevant to form of administration or pharmaceutical composition consistence. Often kind of vehicle must be compatible with other composition of pharmaceutical composition when mixing, and comes into the open the interaction of effect of compound and can cause not being the interaction of pharmaceutically acceptable pharmaceutical composition to can greatly reduce the present invention during patient's administration to avoid. In addition, often kind of vehicle must be pharmaceutically acceptable, such as, has sufficiently high purity.

Suitable pharmaceutically acceptable vehicle can be different according to selected concrete formulation. In addition, pharmaceutically acceptable vehicle can be selected according to their specific functions in the composition. Such as, can select to contribute to some the pharmaceutically acceptable vehicle producing equal one dosage type low temperature. Some the pharmaceutically acceptable vehicle that can contribute to administration measure formulation can be selected. Can select to come into the open compound from health organ or part to some pharmaceutically acceptable vehicle of another organ of health or part to contributing to carrying or transport the present invention during patient's administration. Can some pharmaceutically acceptable vehicle of selective enhancement patient compliance.

Suitable pharmaceutically acceptable vehicle comprises the vehicle of following type: thinner, weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, granulating agent, Drug coating, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, correctives, odor mask, tinting material, anti-hard caking agent, wetting Agent for Printing Inks, sequestrant, fluidizer, tackifier, antioxidant, sanitas, stablizer, tensio-active agent and buffer reagent. Technician is it can be appreciated that some pharmaceutically acceptable vehicle can provide more than a kind of function, and provides alternative function, and this depends on to exist in how many these vehicle and preparation in preparation to there are those other vehicle.

Technician grasps the knowledge and skills of this area, so that they can select the suitable pharmaceutically acceptable vehicle of the appropriate amount for the present invention. In addition, there is the obtainable resource of a large amount of technician, they describe pharmaceutically acceptable vehicle, and for selecting suitable pharmaceutically acceptable vehicle. Example comprises Remington'sPharmaceuticalSciences (MackPublishingCompany), TheHandbookofPharmaceuticalAdditives (GowerPublishingLimited), andTheHandbookofPharmaceuticalExcipients (theAmericanPharmaceuticalAssociationandthePharmaceutical Press).

At Remington:TheScienceandPracticeofPharmacy, 21stedition, 2005, ed.D.B.Troy, LippincottWilliams&Wilkins, Philadelphia, andEncyclopediaofPharmaceuticalTechnology, eds.J.SwarbrickandJ.C.Boylan, 1988-1999, MarcelDekker, NewYork disclose the various carriers for configuring pharmaceutically acceptable composition, with the known technology prepared for it, these documents content separately is incorporated to the present invention by reference. Except any such as because producing any less desirable biological action, or occur to interact with other composition any in harmful way and pharmaceutically acceptable composition and come into the open outside the incompatible any common carrier of compound with the present invention, pay close attention to the scope that its application belongs to the present invention.

Pharmaceutical composition disclosed by the invention uses techniques and methods well known by persons skilled in the art to prepare. The description of some common methods of this area can see Remington'sPharmaceuticalSciences (MackPublishingCompany).

Therefore, on the other hand, the present invention relates to the technique of pharmaceutical compositions, described pharmaceutical composition comprises the present invention and comes into the open compound and pharmaceutically acceptable vehicle, carrier, auxiliary dose, solvent or their combination, and this technique comprises the various composition of mixing. Comprise the present invention to come into the open the pharmaceutical composition of compound, it is possible to mix under such as envrionment temperature and normal atmosphere and prepare.

Compound disclosed by the invention is usually formulated into and is adapted to pass through required approach to the formulation of patient's administration. Such as, formulation comprises those formulations being suitable for following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, and elixir, suspensoid, solution, emulsion, sachet agent and cachet; (2) parenteral admin, such as sterile solution agent, suspensoid and the powder that redissolves; (3) transdermal administration, such as percutaneous plaster agent; (4) rectal administration, such as suppository; (5) suck, such as aerosol, solution and dry powder doses; (6) topical, such as ointment, salve, lotion, solution, paste, sprays, foaming agent and gelifying agent.

In one embodiment, compound disclosed by the invention can be mixed with oral dosage form. In another embodiment, compound disclosed by the invention can be mixed with suction formulation. In another embodiment, compound disclosed by the invention can be mixed with nose administration formulation. In yet another embodiment, compound disclosed by the invention can be mixed with transdermal administration. Also in one embodiment, compound disclosed by the invention can be mixed with topical formulation.

Pharmaceutical composition provided by the invention can with compressed tablet, and development sheet, can chew lozenge, rapidly dissolving tablet, multiple compressing tablet, or enteric coated tablet, sugar-coat or film coated tablet provide. Enteric coated tablet be with can anti-hydrochloric acid in gastric juice effect but dissolve in intestines or the compressed tablet of material dressing of disintegration, thus prevent the sour environment of activeconstituents contact stomach. Enteric coating comprises, but is not limited to, lipid acid, fat, salol, wax, lac, ammonification lac and phthalic acid cellulose acetate ester. Coated tablet is the compressed tablet that sugar-coat surrounds, and it can be beneficial to cover and make us unhappy taste or smell and tablet can be prevented to be oxidized. Thin membrane coated tablet is the compressed tablet with the thin layer of water-soluble substances or plastic film covering. Film coating comprises, but is not limited to, Natvosol, Xylo-Mucine, Macrogol 4000 and phthalic acid cellulose acetate ester. Film coating possesses the general characteristic identical with sweet tablet. Multiple compressing tablet is through the compressed tablet prepared more than a press cycles, comprises multilayer tablet, and pressed coated or dry coating tablet.

Tabules can by powder, the activeconstituents of crystallization or particulate state independent or one or more carriers of describing with the present invention or the incompatible preparation of vehicle group, described carrier and vehicle comprise tackiness agent, disintegrating agent, controlled release polymer, lubricant, thinner and/or tinting material. Sweetener and sweeting agent are particularly useful when forming chewable tablet and lozenge.

Pharmaceutical composition provided by the invention can provide with soft capsule or hard capsule, and it can be prepared by gelatin, methylcellulose gum, starch or alginate calcium. Described hard gelatin capsule, also referred to as dry filled capsules (DFC), forms by two sections, and a slug enters in another section, therefore encloses activeconstituents completely. Soft elastic glue capsule (SEC) is soft, spherical shell, such as gelatin shell, and it is by adding glycerine, sorbyl alcohol or the plasticizing of similar polyvalent alcohol. Soft gelatin shell can comprise sanitas and carry out prophylaxis of microbial growth. Suitable sanitas be as described in the present invention those, comprise Tegosept M and Tegosept E and refer to, and Sorbic Acid. Liquid provided by the invention, semi-solid and solid dosage can be encapsulated in capsule. Suitable liquid and semisolid dosage form are included in propylene carbonate, solution in vegetables oil or triglyceride level and suspensoid. The capsule comprising such solution can as at United States Patent (USP) U.S.Pat.Nos.4,328,245; What describe in 4,409,239 and 4,410,545 prepares. Described capsule can also adopt coating as is known to persons skilled in the art, thus improves or maintain the stripping of activeconstituents.

Pharmaceutical composition provided by the invention can provide with liquid and semisolid dosage form, comprises emulsion, solution, suspensoid, elixir and syrup. Emulsion is two-phase system, and wherein a kind of liquid is dispersed in another kind of liquid in pellet form completely, and it can be oil-in-water-type or water-in-oil-type. Emulsion can comprise pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and sanitas. Suspensoid can comprise pharmaceutically acceptable suspending agent and sanitas. Aqueous alcohol solutions can comprise pharmaceutically acceptable acetal, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal; With the water-soluble solvent with one or more hydroxyl, such as propylene glycol and ethanol. Elixir is transparent, the water-alcohol solution of sweet taste. Syrup is the aqueous solution of dense sugar such as sucrose, and can comprise sanitas. For liquid dosage form, such as, the solution in polyoxyethylene glycol can dilute with enough pharmaceutically acceptable liquid vehicles such as water, with accurately convenient ground administration.

Other useful liquid and semisolid dosage form comprise, but are not limited to comprise activeconstituents provided by the invention and two grades of those formulations changing list-or poly-alkylene glycol, and described list-or poly-alkylene glycol comprise: 1,2-Methylal(dimethoxymethane), diglyme, triglyme, tetraethylene glycol dimethyl ether, polyoxyethylene glycol-350-dme, polyoxyethylene glycol-550-dme, polyoxyethylene glycol-750-dme, wherein 350, the approximate molecular-weight average of 550,750 finger polyoxyethylene glycol. These preparations may further include one or more oxidation inhibitor, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Tenox PG, vitamin-E, quinhydrones, Hydroxycoumarin, thanomin, Yelkin TTS, kephalin, xitix, oxysuccinic acid, sorbyl alcohol, phosphoric acid, hydrosulphite, Sodium Pyrosulfite, thio-2 acid and ester thereof and dithiocarbamate.

Time suitable, it is possible to by the dosage unit preparations microencapsulation of oral administration. The composition extending or maintaining release can also be prepared into, such as, by by microparticle material dressing or be embedded in polymkeric substance, in wax or analogue.

Combination of oral medication provided by the invention can also provide with the form of liposome, micella, microballoon or nanometer system. Micella formulation can be prepared by the method that U.S.Pat.No.6,350,458 describes.

Pharmaceutical composition provided by the invention can provide with granule and the pulvis of non-effervesce or effervesce, to reconstruct liquid dosage form. The pharmaceutically acceptable carrier and the vehicle that use in non-effervescent granule or pulvis can comprise thinner, sweeting agent and wetting agent. The pharmaceutically acceptable carrier and the vehicle that use in effervescent granule or pulvis can comprise organic acid and carbon dioxide source.

All above-mentioned formulations can use tinting material and seasonings.

Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier. Such polymkeric substance comprises polyvinylpyrrolidone, pyran co-polymer, the polyoxyethylene polylysine that poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl l-asparagine phenol or palmitoyl residues replace. In addition, compound disclosed in this invention can be combined with the class Biodegradable polymeric used in the Co ntrolled release realizing medicine, such as, poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, the crosslinked or amphiphilic block copolymer of poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.

Pharmaceutical composition provided by the invention can be mixed with immediately or modification release formulation, comprise delays-, slow release-, pulse-, control-, target to-with sequencing releasing pattern.

Pharmaceutical composition provided by the invention can be prepared jointly with other activeconstituents of the therapeutic action that can not damage expection, or the material with the effect of supplementary expection is prepared jointly.

Pharmaceutical composition provided by the invention can by injecting, and defeated note or implantation administered parenterally, for local or Formulations for systemic administration. The administered parenterally used such as the present invention comprises intravenously, intra-arterial, intraperitoneal, in sheath, in ventricle, in urethra, in breastbone, in cranium, in flesh, in synovial membrane and subcutaneous administration.

Pharmaceutical composition provided by the invention can be mixed with any formulation being suitable for administered parenterally, comprises solution, suspensoid, emulsion, micella, liposome, microballoon, nanometer system and the solid form being suitable for making in a liquid before the injection solution or suspension. Such formulation can be prepared (see Remington:TheScience and PracticeofPharmacy, the same) according to the ordinary method known to the skilled of medicine scientific domain.

The pharmaceutical composition that expection is used for administered parenterally can comprise one or more pharmaceutically acceptable carrier and vehicle, comprises, but is not limited to; containing transporter; water miscibility vehicle, non-transporter, the sanitas of biocide or antimicrobial growth; stablizer; dissolution enhancers, waits penetration enhancer, buffer reagent; oxidation inhibitor; local anesthetic, suspending agent and dispersion agent, wetting agent or emulsifying agent; complexing agent; sequestering agent or sequestrant, frostproofer, cryoprotectant; thickening material, pH adjusting agent and rare gas element.

Suitable comprises containing transporter, but is not limited to: water, salt solution, physiological saline or phosphate buffered salt solution (PBS), sodium chloride injection, Ringers injection liquid, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection liquid. Non-transporter comprises, but is not limited to, the non-volatile oil of plant origin, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, sweet oil, peanut oil, spearmint oil, Thistle oil, the medium chain triglyceride of sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois, and palm seed oil. Water miscibility vehicle comprises, but is not limited to, ethanol, 1,3 butylene glycol, liquid polyoxyethylene glycol (such as Liquid Macrogol and poly(oxyethylene glycol) 400), propylene glycol, glycerine, METHYLPYRROLIDONE, DMAC N,N' dimethyl acetamide and methyl-sulphoxide.

Suitable biocide or sanitas comprise, but are not limited to, phenol, cresols, mercury agent, phenylcarbinol, chlorobutanol, methyl p-hydroxybenzoate and propylparaben, Thiomersalate, benzalkonium chloride (such as benzethonium chloride), Tegosept M and propylben and Sorbic Acid. The suitable penetration enhancer that waits comprises, but is not limited to, sodium-chlor, glycerine and glucose. Suitable buffer reagent comprises, but is not limited to, phosphoric acid salt and Citrate trianion. Suitable antioxidant be as the present invention describe those, comprise hydrosulphite and sodium metabisulfite. Suitable local anesthetic comprises, but is not limited to vovocan. Suitable suspending agent and dispersion agent be as the present invention describe those, comprise Xylo-Mucine, Vltra tears and polyvinylpyrrolidone. Suitable emulsifying agent comprises those of the present invention's description, comprises polyoxyethylene sorbitan monolaurate. Polyoxyethylene refund sorbitol monooleate 80 and triethanolamine oleate ester. Suitable sequestering agent or sequestrant comprise, but are not limited to EDTA. Suitable pH adjusting agent comprises, but is not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agent comprises, but is not limited to cyclodextrin, comprises alpha-cylodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfo group butyl ether-beta-cyclodextrin and sulfo group butyl ether 7-beta-cyclodextrin (CyDex,Lenexa,KS)��

Pharmaceutical composition provided by the invention can be mixed with single dose or multiple dose administration. Described single-dose preparations is packaged in ampoule agent, in bottle or syringe. Described multiple doses parenteral administration must comprise biocide that is antibacterial or fungistatic concentrations. All parenteral administrations must be all aseptic, as known in the art with practice.

In one embodiment, pharmaceutical composition provides with instant sterile solution. In another embodiment, pharmaceutical composition provides with aseptic dried soluble product, comprises lyophilized powder and subcutaneous injection tablet, and it reconstructs with vehicle before use. In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions. In yet another embodiment, the aseptic dry insolubility product that pharmaceutical composition reconstructs with vehicle before being formulated into use. Also 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 modification release formulation, comprise delays-, slow release-, pulse-, control-, target to-with sequencing releasing pattern.

Pharmaceutical composition can be configured to suspensoid, solid, semi-solid or thixotropic fluid, is used as the reservoir administration implanted. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, and its outside polymeric membrane being insoluble to body fluid but allowing the activeconstituents in pharmaceutical composition to diffuse through is surrounded.

The internal matrix being applicable to comprises polymethylmethacrylate, poly-butylacrylic acid methyl esters, plasticising or unplasticised polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, polyisoprene, polyisobutene, polyhutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, dimethione, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as vinylformic acid and methacrylic acid, collagen, the polyvinyl acetate of the partial hydrolysis of cross-linking polyvinyl alcohol and coach.

The outside polymeric membrane being applicable to comprises polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate multipolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, the multipolymer of chlorinatedpolyethylene, polyvinyl chloride, ethylene chloride and vinyl-acetic ester, vinylidene chloride, ethene and propylene, ionomer polyethylene terephthalate, isoprene-isobutylene rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and ethylene/vinyl oxygen base alcohol copolymer.

The pharmaceutical composition being suitable for transdermal administration can be prepared into discontinuous paster agent, it is intended to keeps the time being in close contact an elongated segment with the epidermis of patient. Such as, by ion infiltration delivering active ingredients from paster agent, such as PharmaceuticalResearch, 3 (6), the general description in 318 (1986).

The pharmaceutical composition being suitable for topical can be formulated into salve, ointment, suspensoid, lotion, pulvis, solution, paste, gelifying agent, sprays, aerosol or finish. Such as, salve, ointment and gelifying agent can with water or oil matrix, and applicable thickening material and/or gelifying agent and/or solvent configure. Such matrix can comprise, water, and/or oil such as liquid-liquid paraffin and vegetables oil (such as peanut oil or Viscotrol C), or solvent such as polyoxyethylene glycol. The thickening material and the gelifying agent that use according to medium property comprise soft wax, aluminum stearate, cetearyl alcohol alcohol, polyoxyethylene glycol, lanolin, beeswax, carboxyvinyl polymer and derivatived cellulose, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

Lotion can be prepared with water or oil matrix, and usually also containing one or more emulsifying agents, stablizer, dispersion agent, suspending agent or thickening material.

Compacted under can be there is in externally-applied powder at the powder matrix such as talcum powder being applicable to arbitrarily, lactose or starch. Drops can with comprising one or more dispersion agents, solubilizing agent, and water or the non-aqueous matrix of suspending agent or sanitas are formulated.

Topical formulations can carry out administration by applying one or many every day in affected part; The impermeable plastic wound dressing covering skin is preferentially used. Adhesivity store system can realize continuously or the administration extended.

The purposes of the compounds of this invention and composition

The present invention provides and uses compound disclosed in this invention and medicine composite for curing, prevention, or alleviates Mammals, comprises the medicine of the central nervous system dysfunction of the mankind, it is also possible to for the preparation of the medicine for exciting melatonin receptors.

Specifically; in the composition of the present invention, the amount of compound can detectably optionally exciting melatonin receptors effectively; the compound of the present invention can as treatment mankind's central nervous system (CNS) dysfunction such as somnopathy; stress reaction; seasonal affective disorder; the insomnia that the time difference causes and fatigue, insomnia, dysthymia disorders; anxiety disorder; the medicine of psychotic disease mental disorder, epilepsy, Parkinson's disease; senile dementia; to normal or that pathological seaility is relevant various obstacles, migraine, the loss of memory or alzheimer's disease.

The compound of the present invention can be applied to, but is never limited to, it may also be useful to patient's administration is prevented by the compound of the present invention or the significant quantity of composition, treats or alleviates Mammals, comprises the central nervous system dysfunction disease of the mankind. The central nervous system dysfunction disease of the described mankind, includes, but are not limited to, somnopathy, stress reaction further; dysthymia disorders, anxiety disorder, seasonal affective disorder, the insomnia that the time difference causes and fatigue; schizophrenia, faints from fear, panic attack; melancholia, insomnia, psychotic disease mental disorder; epilepsy, Parkinson's disease, senile dementia; to normal or that pathological seaility is relevant various obstacles, migraine, the loss of memory or alzheimer's disease etc.

The compound of the present invention and pharmaceutical composition, except human treatment is useful, also can be applicable to veterinary treatment pet, the Mammals in the animal of introduced variety and the animal on farm. The example of other animal comprises horse, dog and cat. At this, the compound of the present invention comprises its pharmaceutically acceptable derivates.

Combination therapy

The compounds of this invention can as independent active agent administration, or can with other therapeutic agent administration, comprise and there is same or similar therapeutic activity and other compound safe and efficient is defined as this type of Combined Preparation.

On the one hand, the present invention provides treatment, prevents or improve the method for disease or illness, comprises the present invention that comprises giving safe and effective amount and comes into the open the combination medicine of compound and one or more therapeutic activity agent. In one embodiment, combination medicine comprises 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: sedative hypnotic drug, antipsychotics, antiepileptic drug, antidepressant drug, antihistamine drug, anti-Parkinson's disease class medicine, GABA receptor stimulant and/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, as the medicine of oxidase inhibitor, as adenosine A₁/A₂The medicine of receptor stimulant and the medicine as melatonin receptors agonist.

In another embodiment, the medicine of other described treatment central nervous system dysfunction is midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), nitrazepam (nitrazepam), clonazepam (clonazepam), temazepam (temazepam), flunitrazepam (flunitrazepam), oxazepam (oxazepam), zolpidem (zolpidem), Zaleplone (zaleplon), Zopiclone (zopielone), Lunesta (eszopiclone), general grand (indiplon) tiagabine (tiagabine) in English ground, Gaboxadol (gaboxadol), clomipramine (clomipramine), doxepin (doxepin) paroxetine (paroxetine), Sertraline (sertraline), mirtazapine (mirtazapine), Chloral Hydrate (chloralhydrate), haloperidol (haloperidol), chlorpromazine (chlorpromazine), Carbamzepine (carbamazepine), promethazine (promethazine), lorazepam (lorazepam), hydroxyzine (hydroxyzine), acetylsalicylic acid (aspirin), diphenhydramine (diphenhydramine), Toldrin (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), Agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), Desipramine (desipramine), mirtazapine (mirtazapine), fluoxetine (fluoxetine), trazodone (trazodone), duloxetine (duloxetine), fluvoxamine (fluvoxamine), vilazodone (vilazodone), dapoxetine (dapoxetine), Fa Mokexiting (femoxetine), chlorimipramine (clomipramine), citalopram (citalopram), S-escitalopram (escitalopram), paroxetine (paroxetine), Quetiapine (quetiapine), leoponex (clozapine), imipramine (imipramine), nabilone (nabilone), P-3693A (doxepin), gabapentin (gabapentin), pramipexole (pramipexole), melatonin (circadin), zeisin (chlordiazepoxide), trilafon (perphenazine), suvorexant, XuezangGuben or their arbitrary combination.

On the other hand, the present invention provides and comprises the compounds of this invention and the product of other therapeutical agent of at least one, can be prepared in the treatment simultaneously, the combination used respectively or sequentially. In one embodiment, treatment is the treatment of the disease for relevant to melatonin receptors or symptom. The product that combining preparation provides comprises the composition being present in same pharmaceutical composition to comprise come into the open compound and other treatment agent herein, or come into the open herein compound and the other treatment agent that exist in different forms, such as, and medicine box.

On the other hand, the present invention provides a kind of pharmaceutical composition comprising come into the open compound and another or multiple therapeutical agent herein. In one embodiment, pharmaceutical composition can comprise pharmaceutically acceptable vehicle, carrier, adjuvant or solvent as above.

On the other hand, providing package of the present invention is containing the medicine box of the drug alone composition of two kinds or more, and wherein at least one pharmaceutical composition comprises the present invention and comes into the open compound. In one embodiment, medicine box comprises the instrument, such as container, the bottle separated or the paper tinsel box separated that keep separately described composition. The example of this kind of medicine box is Blister Package, and it is generally used for package troche, capsule etc.

Present invention also offers the compounds of this invention purposes in pivot nervous system dysfunction in the treatment, wherein patient previously (such as in 24 hours) treated with other treatment agent. Present invention also offers the other treatment agent purposes in pivot nervous system dysfunction in the treatment, wherein patient previously (such as in 24 hours) treated with the compounds of this invention.

Compound of coming into the open herein as single-activity component applied or as such as adjuvant, can be used with other medicine jointly. Other medicine described comprises, sedative hypnotic drug, antipsychotics, antiepileptic drug, antidepressant drug, antihistamine drug, anti-Parkinson's disease class medicine, GABA receptor stimulant and/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, as the medicine of oxidase inhibitor, as adenosine A₁/A₂The medicine of receptor stimulant and the medicine as melatonin receptors agonist.

Above-described associating can conveniently be prepared into pharmaceutical composition and use, and therefore, the pharmaceutical composition comprising combination defined above and pharmaceutically acceptable vehicle or carrier represents another aspect of the present invention.

Each compound of these associatings can with alone or in combination pharmaceutical dosage forms order of administration or administration simultaneously. In an embodiment, each compound component is the pharmaceutical dosage forms that combines administration simultaneously. The applicable dosage of known treatment agent is easy to the technician by this area and is understood.

Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, comprises combining of compound disclosed by the invention and other treatment promoting agent.

Above-described, it is possible to come into the open the compound that compound combinationally uses with the present invention, it is possible to by those skilled in the art, according to the method preparation described in above-mentioned document and administration.

Methods for the treatment of

In one embodiment, methods for the treatment of disclosed by the invention comprises and patient in need gives the compounds of this invention of safe and effective amount or comprises the pharmaceutical composition of the compounds of this invention. Each embodiment disclosed by the invention comprises the present invention by patient in need gives 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, is mentioned the method for disease above treating.

In one embodiment, the present invention is come into the open compound or comprise the come into the open pharmaceutical composition of compound of the present invention and can carry out administration by any applicable route of administration, comprises Formulations for systemic administration and topical. Formulations for systemic administration comprises oral administration, parenteral admin, transdermal administration and rectal administration. Typical parenteral admin refers to by injection or administered by infusion, comprises intravenously, with subcutaneous injection or administered by infusion in flesh. Topical comprises and is applied in skin and eye, ear, intravaginal, sucks and intranasal administration. In one embodiment, the present invention is come into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention can be oral administration. In another embodiment, the present invention is come into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention can be inhalation. Also having in an embodiment, the present invention is come into the open compound or to comprise the present invention's compound of coming into the open can be intranasal administration.

In one embodiment, the present invention come into the open compound or comprise the present invention come into the open compound pharmaceutical composition can once daily, or according to dosage regimen, at the appointed time in section, at different timed interval administration several times. Such as, every day is administered once, twice, three times or four times. In one embodiment, it is administered once every day. In yet another embodiment, it is administered twice every day. Can administration until reach the result for the treatment of wanted or maintain the result for the treatment of wanted indefinitely. The present invention is come into the open compound or comprise the come into the open suitable dosage regimen of pharmaceutical composition of compound of the present invention and depend on and such as dilute the pharmacokinetic property of this compound, and distribution and transformation period, these can by determination of technical staff. In addition, the present invention is come into the open compound or comprise the present invention and come into the open the suitable dosage regimen of pharmaceutical composition of compound, comprise the time length implementing the program, depend on the disease being treated, the severity being treated disease, is treated age and the physical appearance of patient, is treated the medical history of patient, the simultaneously character of therapy, it is intended to the factor within the scope of technician's knowledge and experience such as result for the treatment of. Such technician it should also be understood that for individual patient to the reaction of dosage regimen, or along with time lapse individual patient need change time, the dosage regimen adjusting matters can be required.

The present invention come into the open compound can with one or more other therapeutical agents simultaneously, or before it or administration afterwards. The compounds of this invention can distinguish administration with other treatment agent by identical or different way of administration, or with it with pharmaceutical compositions administration.

For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be containing the 1-1000mg that has an appointment, or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or the unit dosage form of about 1-50mg activeconstituents. The treatment significant quantity of compound, pharmaceutical composition or its combination depends on individual species, body weight, age and individual instances, the disease being treated (disorder) or disease (disease) or its severity. Possessing the doctor of conventional technical ability, clinicist or animal doctor can easily determine prevention, treat or suppress the significant quantity of required each activeconstituents in disease (disorder) or disease (disease) development process.

Above quoted dosage characteristic at the favourable Mammals (such as mouse, rat, dog, monkey) of employing or its isolated organ, confirms in the external and in vivo test of tissue and sample. The present invention comes into the open compound with solution, and such as aqueous solution form uses in vitro, it is also possible in such as suspension or the aqueous solution form intestines in body, parenteral, and especially intravenously uses.

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

In addition, compound disclosed by the invention can medicine form administration in the past. In the present invention, the present invention comes into the open " the front medicine " of compound when being to patient's administration, finally can discharge the present invention in body and come into the open the functional derivatives of compound. When giving compound disclosed by the invention with prodrug forms, those skilled in the art can implement the one in following manner and more than: (a) changes onset time in the body of compound; Acting duration in the body of (b) change compound; C () changes the interior conveying of body or the distribution of compound; Solubleness in the body of (d) change compound; And (e) overcomes side effect or other difficult points that compound faces. For the preparation of the typical functional derivatives of front medicine, it is included in body chemically or the variant of compound of mode cracking of enzyme. Comprising and prepare phosphoric acid salt, acid amides, ester, monothioester, these variants of carbonate and carbaminate are well-known to those skilled in the art.

The general synthetic method of the compounds of this invention

Generally, the compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein the definition of substituting group is as shown in formula I. Reaction scheme and embodiment below are used for the further content illustrating the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing other compounds of many present invention suitablely, and other method for the preparation of the compound of the present invention is all contemplated within the scope of the present invention. Such as; the synthesis of the compound according to those non-illustrations of the present invention can successfully be completed by modifying method by the technician of art; as group is disturbed in suitable protection, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines. In addition, reaction disclosed in this invention or known reaction conditions are applicable to the preparation of other compounds of the present invention also generally acknowledgedly.

The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature. Reagent is bought in goods providers such as Ling Kai medicine, AldrichChemicalCompany, Inc., ArcoChemicalCompany and AlfaChemicalCompany, it may also be useful to time all through being further purified, unless other aspects show. General reagent is from Xi Long chemical plant, Shantou, and Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Qingdao Teng Long chemical reagent company limited, and Qingdao Haiyang chemical plant are bought and obtained.

Anhydrous tetrahydro furan is through sodium Metal 99.5 backflow drying and obtains. Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain. Ethyl acetate, DMAC N,N' dimethyl acetamide and sherwood oil are through the prior Dryly use of anhydrous sodium sulphate.

Hereinafter reacting is generally overlap a drying tube (unless showing in other) under nitrogen or argon gas positive pressure or on anhydrous solvent, the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe. Glassware is all dried.

Chromatographic column uses silicagel column. Silica gel (300-400 order) is purchased from Qingdao Haiyang chemical plant. NMR (Nuclear Magnetic Resonance) spectrum is with CDC1₃Or DMSO-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiplet occurs time, abbreviation below will be used: s (singlet, single peak), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, two triplet). Coupling constant, represents with hertz (Hz).

The condition determination of Algorithm (MS) data is: (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent6120 level Four bar HPLC-M. Moving phase: 5%-95% is (containing the CH of 0.1% formic acid₃CN) (containing the H of 0.1% formic acid₂O) ratio in), adopt electron spray ionisation (ESI), under 210nm/254nm, detect with UV.

Use Agilent1260pre-HPLC or Caleseppump250pre-HPLC (pillar model: NOVASEP50/80mmDAC) of pure compound, detects at 210nm/254nm UV.

The use writing a Chinese character in simplified form word below runs through the present invention:

HOAc acetic acid

MeCN,CH₃CN acetonitrile

Cl₃C₂OCl trichoroacetic chloride

CHCl₃Chloroform

CDCl₃Deuterochloroform

DMSO dimethyl sulfoxide (DMSO)

DMSO-d₆Deuterated dimethyl sulfoxide

DMFN, dinethylformamide

POCl₃Phosphorus oxychloride

C₄H₁₀F₃NS diethylin sulfur trifluoride

ClSO₂OH chlorsulfonic acid

EtOAc/EA ethyl acetate

Et-CH₃CH₂-/ethyl

HCl salt acid

MgSO₄Magnesium sulfate

MgCl₂Magnesium chloride

MeOH,CH₃OH methyl alcohol

HCHO formaldehyde

CH₂Cl₂, DCM methylene dichloride

ML, m milliliter

PE sherwood oil (60-90 DEG C)

Na₂CO₃Sodium carbonate

NaHCO₃Sodium bicarbonate

KOH potassium hydroxide

RT room temperature

Rt retention time

NaBH₃CN sodium cyanoborohydride

NaCl sodium-chlor

NaH sodium hydride

Na₂SO₄Sodium sulfate

THF tetrahydrofuran (THF)

DDQ DDQ

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

Synthetic method 1

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

Formula (1) shown in compound and cyanoacetic acid be obtained by reacting formula (2) shown in compound. Formula (2) shown in compound formula dehydroaromatizationof under the effect of oxygenant (DDQ) obtain formula (3) shown in compound, formula (3) shown in compound obtain under the effect of alkali formula (4) shown in compound, formula (4) shown in compound reduction under the effect of reductive agent (such as borine) obtain formula (5) shown in compound, formula (5) shown in compound and excess acetyl chloride obtain formula (6) product. Reaction process is as follows:

Embodiment

Embodiment 1N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) ethanamide

Step 1) synthesis of 2-(7-methoxyl group-3,4-dihydronaphthalene-1-base) acetonitrile

Just 7-methoxyl group-3,4-dihydronaphthalene-1 (2H)-one (5.00g, 28.37mmol), 2-cyanoacetic acid (3.62g, 42.56mmol), enanthic acid (1.0mg, 7.09mmol) in toluene, in (30mL), under 140 DEG C of oil baths, react 48h with benzylamine (0.78mL, 7.09mmol), stopped reaction, is cooled to 25 DEG C. Wash with saturated sodium bicarbonate solution (100mL) and saturated aqueous common salt (40mL) successively, organic phase anhydrous sodium sulfate drying after separatory. Filtering, filtrate decompression is spin-dried for, and it is yellow solid (5.44g, 96.3%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=50/1) obtains title compound.

MS(ESI,pos.ion)m/z:200.2[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 7.12 (d, J=8.4Hz, 1H), 6.77 (dd, J=8.4,2.4Hz, 1H), 6.69 (d, J=2.4Hz, 1H), 6.31 (t, J=4.8Hz, 1H), 3.83 (s, 3H), 3.48 (d, J=1.8Hz, 2H), 2.75 (t, J=7.8Hz, 2H), 2.37-2.34 (m, 2H).

Step 2) synthesis of 2-(7-methoxynaphthalene-1-base) acetonitrile

By 2-(7-methoxyl group-3,4-dihydronaphthalene-1-base) acetonitrile (5.44g, 27.30mmol) with DDQ (7.44g, 32.76mmol) react at 25 DEG C in methylene dichloride (30mL) and spend the night, add 60mL diluted ethyl acetate, filtering, filtrate is washed with saturated sodium bicarbonate solution (40mL) and saturated aqueous common salt (40mL) successively, organic phase anhydrous sodium sulfate drying after separatory. Filtering, filtrate decompression is spin-dried for, and it is yellow solid (3.54g, 65.8%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=60/1) obtains title compound.

MS(ESI,pos.ion)m/z:198.1[M+1]⁺;

1HNMR (600MHz, CDCl3) �� 7.81 (d, J=9.0Hz, 1H), 7.79 (d, J=7.8Hz, 1H), 7.55 (d, J=7.2Hz, 1H), 7.34 (t, J=7.8Hz, 1H), 7.22 (dd, J=9.0,2.4Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 4.08 (s, 2H), 3.97 (s, 3H).

Step 3) synthesis of 2-(7-methoxynaphthalene-1-base)-2-methyl propionitrile

At-30 DEG C, by 2-(7-methoxynaphthalene-1-base) acetonitrile (2.00g, 10.14mmol) with sodium hydride sodium hydride (60%, 2.03g, 50.70mmol) join in 10mL dry DMF, after stirring reaction 1h, add methyl iodide (5.05mL, 81.12mmol), slowly it is warming up to 65 DEG C of reactions to spend the night. Stopped reaction, adds 30mL saturated aqueous common salt cancellation, is extracted with ethyl acetate (30mL �� 3), merges organic phase anhydrous sodium sulfate drying. Filtering, filtrate decompression is spin-dried for, and it is yellow solid (1.83g, 80.3%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=50/1) obtains title compound.

MS(ESI,pos.ion)m/z:226.2[M+1]⁺;

¹HNMR(400MHz,CDCl₃) �� 7.85 (d, J=2.4Hz, 1H), 7.83 (d, J=9.2Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.48 (dd, J=7.6,0.8Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.24 (dd, J=9.2,2.4Hz, 1H), 4.03 (s, 3H), 2.00 (s, 6H).

Step 4) synthesis of 2-(7-methoxynaphthalene-1-base)-2-methyl-prop-1-amine

By 2-(7-methoxynaphthalene-1-base)-2-methyl propionitrile (159mg at 0 DEG C, 706 ��m of ol) join in tetrahydrofuran (THF) (10.0mL), then borine-tetrahydrofuran (THF) (1.0M, 3.9mL, 3.90mmol) is slowly added. React after 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 it is white solid (109mg, 67.2%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:230.1[M+1]⁺;

¹HNMR(400MHz,CDCl₃) �� 7.80 (d, J=8.8Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.46 (dd, J=7.6,0.8Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 7.17 (dd, J=8.8,2.4Hz, 1H), 3.95 (s, 3H), 3.30 (s, 2H), 1.62 (s, 6H).

Step 5) synthesis of N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) ethanamide

By 2-(7-first chomene-1-base)-2-methyl-prop-1-amine (195mg, 850 ��m of ol) and triethylamine (240 �� L, 1.70mmol) join in methylene dichloride (15mL), 0 DEG C of lower slowly dripping of low temperature bath adds Acetyl Chloride 98Min. (90 �� L, 1.28mmol), after dripping, react 3 hours at being transferred to 25 DEG C, stopped reaction. Add 30mL methylene dichloride, with saturated nacl aqueous solution (60mL) washing, organic phase anhydrous sodium sulfate drying after separatory. Filtering, filtrate decompression is spin-dried for, and it is white solid (210mg, 90.9%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=2/1) obtains title compound.

MS(ESI,pos.ion)m/z:272.2[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 7.83 (d, J=1.8Hz, 1H), 7.77 (d, J=9.0Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.44 (d, J=7.8Hz, 1H), 7.27 (t, J=7.8Hz, 1H), 7.15 (dd, J=9.0,2.4Hz, 1H), 3.98 (s, 3H), 3.89 (d, J=6.0Hz, 2H), 1.87 (s, 3H), 1.59 (s, 6H);

¹³CNMR(150MHz,CDCl₃)��170.7,156.8,140.0,132.4,131.1,130.4,128.1,125.7,123.0,117.4,105.8,55.5,48.6,40.5,27.6,23.3��

Embodiment 2N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) ethanamide

Step 1) synthesis of 2-(7-fluoro-3,4-dihydronaphthalene-1-base) acetonitrile

This step title compound prepares with reference to the method described by embodiment 1 step 1, by 7-fluoro-3,4-dihydronaphthalene-1 (2H)-one (2.00g, 12.18mmol), 2-cyanoacetic acid (1.55g, 18.27mmol), enanthic acid (0.43mL, 3.05mmol) with benzylamine (0.33mL, 3.05mmol) reaction preparation in (30mL) in toluene, crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), and it is yellow solid (1.03g, 45.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:188.2[M+1]⁺;

1HNMR(400MHz,CDCl₃) �� 7.13 (dd, J=8.4,6.0Hz, 1H), 6.89 (td, J=8.4,2.8Hz, 1H), 6.81 (dd, J=9.6,2.8Hz, 1H), 6.33 (t, J=4.4Hz, 1H), 3.45 (dd, J=3.6,1.6Hz, 2H), 2.76 (t, J=8.0Hz, 2H), 2.36 (m, 2H).

Step 2) synthesis of 2-(7-fluorine naphthalene-1-base) acetonitrile

This step title compound prepares with reference to the method described by embodiment 1 step 2, by 2-(7-fluoro-3,4-dihydronaphthalene-1-base) (1.03g, 5.50mmol) with DDQ (1.50g, 6.60mmol) 1, reaction preparation in 2-ethylene dichloride (30mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=60/1), it is yellow solid (411mg, 40.3%) that concentrate drying obtains title compound.¹HNMR(400MHz,CDCl₃) �� 7.91 (dd, J=8.8,5.6Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.63 (d, J=7.2Hz, 1H), 7.50-7.41 (m, 2H), 7.33 (td, J=8.8,2.4Hz, 1H), 4.06 (s, 2H).

Step 3) synthesis of 2-(7-fluorine naphthalene-1-base)-2-methyl propionitrile

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 2-(7-fluorine naphthalene-1-base) acetonitrile (600mg, 3.24mmol), methyl iodide (1.61mL, 25.92mmol) with sodium hydride (60%, 1.61mL, 25.92mmol) reaction preparation in DMF (30mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), it is yellow solid (656mg, 94.9%) that concentrate drying obtains title compound.

¹HNMR(600MHz,CDCl₃) �� 8.17 (d, J=12.0Hz, 1H), 7.91 (dd, J=9.0,6.6Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 7.34-7.31 (m, 1H), 1.97 (s, 6H).

Step 4) synthesis of 2-(7-fluorine naphthalene-1-base)-2-methyl-prop-1 amine

This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(7-fluorine naphthalene-1-base)-2-methyl propionitrile (656mg, 3.08mmol) with borine-tetrahydrofuran (THF) (1.0M, 16.9mL, 16.90mmol) reaction preparation, crude product is through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), and it is white solid (537mg, 80.3%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:218.2[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 8.37 (dd, J=9.6,5.4Hz, 1H), 7.70-7.63 (m, 2H), 7.48 (dd, J=9.6,2.4Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=1.8Hz, 1H), 3.25 (s, 2H), 1.58 (s, 6H).

Step 5) synthesis of N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) ethanamide

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(7-fluorine naphthalene-1-base)-2-methyl-prop-1-amine (336mg, 1.55mol), triethylamine (430 �� L, 3.09mmol) with Acetyl Chloride 98Min. (160 �� L, 2.32mmol) reaction preparation in methylene dichloride (15mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is white solid (351mg, 87.5%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:260.1[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 8.08 (d, J=13.2Hz, 1H), 7.83 (t, J=7.8Hz, 1H), 7.71 (d, J=7.8Hz, 1H), 7.47 (d, J=7.2Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 7.23 (t, J=7.8Hz, 1H), 3.81 (d, J=5.4Hz, 2H), 1.83 (s, 3H), 1.55 (s, 6H);

¹³CNMR(150MHz,CDCl₃) �� 170.8,159.8 (d, J=243.0Hz), 141.04 (d, J=5.4Hz), 132.0 (d, J=4.4), 132.0 (d, J=5.1), 128.2,126.2,124.5 (d, J=2.3Hz), 115.3 (d, J=24.9Hz), 110.3 (d, J=22.7Hz), 48.8,40.5,27.8,23.1.

Embodiment 3N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) propionic acid amide

Step 1) synthesis of N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) propionic acid amide

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(7-first chomene-1-base)-2-methyl-prop-1-amine (195mg, 850 ��m of ol), triethylamine (240 �� L, 1.70mmol) with propionyl chloride (90 �� L, 1.28mmol) reaction preparation in methylene dichloride (15mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is white solid (189mg, 78.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:286.3[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 7.81 (d, J=1.8Hz, 1H), 7.77 (d, J=9.0Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.41 (d, J=7.8Hz, 1H), 7.30 (t, J=7.8Hz, 1H), 7.15 (dd, J=9.0,2.4Hz, 1H), 3.98 (s, 3H), 3.79 (d, J=5.4Hz, 2H), 2.27 (q, J=6.0Hz, 2H), 1.55 (s, 6H), 1.02 (t, J=6.0Hz, 3H).

Embodiment 4N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) butyramide

Step 1) synthesis of N-(2-(7-methoxynaphthalene-1-base)-2-methyl-propyl) butyramide

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(7-first chomene-1-base)-2-methyl-prop-1-amine (195mg, 850 ��m of ol), triethylamine (240 �� L, 1.70mmol) with n-butyryl chloride (90 �� L, 1.28mmol) reaction preparation in methylene dichloride (15mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is white solid (198mg, 81.8%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:300.1[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 7.82 (d, J=1.8Hz, 1H), 7.77 (d, J=9.0Hz, 1H), 7.64 (d, J=8.4Hz, 1H), 7.41 (d, J=7.8Hz, 1H), 7.30 (t, J=7.8Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 3.99 (s, 3H), 3.79 (d, J=5.4Hz, 2H), 2.35 (t, J=6.0Hz, 2H), 1.54 (s, 6H), 1.31 (m, 2H), 0.91 (t, J=6.0Hz, 3H).

Embodiment 5N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) propionic acid amide

Step 1) synthesis of N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) propionic acid amide

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(7-fluorine naphthalene-1-base)-2-methyl-prop-1-amine (336mg, 1.55mol), triethylamine (430 �� L, 3.09mmol) with propionyl chloride (160 �� L, 2.32mmol) reaction preparation in methylene dichloride (15mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is white solid (360mg, 85.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:274.3[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 8.13 (d, J=13.2Hz, 1H), 7.86 (t, J=7.8Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.47 (d, J=7.2Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 7.23 (t, J=7.8Hz, 1H), 3.81 (d, J=5.4Hz, 2H), 2.28 (q, J=6.0Hz, 2H), 1.55 (s, 6H), 1.05 (t, J=6.0Hz, 3H).

Embodiment 6N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) butyramide

Step 1) synthesis of N-(2-(7-fluorine naphthalene-1-base)-2-methyl-propyl) butyramide

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(7-fluorine naphthalene-1-base)-2-methyl-prop-1-amine (336mg, 1.55mol), triethylamine (430 �� L, 3.09mmol) with n-butyryl chloride (160 �� L, 2.32mmol) reaction preparation in methylene dichloride (15mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is white solid (334mg, 75.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:288.1[M+1]⁺;

¹HNMR(600MHz,CDCl₃) �� 8.06 (d, J=13.2Hz, 1H), 7.81 (t, J=7.8Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.47 (d, J=7.2Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 3.81 (d, J=5.4Hz, 2H), 2.34 (t, J=5.4Hz, 2H), 1.54 (s, 6H), 1.32 (m, 2H), 0.89 (t, J=5.4Hz, 3H).

Compound 3-7,9-13 obtains according to the synthesis method side of embodiment 1-6:

Biological test

The LC/MS/MS system analyzed comprises Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate automatic sampler, post thermostat container, AgilentG6430 tri-grades of level Four bar mass spectrographs in charged spray ionization (ESI) source. Quantitative analysis carries out under MRM pattern, and the parameter of MRM conversion is as shown in table A:

Table A

Many reaction detection scan	490.2��383.1
		Cracked voltage	230V
Capillary voltage	55V 29 -->
		Dryer temperature	350��
Spraying gun	40psi
		Moisture eliminator flow velocity	10L/min

Analyzing and use AgilentXDB-C18,2.1x30mm, 3.5 ��Ms of posts, inject 5 �� L sample. Analysis condition: moving phase is the aqueous formic acid (A) of 0.1% and the formic acid methanol solution (B) of 0.1%. Flow velocity is 0.4mL/min. Eluent gradient is as shown in tableb:

Table B

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	stop

In addition, also have Agilent6330 series LC/MS/MS spectrograph for what analyze, it is equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314CUV detector; LC/MS/MS spectrograph adopts ESI radioactive source. Each analysis thing is carried out use reference liquid suitable positively charged ion models treated and MRM conversion carries out best analysis. Using CapcellMP-C18 post during analyzing, specification is: 100x4.6mmI.D., 5 ��Ms (Phenomenex, Torrance, California, USA). Moving phase is 5mM ammonium acetate, 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; Post temperature remains on room temperature; Inject 20 �� L sample.

Embodiment A melatonin MT ₁ Receptors bind avidity is tested

Test method

Using radioligand combining method, assessing compound is to the avidity of the humanization MT1 acceptor of Chinese hamster ovary celI transfection. Under 22 DEG C of conditions, to cell membrane homogenate albumen (64 �� g), 0.01nM [¹²⁵I] iodomelatonin and damping fluid (50mMTris-HCl (pH7.4), 5mMMgCl₂And 1%BSA) in the mixed system that formed, add or do not add test compounds, hatch 60 minutes altogether. Standard reference compound is melatonin, in the mixed system of above-mentioned condition, adds 1 ��M of melatonin, for recording non-specific binding value.

Sample after hatching is with 96 like cell collector (Unifilter, Packard) under vacuum by the glass fiber filter (GF/B of pre-dipped 0.3%PEI, Packard), and to use ice-cold 50mMTris-HCl repeatedly to rinse several time. Dry filter membrane, in scintillometer (Topcount, Packard), calculates the radioactivity of residual with scintillation solution (Microscint0, Packard). Experimental result represents with the suppression per-cent relative to control group radioligand specific binding.

Standard reference compound is melatonin, by the experimental data of the melatonin of series concentration, obtains competitive curve.

Data analysis

Using radioligand combining method, assessing compound is to the humanization MT of Chinese hamster ovary celI transfection₁The avidity of acceptor. Test-compound at least tests three times, and data measure IC through Hill equation curve fitting method by competition curve nonlinear regression analysis₅₀Value and Hill coefficient, then calculate by ChengPrusoff equation, calculating K i value.

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

The compound that table 1 embodiment of the present invention provides is to the humanization MT of Chinese hamster ovary celI transfection₁The binding affinity experimental result of acceptor

Embodiment number	Ki(nM)	Embodiment number	Ki(nM)
				Embodiment 1	A	Embodiment 2	A
Embodiment 3	A	Embodiment 4	A
				Embodiment 5	B	Embodiment 6	B

A:0.1��1nM, B:1��10nM, C: > 10nM.

In the description of this specification sheets, reference term " embodiment ", " some embodiments ", " example ", the description of " concrete example " or " some examples " etc. means in conjunction with the concrete feature that this embodiment or example describe, in at least one embodiment that structure, material or feature are contained in the present invention or example. In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example. And, the concrete feature of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner. In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can be carried out combining and combining by the technician of this area.

Although above it has been shown and described that embodiments of the invention, it will be appreciated that above-described embodiment is exemplary, limitation of the present invention can not be interpreted as, above-described embodiment can be changed by the those of ordinary skill of this area within the scope of the invention, amendment, replaces and modification.

Claims (5)

1. a compound, it has following structure:

Or its tautomer or pharmacy acceptable salt.

2. a pharmaceutical composition, it comprises compound according to claim 1 and pharmaceutically acceptable vehicle.

3. pharmaceutical composition according to claim 2, it comprises the medicine of other treatment central nervous system dysfunction further, the medicine of other described treatment central nervous system dysfunction is sedative hypnotic drug, antipsychotics, antiepileptic drug, antidepressant drug, antihistamine drug, anti-Parkinson's disease class medicine, GABA receptor stimulant and/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, as the medicine of oxidase inhibitor, as adenosine A₁/A₂The medicine of receptor stimulant and as the medicine of melatonin receptors agonist or their arbitrary combination.

4. pharmaceutical composition according to claim 3, the medicine of other described treatment central nervous system dysfunction is midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), nitrazepam (nitrazepam), clonazepam (clonazepam), temazepam (temazepam), flunitrazepam (flunitrazepam), oxazepam (oxazepam), zolpidem (zolpidem), Zaleplone (zaleplon), Zopiclone (zopielone), Lunesta (eszopiclone), general grand (indiplon) tiagabine (tiagabine) in English ground, Gaboxadol (gaboxadol), clomipramine (clomipramine), doxepin (doxepin) paroxetine (paroxetine), Sertraline (sertraline), mirtazapine (mirtazapine), Chloral Hydrate (chloralhydrate), haloperidol (haloperidol), chlorpromazine (chlorpromazine), Carbamzepine (carbamazepine), promethazine (promethazine), lorazepam (lorazepam), hydroxyzine (hydroxyzine), acetylsalicylic acid (aspirin), diphenhydramine (diphenhydramine), Toldrin (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), Agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), Desipramine (desipramine), mirtazapine (mirtazapine), fluoxetine (fluoxetine), trazodone (trazodone), duloxetine (duloxetine), fluvoxamine (fluvoxamine), vilazodone (vilazodone), dapoxetine (dapoxetine), Fa Mokexiting (femoxetine), chlorimipramine (clomipramine), citalopram (citalopram), S-escitalopram (escitalopram), paroxetine (paroxetine), Quetiapine (quetiapine), leoponex (clozapine), imipramine (imipramine), nabilone (nabilone), P-3693A (doxepin), gabapentin (gabapentin), pramipexole (pramipexole), zeisin (chlordiazepoxide), trilafon (perphenazine), suvorexant or their arbitrary combination.

5. compound described in claim 1 or the pharmaceutical composition described in claim 2-4 any one are in the purposes prepared in medicine, described medicine is used for prevention, treat or alleviate the relevant central nervous system dysfunction of exciting melatonin receptors, described central nervous system dysfunction is: somnopathy, stress reaction, dysthymia disorders, anxiety disorder, seasonal affective disorder, the insomnia that the time difference causes and fatigue, schizophrenia, faints from fear, panic attack, melancholia, epilepsy, Parkinson's disease, migraine, the loss of memory or alzheimer's disease.