CN107759620A - Octahydro pyrrolo- [3,4 c] azole derivatives and its application method and purposes - Google Patents

Octahydro pyrrolo- [3,4 c] azole derivatives and its application method and purposes Download PDF

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CN107759620A
CN107759620A CN201610673435.1A CN201610673435A CN107759620A CN 107759620 A CN107759620 A CN 107759620A CN 201610673435 A CN201610673435 A CN 201610673435A CN 107759620 A CN107759620 A CN 107759620A
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compound
alkyl
disease
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CN107759620B (en
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金传飞
张英俊
薛亚萍
劳锦花
聂飚
许娟
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Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

Pharmaceutical composition the present invention relates to octahydro pyrrolo- [3,4 c] azole derivatives and its application method and purposes, compound of the present invention and comprising the compound is used for antagonism orexin receptor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition, and they are being treated or prevented and the purposes in orexin receptor relevant disease.

Description

Octahydro pyrrolo- [3,4-c] azole derivatives and its application method and purposes
Invention field
The invention belongs to technical field of pharmaceuticals, and in particular to (octahydro pyrrolo- [3, the 4-c] pyrroles -2 of one kind substitution (1H)-yl) phenyl ketone compound, include the pharmaceutical composition of this kind of compound, and their application method and purposes.More Specifically, compound and pharmaceutical composition of the present invention can be used as orexin receptor antagonists be used for treat, prevent or Mitigate the disease related to orexin receptor.
Background of invention
Orexin (orexin) is also referred to as inferior colliculus krinin, appetite peptide, and it includes orexin-A and orexin B (or inferior colliculus Krinin -1 and inferior colliculus krinin -2), it is a kind of neuropeptide secreted by hypothalamus, its main physiological action has：1. regulation Ingest, orexin can be obviously promoted feed, and be reacted in dose-dependant, and have activated the neuron of regulation feed；2. participate in The regulation of energetic supersession, orexin can dramatically increase metabolic rate；3. participating in the regulation of Sleep-Wake, orexin can suppress quick Eye Movement Sleep, extend the awakening time, block the effect of orexin to promote to sleep；4. participate in endocrine metabolic diseases, orexin It is endocrine on pituitrin to influence clearly；It is 5. related to remuneration sense, learning and memory；6. promote gastric acid secretion；7. promote Drinking-water increases；8. raise blood pressure；9. played an important role in reward system and drug habit mechanism, wait (Piper et al., The novel brain neuropeptide,orexin-A,modulates the sleep-wake cycle of rats.Eur.J.Neuroscience,2000,12(2),726-730；and Sakurai,T.,et al.,The neural circuit of orexin(hypocretin):Maintaining sleep and wakefulness.Nature Review Neuroscience,2007,8:171181).And in terms of biologic importance, orexin-A is more important than orexin B, for example, Orexin-A can strengthen the feeding behaviour after Animal nutrition is limited；Intracerebroventricular orexin-A can increase rat activation level；Appetite Plain A to locus coeruleus nuclear activity be adjusted to pay attention to and the cognitive process such as remember provide important support；Orexin-A can also improve β Memory disorders caused by amyloid；Orexin-A has improvement result to the memory disorders caused by sleep deprivation；Orexin-A It is relevant with the sleep-disorder of some brain injury Diseases；And orexin-A acceptor can adjust relapsing for ***e.
Orexin produces physiological effect by acting on orexin receptor (orexin receptor, OXR).Orexin Acceptor is a kind of G- G-protein linked receptors, has two types, is referred to as OX1Acceptor and OX2Acceptor, wherein OX1Acceptor is to appetite Plain A has selectively, and OX2Acceptor be for orexin-A and orexin B non-selective receptor (Sakurai T.et al., Orexins and orexin receptors:a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573- 585)。OX1Acceptor and OX2Acceptor is almost existed only in brain tissue, and is optionally expressed in brain, wherein OX1Acceptor with High Cell Density And High Expression is in locus coeruleus (locus coeruleus), and it is the nuclei of origin of noradrenergic neuron, and OX2Acceptor With High Cell Density And High Expression in nodular nipple nucleus, it is the nuclei of origin of histaminergic neuron.OX1Acceptor and OX2The expression of both acceptors can See in nuclei of median raphe, it is the nuclei of origin of serotoninergic nerve member, and is found in ventral tegmental area, and it is dopaminergic neuron Nuclei of origin.
As can be seen here, orexin receptor has great importance on pathology, is related to related to a variety of diseases, such as sleeps Dormancy obstacle, depression, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious neuropathy, the heart Border obstacle, panic attack obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, spirit point Split disease, manic depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, op parkinson's Disease, dyskinesia, feeding desorder, headache, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, glycosuria Disease, metabolic disease, immune correlated disease, endocrine relevant disease and hypertension etc..But in the market with orexin receptor Related medicine only has the anti-insomnia medicine Su Woleisheng (Suvorexant) of United States Merck company research and development, and it is that orexin receptor is short of money Anti-agent, the medicine were also once once ratified because of safety issue by the refusal of U.S. FDA.
In consideration of it, the orexin receptor antagonists that exploitation is new, particularly selective OX1Receptor antagonist, to treatment and it is intended to The related disease of plain acceptor has great importance.The invention provides a kind of chemical combination with orexin receptor antagonistic activity Thing, compared with existing similar compound, compound of the invention is to OX1Acceptor shows selectivity, has more preferable drug effect Activity, and toxic side effect is smaller, security is higher, while also has excellent physicochemical property, medicine for property and toxicological characteristics, Therefore, possesses preferable potential applicability in clinical practice.
The content of the invention
Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by overall.Work as the disclosure of the specification With citation it is variant when, be defined by the disclosure of the specification.
The invention provides a kind of compound with orexin receptor antagonistic activity, and in particular to octahydro pyrrolo- [3, 4-c] azole derivatives, and its pharmaceutical composition, the compound and pharmaceutical composition can be used for preparing prevention or treatment with The related disease of orexin receptor.
The compounds of this invention shows good antagonistic activity to orexin receptor, and particularly the compounds of this invention is to OX1 Acceptor shows selectivity, so as to have more preferable drug effect, medicine for property and/or toxicological characteristics, such as good brain/blood plasma ratio (brain plasma ratio), good bioavilability, good metabolic stability, less toxic side effect and high security Deng.Meanwhile the good characteristic of some parameters of the compounds of this invention, such as half-life period, clearance rate, selectivity, bioavilability, chemistry The good characteristic of stability, metabolic stability, permeability of the membrane, dissolubility etc., reduction, the therapeutic index of side effect can be promoted Expansion or tolerance improvement.
Specifically：
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound or formula (I) shown in formula (I) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein：
Hy is triazolyl, the triazolyl optionally by one or more be independently selected from D, F, Cl, Br, I, oxo (=O), C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6The substituent of halogenated alkoxy or benzyl is substituted；With
R1、R2、R3、R4、R5、R6、R7、R8And R9Each there is implication as described in the present invention.
In one embodiment, compound of the present invention, it is shown in compound or formula (II) shown in formula (II) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt or preceding of compound Medicine,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8And R9Each there is implication as described in the present invention.
In one embodiment, the R in formula (I) or formula (II)1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、 Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkyl halide Base, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) ,-C (=O)-(C1-6Alkylamino) ,-O- (CH2)n- C (=O) O- (C1-6Alkyl) ,-O- (CH2)n- COOH、-O-(CH2)n- C (=O) NH2、C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；It independently is with each n 1st, 2,3 or 4.
In one embodiment, the R in formula (I) or formula (II)6、R7、R8And R9Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkane Epoxide, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6 Alkoxy) ,-C (=O)-(C1-6Alkylamino), C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl.
In one embodiment, the R in formula (I) or formula (II)1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、 Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkyl halide Base, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) ,-C (=O)-(C1-4Alkylamino) ,-O- (CH2)n- C (=O) O- (C1-4Alkyl) ,-O- (CH2)n- COOH or-O- (CH2)n- C (=O) NH2。
In one embodiment, the R in formula (I) or formula (II)6、R7、R8And R9Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkane Epoxide, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4 Alkoxy) or-C (=O)-(C1-4Alkylamino).
In one embodiment, the R in formula (I) or formula (II)1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、 Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2、-CH2OH ,-C (= O)NHCH3,-C (=O) N (CH3)2、-O-CH2- C (=O) O-CH3、-O-(CH2)2- C (=O) O-CH3、-O-CH2- C (=O) O- CH2CH3、-O-(CH2)2- C (=O) O-CH2CH3、-O-CH2- C (=O) O-CH2CH2CH3、-O-(CH2)2- C (=O) O- CH2CH2CH3、-O-CH2- C (=O) O-CH (CH3)2、-O-(CH2)2- C (=O) O-CH (CH3)2、-O-CH2-COOH、-O- (CH2)2-COOH、-O-CH2- C (=O) NH2Or-O- (CH2)2- C (=O) NH2。
In one embodiment, the R in formula (I) or formula (II)6、R7、R8And R9Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、- CF2CF3, methoxyl group, ethyoxyl, n-propyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2Or-CH2OH。
In one embodiment, compound of the present invention, its for one of following structure compound or with The stereoisomer of the compound of one of following structure, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes compound of the present invention.
In one embodiment, pharmaceutical composition of the present invention is optionally comprising pharmaceutically acceptable carrier, tax Shape agent, adjuvant or their any combination.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine is prepared, The medicine is used to preventing, treat or mitigating the disease related to orexin receptor.
In one embodiment, the disease related to orexin receptor be sleep-disorder, depression, anxiety disorder, probably Flurried disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior Not normal, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, spirit are wrong Unrest, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, feeding desorder, head Bitterly, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease Disease, endocrine relevant disease or hypertension.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine is prepared, The medicine is used for antagonism orexin receptor.
On the other hand, the side of preparation, separation and the purifying of the compound included the present invention relates to formula (I) or formula (II) Method.
Biological results show that compound provided by the invention can be used as preferable orexin receptor antagonists, especially It is alternatively property OX1Receptor antagonist.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
The content of the invention
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but is not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
There is obvious conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " embodiment " refers to one or more embodiments.
The event or situation that term " optional " or " optionally " refer to then describes can with but not necessarily occur, and this is retouched State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.
Term " optionally by ... substitute ", use can be exchanged with term " unsubstituted or by ... substitute ", i.e., The structure or group are unsubstituted or substituted by one or more substituents of the present invention, wherein the substitution meaning Taste the rational position for occurring that any chemical valence allows in given structure or group.Substituent of the present invention includes, But it is not limited to D, F, Cl, Br, I ,-N3、-CN、-NO2、-OH、-SH、-NH2, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, Alkylthio group, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
In general, term is " substituted " to represent that institute is specifically substituted to one or more of structure or group hydrogen atom Base is substituted.Unless otherwise indicated, a substituent can be substituted in each commutable rational position of group. When in given structural formula more than one position can by selected from the specific substituents of one or more substitute, then substituent It can be substituted each rational position with identical or different in structural formula.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " represents single D-atom.
Term " hetero atom " represents one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), The form of sulphur (S) and phosphorus (P) any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the hydrogen in heterocycle on nitrogen-atoms Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole bases), NH (as the NH in pyrrolidinyl) or NR are (as N- NR in substituted pyrrolidinyl).
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", expression contain 1-20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention Substitution.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 Individual carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein, the alkenyl group is optionally by one or more described in the invention Substituent is substituted, and it includes " cis " and " trans " positioning, or " E " and " Z " positioning.
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a key of carbon-to-carbon sp tri-, wherein, the alkynyl group is optionally by one or more described in the invention Substituent is substituted.
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent that the present invention describes is substituted.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), etc..
Term " haloalkyl " represents that alkyl group is substituted by one or more halogen atoms, and wherein alkyl group has Implication as described in the present invention, such example includes, but is not limited to ,-CF3、-CF2CF3、-CH2CF2CHF2Deng.It is real one Apply in scheme, " haloalkyl " is the C of lower level1-4Haloalkyl the, wherein " C1-4Haloalkyl " includes the C of fluorine substitution1-4 Alkyl, the C of chlorine substitution1-4Alkyl, the C of bromine substitution1-4Alkyl, the C of iodine substitution1-4Alkyl, etc..Specifically, the C of fluorine substitution1-4 Alkyl includes-CH2F、-CHF2、-CF3、-CH2Cl、-CHCl2、-CCl3、-CH2Br、-CHBr2、-CBr3、-CH2CH2F、- CH2CHF2、-CH2CF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-CHFCF3、-CHFCHF2、-CHFCH2F、-CH2CH2CF3、- CH2CF2CHF2Etc..The haloalkyl is optionally substituted by one or more substituents described in the invention.
Term " halogenated alkoxy " represents that alkoxy base is substituted by one or more halogen atoms, wherein alkoxy base Group has implication as described in the present invention, and such example includes, but is not limited to ,-OCF3、-OCF2CF3、-OCH2CF2CHF2 Deng.The halogenated alkoxy is optionally substituted by one or more substituents described in the invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately substituted by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.
Term " alkyl of hydroxyl substitution " represents that alkyl group is substituted by one or more oh groups, wherein alkyl base Group has implication of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl, Etc..
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, represent containing 3-12 ring carbon atom, unit price or Monocyclic, the bicyclic or three-ring system of multivalence, its middle ring can be fully saturated or comprising one or more degrees of unsaturation, but One armaticity ring can not all have.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, represent comprising 3-12 annular atom, monovalent or more The monocyclic, bicyclic or tricyclic system of valency, one or more atoms are independently replaced by hetero atom in its middle ring, the hetero atom With implication as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, but a fragrance Property ring can not all have.
Term " cycloalkyl " represents that containing 3-12 ring carbon atom monovalent or multivalence saturation is monocyclic, bicyclic or tricyclic System.
Term " aryl " represents contain 6-14 annular atom, or 6-10 annular atom, or 6 annular atoms, it is monovalent or more The monocyclic, bicyclic or tricyclic carbocyclic ring system of valency, wherein at least one ring are aromatic.Aromatic yl group is usual, but necessarily Ground is connected by the armaticity ring of aromatic yl group with parent molecule.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring " Change use.The example of aromatic yl group can include phenyl, naphthyl, anthracene, etc..The aromatic yl group is optionally one or more Substituent described in the invention is substituted.
Term " heteroaryl " represents to contain 5-14 annular atom, or 5-10 annular atom, or (the i.e. 5-6 of 5-6 annular atom Member), the monocyclic, bicyclic or tricyclic system of unit price or multivalence, wherein at least one ring is aromatic, and at least one ring includes One or more hetero atoms.Heteroaryl groups are usual, but unnecessarily pass through the armaticity ring and parent molecule of heteroaryl groups Connection.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is substituted by one or more substituents described in the invention.
The example of heteroaryl groups includes, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazole Base (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- thio biphospholes base, 1,3,4- sulphur For di azoly, 1,2,5- thio biphospholes base, pyrazinyl, cyanuro 1,3,5；Also include following bicyclic, but be not limited to these It is bicyclic：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolines Quinoline base, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1, 2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine Base, etc..
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder. For example, the Hy in the present invention can be triazolyl, on the triazolyl any attachable position can as with molecule remaining The connected tie point in part, the specific subformula comprising shown in i-1 to i-14：
Term " stereoisomer " refers to there is identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.It is different that stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometry Structure body (cis/trans) isomers, atropisomer, etc..
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,NewYork,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, represent molecule on one using prefix D and L or R and S Individual or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are to be used to linearly polarized light caused by appointed compound revolve The symbol turned, wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or three-dimensional special When different in nature, such case may occur in which.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include by proton migration the mutual inversion of phases that carries out, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to such some compounds, raw material, composition and/or formulation, and they are cured rationally Learn judge in the range of, suitable for patient tissue contacts and without excessive toxicity, excitant, allergy or with rational profit The symmetrical other problemses of benefit/Hazard ratio and complication, and effective for given application.
Term " prodrug " used in the present invention, represent a compound and be converted into vivo shown in formula (I) or (II) Compound.Such conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for precursor structure Ring.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound include hydroxyl, you can be acylated to obtain the compound of prodrug form.Other pro-drug shapes Formula includes phosphate, if these phosphate compounds are being obtained through the di on parent.It is complete on pro-drug Whole discussion may be referred to documents below：Higuchi et al.,Pro-drugs as Novel Delivery Systems, Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., this is incorporated herein by reference in 2008,51,2328-2345, every document.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through appropriate alkali Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The quaternary ammonium salt that the compound of group is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is appropriate, nontoxic that pharmaceutically acceptable salt further comprises Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, monoethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, for example, dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to trigger individual Thing or medicinal response (such as reduce or inhibitory enzyme or protein active, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevention disease etc.) the compounds of this invention amount.
The present invention relates to substituted (octahydro pyrrolo- [3,4-c] pyrroles -2 (1H)-yl) phenyl ketone compound, its pharmacy Upper acceptable salt, its pharmaceutical composition and its pharmaceutical preparation, they have orexin receptor antagonism, can be used as orexin Receptor antagonist, particularly can alternatively property OX1Receptor antagonist is used to prevent or treat the disease related to orexin receptor Disease, such as sleep-disorder, psychiatry, neurology and neurodegeneration obstacle, pharmacological dependence, habituation, cognitive disorder, motion barrier Hinder, feeding desorder, etc..
Unless otherwise mentioned, all suitable isotope changes of compound of the invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Compound shown in formula (I) or formula (II) can exist with different tautomeric forms, and all these mutual Tautomeric is included within the scope of the present invention.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.Can be by an elevated temperature using normal With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, corresponding nitrogen-containing basic material is aoxidized, or pass through In suitable solvent with cross acid reaction, such as reacted in dichloromethane, ethyl acetate or methyl acetate with peracetic acid, or Reacted in chloroform or dichloromethane with 3- chloroperoxybenzoic acids, prepare the nitrogen oxides of the compounds of this invention.
In addition, when the compound of the present invention forms hydrate or solvate, they are also included within the scope of the present invention It is interior.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within the model of the present invention In enclosing.
Compound shown in formula (I) or formula (II) can exist in a salt form.In one embodiment, the salt refers to medicine Acceptable salt on.The present invention pharmaceutically acceptable salt can use conventional chemical processes by parent compound, alkalescence or Acidic moiety synthesizes.In general, such salt can be by making the free acid form and stoichiometry of these compounds Suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate) reaction, or by making these compounds It is prepared by the suitable acid reaction of free alkali form and stoichiometry.Such reaction generally water or organic solvent or the two Mixture in carry out.Usually, in appropriate cases, it is necessary to using non-aqueous media for example ether, ethyl acetate, ethanol, Isopropanol or acetonitrile.For example " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth The list of the suitable salt of other can be found in (Wiley-VCH, Weinheim, Germany, 2002).
The compounds of this invention is alkaline, therefore is generally possible to be formed by using suitable acid treatment pharmaceutically acceptable Acid-addition salts.Suitable acid includes pharmaceutically acceptable inorganic acid and pharmaceutically acceptable organic acid.Representational medicine Acceptable acid-addition salts include hydrochloride, hydrobromate, nitrate, methyl nitrate, sulfate, disulfate, ammonia on Base sulfonate, phosphate, acetate, hydroxyl acetate, phenyl acetate salt, propionate, butyrate, isobutyrate, valerate, horse Carry out hydrochlorate, hydroxymaleic acid salt, acrylates, fumarate, malate, tartrate, citrate, salicylate, right Aminosalicylate, glycollate, lactate, enanthate, phthalate, oxalates, succinate, benzoate, neighbour Acetoxy-benzoic acid salt, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzene Formates, mandelate, tannate, formates, stearate, ascorbate, palmitate, oleate, acetonate, Pamoate, malonate, laruate, glutarate, glutamate, estolate, mesylate, sulfonate, 2- hydroxyls Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..
Any structural formula that the present invention provides, which is also intended to, represents these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or more Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In radio isotope be present, such as3H、14C and18F those compounds, or non radioactive isotope wherein be present, such as2H and13C.The compound of such isotope enrichment can be used for metabolism research (to use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.18The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound shown in the formula (I) or formula (II) of isotope enrichment can pass through this area skill Tried described by routine techniques known to art personnel or the embodiment in the present invention and preparation process using suitable isotope marks Agent substitutes original used unmarked reagent to prepare.
On the other hand, the present invention relates to the intermediate for preparing compound shown in formula (I) or formula (II).
On the other hand, the present invention relates to the method for preparation, separation and the purifying of compound shown in formula (I) or formula (II).
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound or formula (I) shown in formula (I) or formula (II) or formula (II) institute Show the stereoisomer of compound, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or Prodrug.Described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention composition.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；GennaroA.R.et al., Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and the interaction for the effect of substantially reducing the compounds of this invention during avoiding that patient is administered and can cause not being medicine The interaction of acceptable pharmaceutical composition on.In addition, every kind of excipient must be pharmaceutically acceptable, for example, tool There is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, it may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.It may be selected to can help to some pharmaceutically acceptable figurations for producing stabilizer type Agent.It may be selected to help to carry when patient is administered or transport the compounds of this invention from an organ of body or partly to body Another organ or partial some pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is some pharmaceutically Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably Agent, surfactant and buffer.One skilled in the art will recognize that some pharmaceutically acceptable excipient can provide not A kind of only function, and alternative function is provided, this depends in preparation having in how much excipient and preparation which be present Other a little excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing acts on, or with interaction occurs for any other composition in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pay close attention to its application and belong to the scope of the present invention.
The compounds of this invention is usually formulated as being suitable for the formulation that patient is administered by required approach.For example, formulation It is suitable for the formulation of following method of administration including those：(1) it is administered orally, such as tablet, capsule, caplet agent, pill, lozenge Agent, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, for example, it is sterile Solution, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as suppository；(5) inhale Enter, such as aerosol, solution and dry powder doses；(6) local administration, such as cream, ointment, lotion, solution, paste Agent, spray, foaming agent and gel.
It is used to treat it will also be appreciated that some compounds of the present invention can exist in a free form, or it is if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some nonrestrictive implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
In one embodiment, the compounds of this invention can be configured to peroral dosage form.In another embodiment, it is of the invention Compound can be configured to inhalant dosage form.In another embodiment, the compounds of this invention can be configured to nose administration formulation. In yet another embodiment, the compounds of this invention can be configured to transdermal administration.Also in one embodiment, the present inventionization Compound can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece, it can be beneficial to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Tabletting is by the compressed tablets of more than one press cycles preparation, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active component are single or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, therefore enclose active component completely.Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shell, It is plastified by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active component.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or more The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and preservative can also be included.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Pharmaceutical composition provided by the invention can be configured to be suitable to any formulation to patient's inhalation, such as dry powder Agent, aerosol, supensoid agent or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared Into suitable for the formulation with dry powder doses to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable to the formulation by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes are obtained comprising fine powdered Shape agent.Be especially suitable for the pharmaceutically acceptable excipient dawn known to those skilled in the art of dry powder doses, it includes breast Sugar, starch, mannitol and single-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next Say, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed Amount) define.
Discontinuous paster agent can be prepared into by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
The pharmaceutical composition for being suitable for locally being administered can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can use water or oil Matrix, and suitable thickener and/or gel and/or solvent configure.Such matrix can include, water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Made according to medium property Thickener and gel include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
The compounds of this invention can also be combined with the soluble polymer as target medicine carrier.Such polymer bag Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can be with realizing medicine A kind of Biodegradable polymeric for being used in control release combines, for example, PLA, poly-epsilon-caprolactone, poly butyric, Poe, polyacetals, poly- dihydropyran, crosslinking or the amphiphilic block copolymer of polybutylcyanoacrylate and hydrogel.
Pharmaceutical composition provided by the invention can be by injecting, being transfused or be implanted into parenteral, for local or complete Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any formulation suitable for parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral pharmaceutical composition can include one or more pharmaceutically acceptable carriers and Excipient, include, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resist micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and scattered Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art with practice.
Pharmaceutical composition provided by the invention can with will not to damage other active components of expected therapeutic action common Prepare, or with supplement expected from the material co-formulation that acts on.
In one embodiment, treatment method of the invention includes giving patient in need this hair of safe and effective amount Bright compound or the pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention is included by patient in need Give the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, referred to treat the present invention Disease.
In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable method of administration is administered, including Formulations for systemic administration and local is administered.Formulations for systemic administration include oral administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and intranasal administration.One In individual embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be administered orally.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.Also one is real Apply in example, the compounds of this invention or can be intranasal administration comprising the compounds of this invention.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably be given Medicine, or according to dosage regimen, at the appointed time in section, be administered several times in different time intervals.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, including implement the duration of the program, depending on treated disease, it is treated disease The order of severity of disease, the age of patient under consideration and health, the property of the medical history of patient under consideration while therapy, think The factor in the range of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or over time passage individual patient need change when, in order to be sufficiently accurate it may be desired to adjust matters to Prescription case.
The compounds of this invention can be administered simultaneously, or before it or afterwards with one or more other therapeutic agents.This hair Bright compound can be administered respectively with other therapeutic agents by identical or different method of administration, or therewith with pharmaceutical composition Form is administered.
The compounds of this invention can be with sedative, hypnotic, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole Ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the element that fades can medicament, benzene phenodiazines Leather, barbiturate, 5HT-2 antagonists etc. are used in combination, such as：Adinazolam, allobarbital, alonimid, Alprazolam, amitriptyline, amytal, amoxapine, bentazepam, benzoctamine, brotizolam, biphenylacetone, fourth Spirocyclic ketone, cloth tower barbital, cloth tower are than appropriate, capuride, Carbocloral, chloral betaine, chloraldurate, librium, chlorine rice pa Bright, Clonazepam, Domperidone, Decacil, cloretate, Clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine Aldehyde willow amine, double valproic acids, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west Dissolve, Flurazepam, Fluvoxamine, fluoxetine, fosazepam, glutethimide, Halazepam, hydroxyzine, imipramine, lithium, chlorine hydroxyl go first Stable, Lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles Logical sequence, Buddhist nun's method oxazolone, Nisobamate, intrazepam, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, amobarbital, piperazine Even up, perphenazine, nardil, phenobarbital, prazepam, fenazil, propofol, protriptyline, quazepam, auspicious chlorine West is dissolved, rolipram, quinalbarbitone, Sertraline, Suproclone, Temazepam, thioridazine, Tracazolate, anti-phenyl ring third Amine, Trazodone, triazole benzene phenodiazine, Trepipam, trimeglamide, trichloroethyl phosphate, triperazine, trimethoxy benzoyl Quinoline, trimeprimine, uldazepam, venlafaxine new, Zaleplon, Zolazepam, zolpidem and their salt and composition Etc., or the compounds of this invention can administration while physical method such as light therapy or electro photoluminescence be used in combination.
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When patient is administered, the functional derivatives of the compounds of this invention can be finally discharged in vivo.This hair is given with prodrug forms During bright compound, those skilled in the art can implement one kind in following manner and more than：(a) change and worked inside compound Time；(b) acting duration inside compound is changed；(c) conveying or distribution inside compound are changed；(d) modification Solubility inside compound；And (e) overcomes the side effect or other difficult points that compound faced.For preparing the typical of prodrug Functional derivatives, comprising in vivo chemically or enzyme the variant of compound that cracks of mode.Comprising prepare phosphate, Acid amides, ester, monothioester, these variants of carbonate and carbaminate are well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound and pharmaceutical composition of the present invention, particularly can alternatively property as orexin receptor antagonists OX1Receptor antagonist, it is effective to preventing or treating the disease related to orexin receptor, available for preparing antagonism orexin The medicine of acceptor.
The disease related to orexin receptor may be selected from all types of sleep-disorder, all types of psychiatry, god Learned and neurodegeneration obstacle, all types of pressure correlation syndromes, all types of habituation (especially psychotropic activity thing through disease The use of matter, abuse, seek and recover), it is all types of in healthy population and in psychiatric patient and nervous system disease Cognition dysfunction, all types of feeds or drinking-water obstacle in patient, etc..
In one embodiment, the disease related to orexin receptor includes sleep-disorder, depression, anxiety disorder, fear Disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior are lost Often, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, amentia, Dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, feeding desorder, headache, It is antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune correlated disease, interior Secrete relevant disease or hypertension.
In one embodiment, the disease related to orexin receptor may be selected from sleep-disorder, and it includes all types of The related myodystony of insomnia, Narcolepsy and other hyper somnolence diseases, parasomnia, sleep, not peaceful leg Syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome and sleep phases The insomnia of syndrome or mental illness correlation is retarded or advanced, etc..
In one embodiment, the disease related to orexin receptor may be selected from psychiatry, neurology and nerve change Sexual dysfunction, it includes depression, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxiety nerve Disease, mood disorder, panic attack obstacle, posttraumatic stress disorder, sex dysfunction, mental disease, Parkinson's disease, dementia or essence Refreshing hypoevolutism, etc..
In one embodiment, the disease related to orexin receptor may be selected from cognition dysfunction, and it is included in normal , it is healthy, young, adult or in old crowd transient episodes or chronic seizures all types of attentions, Practise and memory function declines, or the transient episodes or chronic in mental disease, neuropathy, angiocarpy and disease of immune system patient All types of attentions of breaking-out, learning and memory function reduction, etc..
It should be appreciated that in some environmental conditions such as such as pressure or fear, (wherein, pressure may have social source such as Social pressures have physiological sources such as physical stress, including the pressure as caused by fear) promote or accelerate it is any as previously described Illness or disease in the case of, compound of the invention to treat these environment regulation illness or disease be particularly useful 's.
The compound and pharmaceutical composition of the present invention to human treatment except beneficial in addition to, applying also for veterinary treatment and doting on Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, compound of the invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For the description present invention, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, it is The method that the practice present invention is provided.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I) or formula (II).Following reaction scheme and embodiment are used to further lift Example explanation present disclosure.
The professional of art will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), marked by the use of TMS (0ppm) or chloroform (7.26ppm) as reference It is accurate.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet Ofdoublets, double doublet), dt (doublet oftriplets, double triplets).Coupling constant, represented with hertz (Hz).
The condition determination of Algorithm (MS) data is：Level Four bar HPLC-MS (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Pure compound uses pre-HPLC (the pillar types of 1260 pre-HPLC or Calesep pump of Agilent 250 Number：NOVASEP 50/80mm DAC), under 210nm/254nm, detected with UV.
The use of brief word below is through the present invention：
Boc tertbutyloxycarbonyls
CH2Cl2, DCM dichloromethane
Cs2CO3Cesium carbonate
CDC13Deuterochloroform
CuI cuprous iodides
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
Et3N, TEA triethylamines
EtOAc, EA ethyl acetate
EtOH ethanol
G grams
H hours
MeCN、CH3CN acetonitriles
Na2CO3Sodium carbonate
NaOH sodium hydroxides
Na2SO4Sodium sulphate
MgSO4Magnesium sulfate
ML, ml milliliter
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Following synthetic schemes describes the step of preparing the compounds of this invention.Unless otherwise indicated, R1、R2、R3、R4、R5、 R6、R7、R8And R9With definition as described in the present invention.
Synthetic schemes 1
The compounds of this invention 9 can be prepared by the general synthetic method described in synthetic schemes 1, and specific real Apply in example and be described in detail：First, 1,6- benzodiazines -5 (6H) -one 1 obtains compound 2 in a heated condition with chlorinating agent, Simultaneously [3,4-c] pyrroles obtains compound 3 to compound 2 in the basic conditions with 2-Boc- hexahydropyrrolos, and compound 3 passes through function again Change obtains the compound 4 containing different substituents, and compound 4 obtains midbody compound 5 in acid condition.
The o-iodobenzoic acid 6 and 2H-1,2,3- triazoles optionally substituted appropriate alkali exist and heating condition under pass through The effect of catalyst (such as CuI) obtains compound 7, and then compound 7 obtains compound 8 in a heated condition with chlorinating agent, Final compound 8 obtains target compound 9 in the basic conditions with midbody compound 5.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:(5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (5- methyl - 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone synthesis
The synthesis of the chloro- 1,6- benzodiazines of step 1) 5-
It is anti-that 1,6- benzodiazines -5 (6H) -one (3.00g, 20.53mmol) and POCl3 (40mL) are added to 100mL Answer in bottle, reaction is warming up to 100 DEG C and reacted 24 hours.Stop reaction, reaction solution is cooled to room temperature, and it is unnecessary to be evaporated under reduced pressure removing POCl3, remaining solid are quenched using the saturated sodium bicarbonate solution (80mL) of ice, and aqueous phase uses dichloromethane (30mL × 3) Extraction.The organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate decompression be spin-dried for after through silica gel column chromatography separating purification (stone Oily ether/ethyl acetate (v/v)=1/1) obtain title compound (white solid, 3.08g, 91.20%).
MS(ESI,pos.ion)m/z:165.15[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):9.15 (dd, J=4.2,1.5Hz, 1H), 8.71~8.60 (m, 1H), 8.53 (d, J=5.9Hz, 1H), 7.90 (d, J=5.8Hz, 1H), 7.64 (dd, J=8.5,4.3Hz, 1H)
The conjunction of step 2) 5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate Into
By the chloro- 1,6- benzodiazines (0.93g, 5.65mmol) of 5-, hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-formic acid The tert-butyl ester (1.00g, 4.71mmol), three (dibenzalacetone) two palladium (0.43g, 0.47mmol), 2- dicyclohexyls phosphorus -2,4, 6- tri isopropyl biphenyls (0.46g, 0.94mmol), sodium tert-butoxide (1.40g, 14.1mmol) and toluene (20mL) are added sequentially to In 100mL single port bottles, under nitrogen protection, reaction is warming up to 120 DEG C and reacted 36 hours.Stop reaction, reaction solution is evaporated under reduced pressure and removed Go after solvent to obtain title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/1) (light yellow Liquid, 1.15g, 71.7%).
MS(ESI,pos.ion)m/z:341.40[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.88 (dd, J=4.1,1.2Hz, 1H), 8.46 (d, J=8.5Hz, 1H), 8.19 (d, J=5.8Hz, 1H), 7.30 (dd, J=8.6,4.2Hz, 1H), 7.24 (d, J=5.8Hz, 1H), 4.05 (dd, J=10.9,7.1Hz, 2H), 3.78~3.70 (m, 2H), 3.64 (d, J=4.6Hz, 2H), 3.40 (d, J=9.8Hz, 1H), 3.32 (d, J=8.0Hz, 1H), 3.02~2.96 (m, 2H), 1.45 (s, 9H)
The synthesis of step 3) 5- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazines
By 5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate (1.10g, 3.23mmol) it is dissolved in dichloromethane (10mL), the ethyl acetate solution (10mL) of lower addition hydrogen chloride, room temperature is stirred at room temperature Reaction 2 hours.Reaction solvent evaporated obtains title compound (light yellow solid, 0.88g, 98.4%).
MS(ESI,pos.ion)m/z:241.30[M+H]+；
1H NMR(D2O,400MHz,)δ(ppm):9.39 (d, J=8.8Hz, 1H), 9.21 (d, J=5.1Hz, 1H), 8.06 (d, J=4.9Hz, 1H), 8.04 (d, J=3.3Hz, 1H), 7.44 (d, J=7.2Hz, 1H), 4.53 (dd, J=11.7, 7.1Hz, 2H), 4.23 (dd, J=11.9,3.6Hz, 2H), 3.80 (dd, J=12.3,7.0Hz, 2H), 3.64~3.54 (m, 2H), 3.49 (dd, J=12.4,4.9Hz, 2H)
The synthesis of step 4) 5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid
By 2H-1,2,3- triazoles (3.45g, 50mmol), the iodo- 5- methyl benzoic acids (5.24g, 20mmol) of 2-, carbonic acid Caesium (11.72g, 36mmol), trans-N, N'- dimethyl -1,2- cyclohexanediamine (0.51g, 3.6mmol), cuprous iodide (0.38g, 2mmol) and DMF (30mL) are added sequentially in 100mL single necked round bottom flask, under nitrogen protection Reaction solution is gradually heating to 100 DEG C and reacted 4 hours.Stop reaction, cooling, reaction solution water (60mL) dilutes and uses ethyl acetate (200mL × 2) extract.It is 1~2 that water layer is acidified to pH with concentrated hydrochloric acid, then adds ethyl acetate (200mL × 2) extraction, gained Organic layer anhydrous sodium sulfate drying, filtering, filtrate decompression be spin-dried for after through column chromatographic isolation and purification (methylene chloride/methanol (v/v) =50/1) title compound (yellow solid, 2.76g, 68%) is obtained.
MS(ESI,neg.ion)m/z:202.1[M-H]-；
1H NMR(CD3OD,600MHz)δ(ppm):7.88 (s, 2H), 7.66 (d, 1H), 7.59 (d, J=8.2Hz, 1H), 7.50~7.48 (dd, J=8.1Hz, 1.1Hz, 1H), 2.45 (s, 3H)；
13C NMR(CD3OD,151MHz)δ(ppm):169.8,140.7,137.5,136.7,133.5,131.5,129.3, 126.0,21.0.
The synthesis of step 5) 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid (2.03g, 10mmol) is added to 100mL single port In round-bottomed flask, dissolved with anhydrous methylene chloride (20mL), then be slowly added into thionyl chloride (15mL, 200mmol) and pyridine (0.15mL,2mmol).Reaction solution is gradually heating to flow back, and reaction stops reaction, cooling after 3 hours, and decompression slowly boils off molten Agent, products therefrom are directly entered in next step.
Step 6) (5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (5- methyl -2- (2H-1,2,3- triazole -2- bases) phenyl) ketone synthesis
By 5- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazines (0.40g, 1.45mmol), three Ethamine (0.58g, 5.78mmol) and dichloromethane (20mL) are added in 100mL single port bottles, are reacted on 0 DEG C and are stirred 10 minutes Afterwards, it is slowly dropped into the dichloromethane of 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.48g, 2.17mmol) (10mL) solution.Reaction solution continues to switch to react at room temperature after stirring 30 minutes at 0 DEG C.Decompression boils off molten after reacting 12 hours Agent, remaining solid are dissolved using dichloromethane (30mL), are then washed, had with water (20mL) and saturated aqueous common salt (20mL) successively Machine layer directly carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/2), and to obtain title compound (yellowish Color dope, 0.45g, 73.15%).
MS(ESI,pos.ion)m/z:426.10[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.91 (dd, J=4.1,1.2Hz, 1H), 8.45 (d, J=8.5Hz, 1H), 8.22 (d, J=5.8Hz, 1H), 7.83 (d, J=8.3Hz, 1H), 7.74 (s, 2H), 7.36~7.29 (m, 2H), 7.28 (d, J=5.9Hz, 1H), 7.24 (s, 1H), 4.08 (dd, J=10.7,7.5Hz, 1H), 3.95 (dd, J=10.8,7.1Hz, 1H), 3.88 (dd, J=12.6,7.6Hz, 1H), 3.80 (dd, J=10.8,5.3Hz, 1H), 3.73 (dd, J=12.6, 4.0Hz, 1H), 3.68 (dd, J=10.7,3.6Hz, 1H), 3.39 (s, 1H), 3.11~2.91 (m, 3H), 2.40 (s, 3H)；
13C NMR(CDCl3,150MHz)δ(ppm):168.4,157.3,153.3,152.9,144.9,138.6,135.8, 135.3,134.4,133.6,130.7,129.7,128.3,122.2,119.5,115.0,113.1,51.6,49.6,41.1, 21.0.
Embodiment 2:(5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (2- (2H- 1,2,3- triazole -2- bases) phenyl) ketone synthesis
The synthesis of step 1) 2- (2H-1,2,3- triazole -2- bases) benzoic acid
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e., by 2H-1,2,3- tri- Nitrogen azoles (0.7g, 10.08mmol), 2- iodo-benzoic acids (1g, 4.03mmol), cesium carbonate (2.36g, 7.2mmol), trans-N, N'- Dimethyl -1,2- cyclohexanediamine (0.103g, 0.752mmol) and cuprous iodide (0.077g, 0.403mmol) are in N, N- dimethyl In formamide (18mL) prepared by reaction, and crude product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) To title compound (yellow solid, 0.511g, 67%).
MS(ESI,neg.ion)m/z:188.1[M-H]-；
1H NMR(DMSO-d6,600MHz)δ(ppm):13.06 (s, 1H), 8.08 (s, 2H), 7.78~7.75 (m, 2H), 7.72~7.68 (m, 1H), 7.60~7.57 (m, 1H)；
13C NMR(DMSO-d6,151MHz)δ(ppm):167.7,137.5,136.3,131.7,129.6,128.9, 128.5,124.4.
The synthesis of step 2) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e., by 2- (2H-1,2,3- Triazole -2- bases) benzoic acid (0.37g, 1.96mmol) anhydrous methylene chloride (20mL) dissolves, then is slowly added into thionyl chloride (6mL, 82.7mmol) and pyridine (0.04mL, 0.5mmol).Reaction solution is gradually heating to flow back, and reaction stops anti-after 3 hours Should, cooling, decompression slowly boils off solvent, and products therefrom is directly entered in next step.
Step 3) (5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (2- (2H-1, 2,3- triazole -2- bases) phenyl) ketone synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 5- (hexahydropyrrolos [3,4-c] pyrroles -2 (1H)-base -1,6- benzodiazines (0.30g, 1.08mmol), triethylamine (0.33g, 3.25mmol) and 2- Prepared by the reaction in dichloromethane (30mL) of (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.34g, 1.63mmol), thick production Product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/2) obtain title compound (light yellow solid, 0.27g, 60.54%).
MS(ESI,pos.ion)m/z:412.45[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.90 (dd, J=4.1,1.2Hz, 1H), 8.44 (d, J=8.5Hz, 1H), 8.21 (d, J=5.8Hz, 1H), 7.97 (d, J=8.1Hz, 1H), 7.80~7.70 (m, 2H), 7.54~7.48 (m, 1H), 7.45~7.39 (m, 2H), 7.31 (dd, J=8.5,4.2Hz, 1H), 7.30~7.25 (m, 1H), 4.08 (dd, J= 10.8,7.5Hz, 1H), 3.95 (dd, J=10.9,7.1Hz, 1H), 3.89 (dd, J=12.6,7.6Hz, 1H), 3.81 (dd, J =10.9,5.3Hz, 1H), 3.77~3.66 (m, 2H), 3.45~3.35 (m, 1H), 3.12~2.93 (m, 3H)；
13C NMR(CDCl3,151MHz)δ(ppm):168.2,157.3,153.4,153.0,144.8,136.0,135.8, 135.6,134.3,130.1,129.9,128.3,128.0,122.3,119.5,114.9,113.3,51.7,49.7,41.1.
Embodiment 3:(5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone synthesis
The synthesis of the fluoro- 6- of step 1) 2- (2H-1,2,3- triazole -2- bases) benzoic acid
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e., by 2H-1,2,3- tri- It is nitrogen azoles (6.9g, 100mmol), 2-Fluoro-6-iodobenzoic acid (10.64g, 40mmol), cesium carbonate (23.4g, 71.7mmol), anti- Formula-N, N'- dimethyl -1,2- cyclohexanediamine (1.02g, 7.04mmol) and cuprous iodide (0.76g, 4.0mmol) are in N, N- bis- In NMF (50mL) prepared by reaction, and crude product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/ 1) title compound (yellow solid, 5.62g, 67.90%) is obtained.
MS(ESI,pos.ion)m/z:208.10[M+H]+
1H NMR(DMSO-d6,400MHz)δ(ppm):13.66 (s, 1H), 8.16 (s, 2H), 7.79 (d, J=8.2Hz, 1H), 7.68 (td, J=8.2,6.2Hz, 1H), 7.44 (t, J=8.8Hz, 1H)
The synthesis of the fluoro- 6- of step 2) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e., by the fluoro- 6- (2H- of 2- 1,2,3- triazole -2- bases) benzoic acid (0.69g, 3.33mmol) anhydrous methylene chloride (20mL) dissolves, then is slowly added into chlorine Change sulfoxide (8mL, 109.0mmol) and DMF (0.04mL, 0.5mmol).Reaction solution is gradually heating to flow back, and reaction stops after 3 hours Only react, cool down, decompression slowly boils off solvent, and products therefrom is directly entered in next step.
Step 3) (5- (1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 5- (hexahydropyrrolos [3,4-c] pyrroles -2 (1H)-base -1,6- benzodiazines (0.30g, 1.08mmol), triethylamine (0.33g, 3.25mmol) and 2- Fluoro- 6- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chlorides (0.37g, 1.63mmol) reaction system in dichloromethane (30mL) Standby, it is (light yellow that crude product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/2) obtains title compound Dope, 0.34g, 73.06%).
MS(ESI,pos.ion)m/z:430.20[M+H]+；
1H NMR(CDCl3,600MHz,)δ(ppm):9.00 (s, 1H), 8.79 (dd, J=18.9,8.0Hz, 1H), 7.89 (d, J=31.9Hz, 1H), 7.81~7.68 (m, 3H), 7.52 (s, 1H), 7.44 (dd, J=14.1,7.9Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J=23.4,8.3Hz, 1H), 4.31 (d, J=46.7Hz, 2H), 4.12~3.54 (m, 5H), 3.34~ 3.11(m,3H).
Embodiment 4:(((hexahydropyrrolo is simultaneously by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and ethyl acetate synthesis
The synthesis of the chloro- 1,6- benzodiazines -1- oxides of step 1) 5-
Chloro- 1, the 6- benzodiazines (11.00g, 66.83mmol) of 5- are dissolved in dichloromethane (200mL), to it at 0 DEG C In be slowly added to metachloroperbenzoic acid (17.30g, 100.2mmol), then turn to react at room temperature.After reaction terminates, reaction solution Washed with saturated sodium carbonate solution (200mL), the organic phase of separation passes through water (200mL × 3) and saturated aqueous common salt successively (200mL) is washed, and then with anhydrous sodium sulfate drying, filtering, is evaporated under reduced pressure after removing solvent through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) obtains title compound (light yellow solid, 10.79g, 89.40%).
MS(ESI,pos.ion)m/z:181.15[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.83 (d, J=6.2Hz, 1H), 8.56 (d, J=6.0Hz, 1H), 8.34 (d, J=6.0Hz, 1H), 8.10 (d, J=8.7Hz, 1H), 7.70 (dd, J=8.7,6.2Hz, 1H)
Step 2) 5- (5- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- diazas The synthesis of naphthalene -1- oxides
Method of this step title compound with reference to described by the step 2 of embodiment 1 is prepared, i.e. chloro- 1, the 6- phenodiazines of 5- Miscellaneous naphthalene -1- oxides (0.10g, 0.55mmol), hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate (0.14g, 0.66mmol), palladium (0.012g, 0.06mmol), 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyls (0.07g, 0.11mmol) protect to react at 100 DEG C 24 hours and prepare with sodium carbonate (0.12g, 1.11mmol) nitrogen in toluene (6mL), Crude product through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=40/1) obtain title compound (yellow solid, 0.13g, 65.87%).
MS(ESI,pos.ion)m/z:357.25[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.54 (d, J=6.1Hz, 1H), 8.26 (d, J=6.0Hz, 1H), 8.05 (d, J=8.8Hz, 1H), 7.85 (d, J=6.0Hz, 1H), 7.20 (dd, J=8.7,6.2Hz, 1H), 4.09 (dd, J= 11.1,7.1Hz, 2H), 3.77 (d, J=10.2Hz, 2H), 3.72~3.62 (m, 2H), 3.42 (d, J=9.9Hz, 1H), 3.38 ~3.29 (m, 1H), 3.10~2.98 (m, 2H), 1.47 (s, 9H)
Step 3) 5- (2- oxo -1,2- dihydro -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 The synthesis of (1H)-t-butyl formate
By 5- (5- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazines -1- Oxide (0.50g, 1.40mmol), triethylamine (0.42g, 4.21mmol) and tetrahydrofuran (20mL) are added to 100mL reactions In bottle, TFAA (1.79g, 8.42mmol) is slowly added dropwise at 0 DEG C thereto, then reaction solution continues to react at 0 DEG C 1.5 hour.Stop reaction, add methanol (20mL) and reaction is quenched, be evaporated under reduced pressure and remove solvent, solid uses saturated sodium bicarbonate Solution (100mL) washs, and is extracted with dichloromethane (20mL × 3).Organic phase anhydrous sodium sulfate drying, filtering, decompression are steamed Distillation is gone after solvent to obtain title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/1) (shallow Yellow solid, 0.38g, 76.0%).
MS(ESI,pos,ion)m/z:357.40[M+H]+；
1HNMR(CDCl3,400MHz)δ(ppm):12.16 (s, 1H), 8.14 (d, J=9.9Hz, 1H), 8.06 (d, J= 5.6Hz, 1H), 6.69 (d, J=5.6Hz, 1H), 6.54 (d, J=9.9Hz, 1H), 3.99 (dd, J=10.7,7.0Hz, 2H), 3.72~3.67 (m, 2H), 3.66~3.61 (m, 2H), 3.42~3.32 (m, 2H), 3.02~2.96 (m, 2H), 1.47 (s, 9H).
Step 4) 5- (2- (2- ethyoxyl -2- oxoethoxies) -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4- C] pyrroles -2 (1H)-t-butyl formate synthesis
By 5- (2- oxo -1,2- dihydro -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-first Tert-butyl acrylate (1.24g, 3.48mmol), 2- bromoacetates (1.74g, 10.4mmol), potassium carbonate (1.46g, 10.4mmol) It is added in 100mL reaction bulbs, reacts at room temperature 12 hours with DMF (15mL).Stopping reaction, reaction solution adds water (50mL) to dilute, And extracted with dichloromethane (50mL × 3).The organic phase of merging is washed with water (50mL × 2), anhydrous sodium sulfate drying, filtering, It is evaporated under reduced pressure after removing solvent and obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/1) Thing (thick pale yellow thing, 1.10g, 71.4%).
MS(ESI,pos.ion)m/z:443.25[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.09 (d, J=6.0Hz, 1H), 8.03 (d, J=10.0Hz, 1H), 6.56 (d, J=9.9Hz, 1H), 6.38 (d, J=6.0Hz, 1H), 4.99 (s, 2H), 4.22 (q, J=7.1Hz, 2H), 3.94 (dd, J=10.8,7.1Hz, 2H), 3.62 (d, J=8.6Hz, 4H), 3.39~3.25 (m, 2H), 2.95 (d, J=5.1Hz, 2H), 1.45 (s, 9H), 1.26 (t, J=7.2Hz, 3H)
Step 5) 2- ((5- hexahydropyrrolos simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) acetic acid second The synthesis of ester
By 5- (2- (2- ethyoxyl -2- oxoethoxies) -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up -2 (1H)-t-butyl formates (1.10g, 2.49mmol) dichloromethane (10mL) to dissolve, lower addition hydrogen chloride is stirred at room temperature Ethyl acetate solution (10mL), then reaction solution react at room temperature 2 hours.Stop reaction, be evaporated under reduced pressure removing solvent and obtain To title compound (light yellow solid, 0.93g, 98.8%).
MS(ESI,pos.ion)m/z:343.20[M+H]+；
1H NMR(D2O,400MHz)δ(ppm):8.43 (d, J=10.2Hz, 1H), 7.87 (d, J=7.5Hz, 1H), 7.01 (d, J=7.5Hz, 1H), 6.75 (d, J=10.2Hz, 1H), 5.13 (s, 2H), 4.26~4.15 (m, 4H), 3.94 (dd, J= 11.1,3.0Hz, 2H), 3.67 (dd, J=11.4,6.0Hz, 2H), 3.47~3.30 (m, 4H), 1.20 (t, J=7.1Hz, 3H).
Step 6) 2- ((5- (and 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) ethyl acetate synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) ethyl acetate (0.19g, 0.50mmol), triethylamine (0.15g, 1.51mmol) and 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.17g, 0.75mmol) is two In chloromethanes (30mL) prepared by reaction, and crude product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) Obtain title compound (thick pale yellow thing, 0.22g, 83.13%).
MS(ESI,pos.ion)m/z:528.30[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.09 (d, J=6.0Hz, 1H), 7.97 (d, J=9.9Hz, 1H), 7.81 (d, J=8.3Hz, 1H), 7.74 (d, J=5.1Hz, 2H), 7.29 (d, J=6.5Hz, 1H), 7.21 (s, 1H), 6.54 (d, J=9.9Hz, 1H), 6.39 (d, J=6.0Hz, 1H), 4.98 (s, 2H), 4.22 (q, J=7.1Hz, 2H), 4.00~3.39 (m, 8H), 3.08 (q, J=7.3Hz, 2H), 2.38 (s, 3H), 1.23 (s, 3H)
Embodiment 5:(((hexahydropyrrolo is simultaneously [3,4-c] by 5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- Pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and ethyl acetate synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) ethyl acetate (0.35g, 0.92mmol), triethylamine (0.28g, 2.77mmol) and 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.29g, 1.39mmol) is in dichloromethane In (30mL) prepared by reaction, and crude product is marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) Topic compound (thick pale yellow thing, 0.37g, 77.97%).
MS(ESI,pos.ion)m/z:514.30[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.12 (d, J=5.9Hz, 1H), 8.00 (d, J=9.3Hz, 2H), 7.80 (s, 2H), 7.60~7.49 (m, 1H), 7.44 (d, J=4.3Hz, 2H), 6.57 (d, J=9.9Hz, 1H), 6.41 (d, J =5.9Hz, 1H), 5.02 (d, J=1.7Hz, 2H), 4.25 (q, J=7.1Hz, 2H), 3.98 (dd, J=10.9,7.3Hz, 1H), 3.87 (ddd, J=19.2,11.8,7.4Hz, 2H), 3.79~3.65 (m, 2H), 3.60 (dd, J=10.9,4.6Hz, 1H), 3.41 (s, 1H), 3.13~2.89 (m, 3H), 1.29 (s, 3H)
Embodiment 6:2- ((5- (and 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) ethyl acetate synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) ethyl acetate (0.35g, 0.92mmol), triethylamine (0.28g, 2.77mmol) and the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.31g, 1.39mmol) is in dichloro In methane (30mL) prepared by reaction, and crude product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) To title compound (thick pale yellow thing, 0.39g, 79.42%).
MS(ESI,pos.ion)m/z:532.30[M+H]+；
1HNMR(CDCl3,400MHz)δ(ppm):8.13 (d, J=5.9Hz, 1H), 8.03 (q, J=8.8Hz, 1H), 7.86 (dd, J=10.9,7.0Hz, 1H), 7.82 (d, J=5.4Hz, 1H), 7.82~7.79 (m, 1H), 7.54~7.47 (m, 1H), 7.17 (t, J=8.2Hz, 1H), 6.68~6.53 (m, 1H), 6.42 (dd, J=14.4,6.0Hz, 1H), 5.10~4.95 (m, 2H), 4.25 (q, J=7.1Hz, 2H), 4.06~3.59 (m, 7H), 3.35~3.07 (m, 3H), 1.29 (s, 3H)
Embodiment 7:(((hexahydropyrrolo is simultaneously by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and acetic acid synthesis
By 2-, (((hexahydropyrrolo is simultaneously [3,4-c] by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- Pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) ethoxyacetic acid ethyl ester (0.50g, 0.95mmol) is added to 100mL single port In bottle, cesium carbonate (0.93g, 2.84mmol) and methanol (30mL) are then added, 60 DEG C of reactions are overnight.Stop reaction, with dilute salt Acid regulation reaction solution is 2.0 to pH, is then evaporated under reduced pressure and removes solvent, crude product is through silica gel column chromatography separating purification (dichloromethane Alkane/methanol (v/v)=20/1) obtain title compound (light yellow solid, 0.38g, 79.96%).MS(ESI,pos.ion)m/ z:500.21[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.16 (d, J=5.8Hz, 1H), 7.99 (d, J=9.9Hz, 1H), 7.81 (d, J=8.5Hz, 1H), 7.75 (s, 2H), 7.35~7.29 (m, 1H), 6.75~6.59 (m, 2H), 6.54 (d, J= 9.9Hz, 1H), 4.83 (s, 2H), 4.00~3.90 (m, 1H), 3.91~3.79 (m, 2H), 3.73~3.61 (m, 2H), 3.56 (dd, J=10.9,4.5Hz, 1H), 3.46~3.28 (m, 1H), 3.09~2.84 (m, 3H), 2.43 (s, 3H)
Embodiment 8:(((hexahydropyrrolo is simultaneously [3,4-c] by 5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- Pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and acetic acid synthesis
Method of this step title compound with reference to described by the step 1 of embodiment 7 is prepared, i.e. 2- ((5- (5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazines - 2- yls) epoxide) ethyl acetate (0.50g, 0.97mmol) and cesium carbonate (0.95g, 2.92mmol) be 60 DEG C in methanol (30mL) Prepared by reaction, crude product obtains title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) (light yellow solid, 0.36g, 75.68%).
MS(ESI,pos.ion)m/z:486.19[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.12 (d, J=5.9Hz, 1H), 7.99 (d, J=9.7Hz, 1H), 7.80 (d, J=8.5Hz, 1H), 7.77 (s, 2H), 7.31~7.26 (m, 1H), 6.73~6.59 (m, 2H), 6.54 (d, J= 9.8Hz, 1H), 4.85 (s, 2H), 4.01~3.97 (m, 1H), 3.91~3.77 (m, 2H), 3.73~3.61 (m, 2H), 3.54 (dd, J=10.9,4.5Hz, 1H), 3.46~3.27 (m, 1H), 3.09~2.83 (m, 3H)
Embodiment 9:2- ((5- (and 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) acetic acid synthesis
Method of this step title compound with reference to described by the step 1 of embodiment 7 is prepared, i.e. 2- ((5- (5- (2- Fluoro- 6- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- phenodiazines Miscellaneous naphthalene -2- bases) epoxide) ethyl acetate (0.50g, 0.94mmol) and cesium carbonate (0.92g, 2.82mmol) be in methanol (30mL) Prepared by 60 DEG C of reactions, crude product obtains title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) Thing (light yellow solid, 0.38g, 80.1%).
MS(ESI,pos.ion)m/z:504.18[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.13 (d, J=5.8Hz, 1H), 7.97 (d, J=10.0Hz, 1H), 7.83 (d, J=8.7Hz, 1H), 7.73 (s, 2H), 7.36~7.29 (m, 1H), 6.77~6.57 (m, 2H), 4.81 (s, 2H), 4.03~3.90 (m, 1H), 3.93~3.79 (m, 2H), 3.71~3.61 (m, 2H), 3.54 (dd, J=10.7,4.5Hz, 1H), 3.45~3.28 (m, 1H), 3.09~2.87 (m, 3H)
Embodiment 10:(((hexahydropyrrolo is simultaneously by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and acetamide synthesis
Hexahydropyrrolo is simultaneously [3,4-c] by step 1) 5- (2- (2- amino -2- oxoethoxies) -1,6- benzodiazine -5- bases) The synthesis of pyrroles -2 (1H)-t-butyl formate
By 5- (2- (2- ethyoxyl -2- oxoethoxies) -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up -2 (1H)-t-butyl formates (0.50g, 1.17mmol) to add in 100mL reaction bulbs, then add the methanol solution of ammonia (20mL), reaction solution stop reaction after being stirred at room temperature 72 hours, are evaporated under reduced pressure and remove solvent, and crude product separates through silica gel column chromatography Purifying (methylene chloride/methanol (v/v)=50/1) obtains title compound (light yellow solid, 0.44g, 92.12%).
MS(ESI,pos.ion)m/z:414.23[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.10 (d, J=5.8Hz, 1H), 8.01 (d, J=9.9Hz, 1H), 6.58 (d, J=9.7Hz, 1H), 6.34 (d, J=6.0Hz, 1H), 5.01 (s, 2H), 3.92 (dd, J=10.7,7.2Hz, 2H), 3.63 (d, J=8.6Hz, 4H), 3.39~3.27 (m, 2H), 2.95 (d, J=5.1Hz, 2H), 1.43 (s, 9H)
Step 2) 2- ((5- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) The synthesis of acetamide
By 5- (2- (2- amino -2- oxoethoxies) -1,6- benzodiazine -5- bases) hexahydropyrrolo simultaneously [3,4-c] pyrroles - 2 (1H)-t-butyl formates (1.00g, 2.42mmol) are dissolved in dichloromethane (10mL), and lower addition hydrogen chloride is stirred at room temperature Ethyl acetate solution (10mL), then reaction solution react at room temperature 2 hours.Stop reaction, be evaporated under reduced pressure removing solvent and obtain Title compound (light yellow solid, 0.95g, 95.3%).
MS(ESI,pos.ion)m/z:314.16[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.41 (d, J=10.3Hz, 1H), 7.88 (d, J=7.5Hz, 1H), 7.02 (d, J=7.5Hz, 1H), 6.69 (d, J=10.2Hz, 1H), 4.63 (s, 2H), 4.26~4.17 (m, 4H), 3.69 (dd, J=11.4,6.0Hz, 2H), 3.49~3.35 (m, 4H)
Step 3) 2- ((5- (5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) acetamide synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) acetamide (0.50g, 1.60mmol), triethylamine (0.48g, 4.80mmol) and 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.53g, 2.39mmol) is two In chloromethanes (30mL) prepared by reaction, and crude product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) To title compound (light yellow solid, 0.66g, 82.56%).
MS(ESI,pos.ion)m/z:499.40[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.12 (d, J=5.9Hz, 1H), 8.00 (d, J=9.9Hz, 1H), 7.83 (d, J=8.3Hz, 1H), 7.76 (s, 2H), 7.36~7.27 (m, 1H), 7.22 (s, 1H), 6.77~6.59 (m, 2H), 6.55 (d, J=9.9Hz, 1H), 5.90 (s, 1H), 4.87 (s, 2H), 4.02~3.90 (m, 1H), 3.91~3.77 (m, 2H), 3.73~3.62 (m, 2H), 3.56 (dd, J=10.9,4.5Hz, 1H), 3.48~3.28 (m, 1H), 3.07~2.84 (m, 3H), 2.41(s,3H)；
13C NMR(CDCl3,150MHz)δ(ppm):169.4,168.4,162.0,157.7,148.5,147.5,138.6, 137.1,135.8,133.6,130.7,129.8,128.3,122.2,117.3,104.2,101.2,51.6,46.5,46.0, 41.0,21.0.
Embodiment 11:(((hexahydropyrrolo is simultaneously [3,4-c] by 5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- Pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and acetamide synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) acetamide (0.45g, 1.44mmol), triethylamine (0.44g, 4.31mmol) and 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.45g, 2.15mmol) is in dichloromethane In (30mL) prepared by reaction, and crude product obtains title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) Compound (light yellow solid, 0.57g, 82.63%).
MS(ESI,pos.ion)m/z:485.10[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.13 (d, J=5.9Hz, 1H), 7.99 (t, J=9.2Hz, 2H), 7.79 (s, 2H), 7.59~7.48 (m, 1H), 7.44 (t, J=6.3Hz, 2H), 6.72 (d, J=5.9Hz, 1H), 6.55 (d, J =9.9Hz, 2H), 5.87 (s, 1H), 4.86 (s, 2H), 3.96 (dd, J=10.9,7.3Hz, 1H), 3.93~3.77 (m, 2H), 3.69 (dd, J=11.7,4.7Hz, 2H), 3.59 (dd, J=10.9,4.6Hz, 1H), 3.48~3.28 (m, 1H), 3.05 (d, J =7.3Hz, 2H), 2.94 (d, J=5.9Hz, 1H)；
13C NMR(CDCl3,100MHz)δ(ppm):169.5,168.3,162.1,157.9,148.7,147.6,137.2, 136.2,135.9,130.2,130.1,128.4,128.1,122.4,117.4,104.4,101.4,54.7,51.8,49.7, 41.2.
Embodiment 12:(((hexahydropyrrolo is simultaneously by 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) by 5- by 2- [3,4-c] pyrroles -2 (1H)-yl) -1,6- benzodiazine -2- bases) epoxide) and acetamide synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., by 2- ((5- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles -2 (1H) -1,6- benzodiazine -2- bases) epoxide) acetamide (0.40g, 1.28mmol), triethylamine (0.39g, 3.83mmol) and the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.43g, 1.91mmol) is in dichloro In methane (30mL) prepared by reaction, and crude product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) Title compound (light yellow solid, 0.52g, 81.75%).
MS(ESI,pos.ion)m/z:503.21[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.13 (dd, J=5.7,3.5Hz, 1H), 8.03 (t, J=9.2Hz, 1H), 7.96~7.64 (m, 3H), 7.49 (tt, J=12.1,6.0Hz, 1H), 7.16 (t, J=8.4Hz, 1H), 6.72 (dd, J =13.0,5.9Hz, 1H), 6.56 (dd, J=18.2,9.9Hz, 2H), 5.90 (s, 1H), 4.96~4.76 (m, 2H), 4.09~ 3.83 (m, 3H), 3.82~3.51 (m, 4H), 3.29 (dd, J=10.5,3.7Hz, 1H), 3.19~2.95 (m, 2H)
Biologic test
Embodiment A the compounds of this invention is to humanization OX1The antagonism experiment of acceptor
Test method
This hair is evaluated with influence of the fluorescence detection detection the compounds of this invention to the cell calcium current of agonist induction Bright compound is to expressing the humanization OX on Chinese hamster ovary cell (CHO)1The antagonistic ability of acceptor.Cell is suspended in In DMEM culture mediums (invitrogen), then with 2 × 104The Density Distribution of cells/well is in micro reaction plate.It will contain glimmering The Hank of light probe (Fluo4 NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids (invitrogen) Balanced salt solution (HBSS, invitrogen) (pH=7.4) is added in above-mentioned micro reaction plate, then arises from 37 with cell one DEG C be incubated 60min, then at 22 DEG C incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and add test compound or with reference to antagonist or Hank balanced salt solutions, 3nM appetite is added after 5min Plain A or Hank balanced salt solutions (blank control), the change of fluorescence intensity is then measured, it is dense with free intracellular calcium Degree is changing into positive correlation.Experimental result is represented with the suppression percentage relative to control group 3nM orexin-As.
Standard is SB334867 with reference to antagonist, amount effect curve is obtained by the experiment test of series concentration, so as to calculate Go out IC50Value.
For experimental result referring to table 1, table 1 is the compound of section Example of the present invention offer to OX1The antagonism of acceptor Experimental result.
1 compound provided in an embodiment of the present invention of table is to OX1The antagonism experimental result of acceptor
Test result indicates that the compounds of this invention is to OX1Acceptor shows preferable antagonism.
Embodiment B the compounds of this invention is to humanization OX2The antagonism experiment of acceptor
Test method
This hair is evaluated with influence of the fluorescence detection detection the compounds of this invention to the cell calcium current of agonist induction Bright compound is to expressing the humanization OX on HEK-293 cells2The antagonistic ability of acceptor.Cell is suspended in DMEM culture mediums (invitrogen) in, then with 3 × 104The Density Distribution of cells/well is in micro reaction plate.Fluorescence probe will be contained The Hank balanced salt solutions of (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids (HBSS, Invitrogen) (PH=7.4) is added in above-mentioned micro reaction plate, and 37 DEG C of incubation 60min are then arised from cell one, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and adds testization Compound or with reference to antagonist or Hank balanced salt solutions, it is (empty to add 10nM orexin B or Hank balanced salt solution after 5min White control), the change of fluorescence intensity is then measured, it is changing into positive correlation with free intracellular calcium concentration.Experiment knot Fruit is represented with the suppression percentage relative to control group 10nM orexins B.
Standard is JNJ10397049 with reference to antagonist, amount effect curve is obtained by the experiment test of series concentration, so as to count Calculate IC50Value.
For experimental result referring to table 2, table 2 is the compound of section Example of the present invention offer to OX2The antagonism of acceptor Experimental result.
2 compound provided in an embodiment of the present invention of table is to OX2The antagonism experimental result of acceptor
Test result indicates that the compounds of this invention is to OX2Acceptor shows preferable antagonism.
Pharmacokinetic Evaluation after embodiment C rats, dog and monkey intravenous or the quantitative the compounds of this invention of gavage
The present invention is assessed pharmacokinetic of the compounds of this invention in rat, dog and monkey body, is moved Thing information refers to Table A.
Table A animal subject information table of the present invention
Test method
By the compounds of this invention with 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline salt The form of the aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, animal subject is carried out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25th, 0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and under 3,000 or 4,000rpm from The heart 10 minutes, plasma solutions are collected, and preserved at -20 DEG C or -70 DEG C.For gastric infusion group, dosage 2.5mg/ Kg or 5mg/kg, vein takes when then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour Blood (0.3mL), and centrifuged 10 minutes under 3,000 or 4,000rpm, plasma solutions are collected, and protected at -20 DEG C or -70 DEG C Deposit.Positive control is suvorexant.
The plasma solutions obtained are collected to above-mentioned each group and carry out LC-MS/MS analyses.Analysis result shows, chemical combination of the present invention Thing is big with exposure value, and clearance rate is low, the preferable pharmacokinetic property such as bioavilability height.Illustrate the compounds of this invention Druggability is more preferable, has more preferable potential applicability in clinical practice.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the feature for combining the embodiment or example description It is contained at least one embodiment or example of the present invention.In this manual, need not to the schematic representation of above-mentioned term Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be any Combined in an appropriate manner in individual or multiple embodiments or example.In addition, in the case of not conflicting, the technology of this area Different embodiments or example and the feature of different embodiments or example described in this specification can be combined by personnel And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (10)

1. a kind of compound, it is stereoisomer, the tautomerism of compound shown in compound or formula (I) shown in formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein：
Hy is triazolyl, and the triazolyl is optionally independently selected from D, F, Cl, Br, I, oxo (=O), C by one or more1-6 Alkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6The substituent of halogenated alkoxy or benzyl is substituted；
R1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (= O)NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) ,-C (=O)-(C1-6Alkylamino) ,- O-(CH2)n- C (=O) O- (C1-6Alkyl) ,-O- (CH2)n-COOH、-O-(CH2)n- C (=O) NH2、C3-6Cycloalkyl, C2-9Heterocycle Base, C6-10Aryl or C1-9Heteroaryl；
R6、R7、R8And R9It is each independently H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Hydroxyl takes The alkyl ,-C (=O)-(C in generation1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) ,-C (=O)-(C1-6Alkylamino), C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；With
Each n independently is 1,2,3 or 4.
2. compound according to claim 1, it is vertical for compound shown in the compound or formula (II) shown in formula (II) Body isomers, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
3. compound according to claim 1 or 2, wherein R1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、 Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkyl halide Base, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) ,-C (=O)-(C1-4Alkylamino) ,-O- (CH2)n- C (=O) O- (C1-4Alkyl) ,-O- (CH2)n- COOH or-O- (CH2)n- C (=O) NH2。
4. compound according to claim 1 or 2, wherein R6、R7、R8And R9Be each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alcoxyl Base, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkane Epoxide) or-C (=O)-(C1-4Alkylamino).
5. compound according to claim 1 or 2, wherein R1、R2、R3、R4And R5It is each independently H, D ,-CD3、F、 Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2、-CH2OH ,-C (= O)NHCH3,-C (=O) N (CH3)2、-O-CH2- C (=O) O-CH3、-O-(CH2)2- C (=O) O-CH3、-O-CH2- C (=O) O- CH2CH3、-O-(CH2)2- C (=O) O-CH2CH3、-O-CH2- C (=O) O-CH2CH2CH3、-O-(CH2)2- C (=O) O- CH2CH2CH3、-O-CH2- C (=O) O-CH (CH3)2、-O-(CH2)2- C (=O) O-CH (CH3)2、-O-CH2-COOH、-O- (CH2)2-COOH、-O-CH2- C (=O) NH2Or-O- (CH2)2- C (=O) NH2。
6. compound according to claim 1 or 2, wherein R6、R7、R8And R9Be each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3、 Methoxyl group, ethyoxyl, n-propyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2Or-CH2OH。
7. compound according to claim 1 or 2, it is for the compound with one of following structure or with one of following It is the stereoisomer of the compound of structure, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable Salt or prodrug,
8. a kind of pharmaceutical composition, it includes the compound described in claim 1-7 any one；With
Described pharmaceutical composition optionally includes pharmaceutically acceptable carrier, excipient, adjuvant or their any combination.
9. the pharmaceutical composition described in compound or claim 8 described in claim 1-7 any one is in medicine is prepared Purposes, the medicine be used for prevent, treat or mitigate the disease related to orexin receptor.
10. purposes according to claim 9, wherein the disease related to orexin receptor is sleep-disorder, depression It is disease, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, terrified Break out obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic Depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, Feeding desorder, headache, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, Immune correlated disease, endocrine relevant disease or hypertension.
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