CN108409728A - Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives and application thereof - Google Patents

Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives and application thereof Download PDF

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CN108409728A
CN108409728A CN201710070005.5A CN201710070005A CN108409728A CN 108409728 A CN108409728 A CN 108409728A CN 201710070005 A CN201710070005 A CN 201710070005A CN 108409728 A CN108409728 A CN 108409728A
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alkyl
compound
alkoxy
present
pharmaceutical composition
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CN108409728B (en
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金传飞
易超
张英俊
段振芳
王克柱
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Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

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Abstract

The present invention relates to phenyl octahydro 1H pyridos [1,2 a] pyrazines derivatives and its application methods and purposes, specifically disclose a kind of phenyl octahydro 1H pyridos [1,2 a] pyrazines derivatives and its pharmaceutical composition for inhibiting 5 hydroxytryptamine reuptakes.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and their purposes in pivot nervous system dysfunction, the especially disturbance of emotion in the treatment.

Description

Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives and application thereof
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating central nervous system dysfunction, especially feelings The compound and composition and its application method and purposes of sense obstacle.Particularly, of the present invention is that can be used as 5- hydroxyl colors Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives of amine reuptaking inhibitor.
Background technology
Serotonin (5-HT, serotonin), a kind of neurotransmitter for transmitting signal in brain and nervous system, In central nervous system (CNS) dysfunction, especially in anxiety, depression, invasion and impulsion mood, important angle play Color.Serotonin Transporter (5-HT transporter, 5-HTT/serotonin transporter, SERT) is a kind of right 5-HT has the transmembrane transporter of high affinity, it reuptakes serotonin from nerve synapse gap and enters presynaptic god Through member, the concentration of synaptic cleft serotonin is directly affected.
In history, the drug therapy of the disturbance of emotion start from the 1950s, including tricyclic antidepressant (TCAs) and Monoamine oxidase inhibitors (MAOIs), these drugs are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl colors Amine) blocking effect play curative effect.However, the non-selective and undesirable side effect to target limits making for they With.To in the 1980s, selective serotonin reuptake inhibitor (selective serotonin reuptake Inhibitors, SSRIs) appearance, change this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect It is small, even if (Sarko J.Andidepressant, old and new.A review smaller if the toxicity of excessive use generation of their adverse effects and toxicity in overdose.Emerg Med Clin North Am, 2000；18(4):637-54).Selective serotonin reuptake inhibitor mainly generates inhibiting effect to 5-HT transporters, Can effectively by with 5-HT transporters in conjunction with by inhibit central nervous system presynaptic membrane from synaptic cleft absorb 5-HT, increase For the 5-HT actually utilized in gap, to achieve the purpose that treatment.
All with the relevant indication of serotonin dysfunction, depression is most important, because being defended according to the world Raw Organization, depression have become the fourth-largest burden property disease of the mankind.The year two thousand twenty is expected, the disability of depression adjusts the service life Annual meeting leaps to the second of all diseases.(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMC Med.2011,9:90)。
However, the phenomenon that clinical research in relation to depression shows not responding to known SSRIs is very prominent, another It usually will appear delay through the therapeutic effect that commonly overlooked factor is SSRIs in anti depressant therapy, symptom is being treated sometimes It is former week in can also deteriorate.In addition, sex dysfunction is common side effect for SSRIs.It is therefore desirable to develop energy Enough compounds for improving treatment depression and other serotonin relevant diseases.
Invention content
The present invention provides a kind of noval chemical compounds with serotonin reuptake transporter inhibitory activity, have preferable clinic and answer Use foreground.Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts have later More complete explanation.All bibliography in this specification are incorporated in this by whole.When the disclosure of the specification with When citation is variant, it is subject to the disclosure of the specification.
The present invention relates to a kind of novel phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives, are transported with 5-HT Body (SERT) has stronger binding affinity, can inhibit 5-HT reuptakes, so as to be used to prepare treatment central nervous system The drug of (CNS) dysfunction of uniting, is especially used to prepare the drug of the treatment disturbance of emotion, and the disturbance of emotion includes but not It is limited to, it is depression, anxiety disorder, social phobia, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, terrified Obstacle and posttraumatic stress disorder.
The compounds of this invention property is stablized, good security, has good pharmacodynamics and pharmacokinetic property, such as Good brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., therefore Has preferable potential applicability in clinical practice.
Pharmaceutical composition the present invention also provides the method for preparing this kind of compound and containing such compound.
On the one hand, it is compound shown in formula (I) compound represented or formula (I) the present invention relates to a kind of compound Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein, Q, m, each R1、R2And R3With meaning of the present invention.
In some embodiments, Q is-O- ,-S- ,-SO- ,-SO2-、-CH2Or-NH-.
In some embodiments, 0,1,2,3,4 or 5 m.
In some embodiments, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、- COOH、-CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alcoxyl Base), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6 Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In some embodiments, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6 Halogenated alkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In some embodiments, R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6 Halogenated alkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In some embodiments, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、- COOH、-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynes Base, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4What alkylamino or hydroxyl replaced C1-C4Alkyl.
In some embodiments, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、 C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
In some embodiments, R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、 C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
In some embodiments, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、- COOH、-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygen Base.
In some embodiments, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、 Methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In some embodiments, R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、 Methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In some embodiments, compound of the present invention is compound or tool with one of following structure There are the stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmacy Upper acceptable salt or its prodrug：
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention Object.
In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable figuration Agent, carrier, adjuvant or their arbitrary combination.
In some embodiments, pharmaceutical composition of the present invention includes further treatment central nervous system The drug of the drug of dysfunction, the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, conduct The salts drugs of mood stabilizers, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, as choosing Drug, nervous stimulants, nicotinic antagonists or their the arbitrary combination of selecting property serotonin reuptake inhibitor.
In other embodiments, the drug that the present invention treats central nervous system dysfunction is amitriptyline (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), Prozac (fluoxetine), Trazodone (trazodone), Sertraline (sertraline), Duloxetine (duloxetine), Fluvoxamine (fluvoxamine), Milnacipran (milnacipran), left-handed Milnacipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), Venlafaxine (venlafaxine), Dapoxetine hydrochloride (dapoxetine), Nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), Olanzapine (olanzapine), Quetiapine (quetiapine), Risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), Clozapine (clozapine), modafinil (modafinil), Mecamylamine (mecamylamine), card Ergot woods (cabergoline), adamantane (adamantane), imipramine (imipramine), Pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinindium (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), Pipamperone (pipamperone), dimension for smooth (vestipitant), Librium (chlordiazepoxide), perphenazine (perphenazine) or their arbitrary combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating central nervous system dysfunction.For example, in one embodiment, the drug is used for It prevents, treats or mitigates mammalian central nervous system dysfunction, in another embodiment, the drug is for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In some embodiments, the central nervous system dysfunction refers to depression, anxiety disorder, social phobia Disease, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, spirit point Split disease, sleep disturbance, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain barrier Hinder, cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal Symptom and premenstrualtension syndrome.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating the disturbance of emotion.
In some embodiments, the disturbance of emotion includes but is not limited to depression, anxiety disorder, social phobia Disease, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for inhibiting serotonin reuptake transporter.
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
Biological results show that the compounds of this invention has strong affinity to people source 5-HT transporters (SERT), and It can be used as preferable selective serotonin reuptake inhibitor.
In addition, there is some compounds of the invention serotonin reuptake transporter inhibition and norepinephrine reuptake to inhibit Property synergy, other of the invention compounds have serotonin reuptake transporter inhibition and dopamine reuptake inhibition There are serotonin, norepinephrine and the triple reuptakes of dopamine to inhibit to make for synergy, the other compound of the present invention With.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted 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 Content in terms of him will make more specific complete description below.
Detailed description of the invention book
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 that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention 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 not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, 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 identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March,John Wiley&Sons,New York:Description in 2007, entire contents are incorporated by reference into the present invention.
There is apparent 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, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.
Term " stereoisomer " refers to having identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, rotamer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to some such compounds, raw material, composition and/or dosage form, they are cured rationally Learn judge in the range of, be suitable for patient tissue contacts and without excessive toxicity, irritation, allergy or with rational profit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched State the case where occurring including the wherein described event or situation and the case where wherein it does not occur.For example, " optional key " refers to The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or a kind of compound for being included as example, subclass and the present invention special inside embodiment.
Term " optionally by ... replaces ", can be exchanged with term " unsubstituted or by ... .. replaces " makes With that is, described structure is unsubstituted or is replaced by one or more substituent groups of the present invention, of the present invention to take Dai Ji includes, but are not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, naphthenic base, Heterocycle, aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, not influencing mutually, can also indicating in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " undersaturated " expression part.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is respectively represented it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Term " halogen " and " halogenated " 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 ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group 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 A 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), tertiary butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention The substituent group stated is replaced comprising the positioning of " cis " and " trans ", or " E " and " Z " positioning.
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one tri- keys of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention The substituent group stated is replaced.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning 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 group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 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 " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom； In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), ethylmercapto group (EtS ,- SCH2CH3), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH2CH2CH3), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH (CH3)2), 1- butylthios (n-BuS, n- butylthio ,-SCH2CH2CH2CH3), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur Base ,-SCH2CH(CH3)2), 2- butylthios (s-BuS, s- butylthio ,-SCH (CH3)CH2CH3), 2- methyl -2- rosickyite bases (t- BuS, t- butylthio ,-SC (CH3)3), etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..The alkylamino radicals are optionally by one or more sheets The described substituent group of invention is replaced.
Term " alkyl of hydroxyl substitution " indicates that alkyl group is replaced by one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyls, 2- hydroxyls -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyls etc..
Term " halogenated alkyl " indicates that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF3、-CH2CF3、-CHFCH3、-CH2CH2F、- CF2CH3Deng.In one embodiment, C1-C6Halogenated alkyl includes fluorine-substituted C1-C6Alkyl；In another embodiment, C1- C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl；In yet another embodiment, C1-C2Halogenated alkyl includes fluorine-substituted C1-C2 Alkyl.
Term " halogenated alkoxy " indicates that alkoxy base is replaced by one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF3、-OCH2CF3、-OCHFCH3、- OCH2CH2F、-OCF2CH3Deng.In one embodiment, C1-C6Halogenated alkoxy includes fluorine-substituted C1-C6Alkoxy；Another In embodiment, C1-C4Halogenated alkoxy includes fluorine-substituted C1-C4Alkoxy；In yet another embodiment, C1-C2Alkyl halide Oxygroup includes fluorine-substituted C1-C2Alkoxy.
As described in the invention, substituent group draws one and is keyed to the member ring systems formed on the ring at center (such as formula a institutes Show) represent that substituent group is any on ring to be may replace or any rational position can be carried out replacing.For example, formula a is represented on ring Any possible substituted position can be substituted base R substitutions, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.It is completely begged for about pro-drug By following documents can be referred to：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., 2008,51,2328-2345, every document are included herein by reference.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" 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 fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.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 recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and 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, niacin Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through alkali appropriate 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 compound of group is formed by quaternary ammonium salt.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..Pharmaceutically acceptable salt further comprises appropriate, nontoxic 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-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
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, such as 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 " refers to when delivering medicine to main body come when treating disease, the component of compound is enough to this disease The treatment of disease works." therapeutically effective amount " can be with the item of compound, disease and severity and main body to be treated Part, the age, weight, gender etc. and change.
Phenyl octahydro -1H- pyridos [1,2-a] pyrazines derivatives of the present invention, pharmaceutically acceptable salt, medicine Object preparation and combinations thereof, may be used as selective serotonin reuptake inhibitor, hinder to mankind's central nervous system function Hinder, the treatment of the especially disturbance of emotion has the potential purposes, the disturbance of emotion to include but is not limited to, depression, anxiety disorder, It stress hinder after social phobia, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder and wound Hinder.
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be normal by using at an elevated temperature Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts with peracid in suitable solvent, such as is reacted with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or It is reacted with 3- chloroperoxybenzoic acids in chloroform or dichloromethane, prepares the nitrogen oxides of the compounds of this invention.
Compound can exist in a salt form shown in formula (I).In one embodiment, the salt refers to that can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be used to prepare and/or purify compound shown in formula (I) and/or for detaching compound shown in this formula (I) Enantiomer intermediate.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid of metered amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it needs to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile. Such as " 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 (Wiley-VCH, Weinheim, Germany, 2002) list of the other suitable for salt can be found in.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A 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, the present invention relates to the intermediates for preparing compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combination thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound or its individual stereoisomer shown in formula (I), isomery The racemic or non-racemic mixture of body or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
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；Gennaro A.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.
It will also be appreciated that certain compounds of the present invention can exist for treating in a free form, or if it is appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted 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.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid that can substantially reduce disclosed compound of present invention when administering to a patient and can cause not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, each excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resources 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)。
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof, the technique include that mixing is each Kind ingredient.Include the pharmaceutical composition of disclosed compound of present invention, can be mixed under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can be with compressed tablets, development piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet, intestines Molten, sugar-coat or Film coated tablets provide.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral medication.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.
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 common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral, for part or entirely Body is administered.As the parenteral that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form 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 dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.
Discontinuous patch agent can be prepared 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 patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.
The purposes of the compounds of this invention and composition
Compound and pharmaceutical composition provided by the invention can be used for preparing for preventing, treating or mitigating mammal, The drug of central nervous system dysfunction including the mankind can be used for preparing the medicine for inhibiting serotonin reuptake transporter Product.
Specifically, the amount of compound effectively detectably can selectively inhibit 5- hydroxyls in the composition of the present invention The reuptake of tryptamines, the compound of the present invention can be used as treatment mankind's central nervous system (CNS) dysfunction, especially feelings Feel the drug of obstacle, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, obsessive-compulsive disorder, terrified Breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate central nervous system dysfunction disease.It is described in response to serotonin The central nervous system dysfunction of regulation and control further comprises but is not limited to that depression, social phobia, is forced at anxiety disorder Disease, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, is slept at panic attack Dormancy obstacle, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognition Obstacle, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and Premenstrualtension syndrome etc..
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, the compound of the present invention includes its pharmaceutically acceptable derivates.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with Once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.The present invention Open compound can simultaneously, or before it or later be administered with one or more other therapeutic agents.The compounds of this invention can To be administered respectively by identical or different administration route with other therapeutic agents, or it is administered therewith with same pharmaceutical compositions.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields 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 for the preparation of the compounds of 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 It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to 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 suitable for 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 quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Tenglong 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 sodium metal reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (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 spectrometers.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as with reference to mark 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 of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level four bars HPLC-M (column models of Agilent： Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% first The CH of acid3CN) (containing the H of 0.1% formic acid2O the ratio in) at 210nm/254nm, is used using electron spray ionisation (ESI) UV is detected.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), it is detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DIPEA N, N- diisopropylethylamine
DMSO dimethyl sulfoxide (DMSO)s
MeCN、CH3CN acetonitriles
EtOAc, EA ethyl acetate
MeOH methanol
G grams
H hours
ML, ml milliliters
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention times
N2Nitrogen
H2Hydrogen
NaCl sodium chloride
KCl potassium chloride
Na2SO4Sodium sulphate
NaNO2Sodium nitrite
KI potassium iodide
Pd/C palladium carbons
Pd2(dba)3Tris(dibenzylideneacetone) dipalladium
HCl hydrochloric acid
T-BuOK potassium tert-butoxides
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
BSA bovine serum albumins
Following synthetic schemes describes the step of preparing disclosed compound of present invention, unless otherwise stated, wherein each R1、R2、 R3There is definition of the present invention with m.
Synthetic schemes 1
Compound (5) can be prepared by following process：The fluoro- 2- nitrobenzenes of 1- containing different substituents (1) Under alkaline condition with octahydro -1H- pyridos [1,2-a] pyrazine containing different substituents be obtained by the reaction compound (2), compound (2) by palladium carbon catalytic hydrogenation obtain compound (3), compound (3) pass through successively diazotising, iodine replace to obtain compound (4), Compound (4) with the benzenethiol containing different substituents be coupled to obtain under palladium chtalyst compound (5)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:The conjunction of 2- (2- ((2,4- 3,5-dimethylphenyls) is thio) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine At
The synthesis of step 1) 2- (2- nitrobenzophenones) octahydro -1H- pyridos [1,2-a] pyrazine
Successively by the fluoro- 2- nitrobenzenes (1.2g, 8.56mmol) of 1-, octahydro -1H- pyridos [1,2-a] pyrazine (1.0g, 7.13mmol), n,N-diisopropylethylamine (1.9mL, 10.7mmol) is added in n,N-Dimethylformamide (20mL), nitrogen The lower reaction of protection is warming up to 90 DEG C and reacts 4 hours.After reaction, it is cooled to room temperature, reaction solution adds water (80mL) to dilute, dichloro Methane (30mL × 3) extracts, and merges organic phase, is washed successively by water (50mL), saturated salt solution (50mL), and anhydrous sodium sulfate is dry Dry, vacuum distillation removes solvent, and gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=5:1) into One step purifies to obtain title compound (yellow oil, 1.74g, 93.4%).
MS(ESI,pos.ion)m/z:262.25[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.71 (dd, J=8.1,1.5Hz, 1H), 7.46-7.36 (m, 1H), 7.10 (dd, J=8.3,0.9Hz, 1H), 7.01-6.95 (m, 1H), 3.13 (dt, J=7.7,2.6Hz, 1H), 3.05 (td, J= 11.6,2.7Hz, 1H), 2.99 (dt, J=11.6,2.5Hz, 1H), 2.82 (d, J=11.3Hz, 1H), 2.75 (dt, J= 11.3,2.4Hz, 1H), 2.64 (dd, J=11.4,10.3Hz, 1H), 2.43 (td, J=11.4,3.2Hz, 1H), 2.16-2.06 (m, 2H), 1.73 (dd, J=11.3,1.7Hz, 1H), 1.67-1.54 (m, 2H), 1.50 (d, J=12.2Hz, 1H), 1.29 (dt, J=12.8,4.0Hz, 1H), 1.24-1.18 (m, 1H)
The synthesis of step 2) 2- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) aniline
2- (2- nitrobenzophenones) octahydro -1H- pyridos [1,2-a] pyrazines (1.7g, 6.5mmol) are added to methanol In (30mL), 10% palladium carbon (200mg) is added under atmosphere of hydrogen, reacts at room temperature 9 hours.Stop reaction, filter, collects filtrate, Vacuum distillation removes solvent, and gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=5:1) into one Step purifying obtains title compound (red oil, 1.40g, 93.0%).
MS(ESI,pos.ion)m/z:232.25[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.83 (dd, J=7.8,1.4Hz, 1H), 7.45-7.32 (m, 1H), 7.10 (dd, J=8.3,0.9Hz, 1H), 7.03 (dd, J=8.0,1.4Hz, 1H), 3.13 (dt, J=7.7,2.6Hz, 1H), 3.05 (td, J=11.6,2.7Hz, 1H), 2.99 (dt, J=11.6,2.5Hz, 1H), 2.82 (d, J=11.3Hz, 1H), 2.75 (dt, J=11.3,2.4Hz, 1H), 2.64 (dd, J=11.4,10.3Hz, 1H), 2.43 (td, J=11.4,3.2Hz, 1H), 2.16-2.06 (m, 2H), 1.73 (dd, J=11.3,1.7Hz, 1H), 1.67-1.54 (m, 2H), 1.50 (d, J=12.2Hz, 1H), 1.29 (dt, J=12.8,4.0Hz, 1H), 1.24-1.18 (m, 1H)
The synthesis of step 3) 2- (2- iodophenyls) octahydro -1H- pyridos [1,2-a] pyrazine
2- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) aniline (1.4g, 6.05mmol) is added to acetonitrile The in the mixed solvent of (30mL) and water (8mL), reaction are placed under the conditions of 0 DEG C, and hydrochloric acid (8mL) and Asia are sequentially added under nitrogen protection Potassium iodide (1.31g, 7.87mmol) is added in sodium nitrate (0.5g, 7.26mmol), reaction after forty minutes, and reaction after ten minutes switchs to It reacts at room temperature and stays overnight.After reaction, reaction solution adds water (40mL) to dilute, and dichloromethane (20mL × 3) extraction merges organic Phase is washed by water (50mL), saturated salt solution (50mL) successively, and anhydrous sodium sulfate drying, vacuum distillation removes solvent, and gained is thick Product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=1:1) it is further purified to obtain title compound (Huang Color grease, 0.79g, 38%).
MS(ESI,pos.ion)m/z:343.15[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.83 (dd, J=7.8,1.4Hz, 1H), 7.29 (td, J=7.9, 1.4Hz, 1H), 7.03 (dd, J=8.0,1.4Hz, 1H), 6.77 (td, J=7.7,1.5Hz, 1H), 3.21-3.16 (m, 1H), 3.07 (dt, J=11.1,2.5Hz, 1H), 2.93 (td, J=11.4,2.6Hz, 1H), 2.88 (d, J=11.3Hz, 1H), 2.84 (dt, J=11.0,2.3Hz, 1H), 2.54 (m, 2H), 2.28-2.21 (m, 1H), 2.15 (td, J=11.5,3.6Hz, 1H), 1.77 (d, J=12.8Hz, 1H), 1.71-1.61 (m, 3H), 1.55 (dd, J=7.1,6.0Hz, 1H), 1.37-1.23 (m, 3H).
The synthesis of step 4) 2- (2- ((2,4- 3,5-dimethylphenyls) is thio) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine
Successively by 2- (2- iodophenyls) octahydro -1H- pyridos [1,2-a] pyrazine (0.3g, 0.88mmol), 2,4- dimethyl Benzenethiol (0.18g, 1.3mmol), tris(dibenzylideneacetone) dipalladium (41mg, 0.044mmol), bis- (2- diphenylphosphines phenyl) Ether (72mg, 0.13mmol) and potassium tert-butoxide (0.2g, 1.80mmol) are added in DMSO (12mL), are reacted and are risen under nitrogen protection Temperature to 130 DEG C react 30 hours.After reaction, it is cooled to room temperature, reaction solution adds water (20mL) to dilute, dichloromethane (10mL × 3) it extracts, merges organic phase, use water (30mL), saturated salt solution (30mL) to wash successively, anhydrous sodium sulfate drying, decompression is steamed Distillation goes solvent, gained crude product to pass through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=2:1) it is further purified Obtain title compound (yellow oil, 0.25g, 81%).
MS(ESI,pos.ion)m/z:353.25[M+H]+；
1H NMR(600MHz,CDCl3) δ 7.33 (d, J=7.7Hz, 1H), 7.16 (s, 1H), 7.08 (d, J=4.3Hz, 2H), 7.03 (d, J=7.1Hz, 1H), 6.94-6.87 (m, 1H), 6.51 (d, J=7.8Hz, 1H), 3.65 (m, 2H), 3.34 (m, 3H), 3.24 (t, J=11.5Hz, 1H), 3.08 (m, 2H), 2.69 (d, J=11.0Hz, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 2.05 (d, J=13.7Hz, 1H), 1.95 (m, 2H), 1.85 (m, 2H), 1.53 (dd, J=9.7,3.6Hz, 1H)；
13C NMR(150MHz,CDCl3)δ(ppm):146.8,142.2,139.6,136.1,134.4,131.9,128.0, 127.1,126.4,126.0,125.7,120.6,64.1,54.9,54.4,54.4,48.8,26.6,22.9,22.1,21.2, 20.6；
HPLC:95.60%.
Embodiment 2:2- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- aminomethyl phenyls) octahydro -1H- pyridos [1,2-a] The synthesis of pyrazine
The synthesis of step 1) 2- (4- methyl -2- nitrobenzophenones) octahydro -1H- pyridos [1,2-a] pyrazine
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e. the fluoro- 4- methyl -2- of 1- Nitrobenzene (1.33g, 8.56mmol), octahydro -1H- pyridos [1,2-a] pyrazine (1.0g, 7.13mmol) and N, N- diisopropyl 90 DEG C of reactions are prepared ethamine (1.9mL, 10.7mmol) for 4 hours under nitrogen protection in DMF (20mL).Gained crude product passes through silicon Glue-line analyses chromatographic column (petroleum ether:Ethyl acetate (V:V)=1:1) be further purified to obtain title compound (yellow oil, 1.9g, 97.0%).
MS(ESI,pos.ion)m/z:276.25[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.04 (d, J=2.0Hz, 1H), 7.59 (dd, J=8.8,2.1Hz, 1H), 7.07 (d, J=8.8Hz, 1H), 3.25-3.21 (m, 2H), 3.08 (d, J=12.3Hz, 1H), 2.86-2.79 (m, 2H), 2.77 (dt, J=11.5,2.4Hz, 1H), 2.44-2.34 (m, 1H), 2.24 (s, 3H), 2.12-1.06 (m, 2H), 1.76 (d, J =13.1Hz, 1H), 1.66 (d, J=13.2Hz, 1H), 1.62-1.54 (m, 1H), 1.51 (d, J=12.1Hz, 1H), 1.23- 1.89(m,2H).
The synthesis of step 2) 2- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) -5- methylanilines
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e. 2- (4- methyl -2- nitre Base phenyl) octahydro -1H- pyridos [1,2-a] pyrazine (1.9g, 6.9mmol) and 10% palladium carbon (200mg) be at methanol (30mL) In, it reacts at room temperature 9 hours and prepares under atmosphere of hydrogen.Gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=5:1) it is further purified to obtain title compound (red oil, 1.4g, 83.0%).
MS(ESI,pos.ion)m/z:246.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.70 (d, J=1.5Hz, 1H), 7.13 (dd, J=8.0,1.3Hz, 1H), 6.95 (d, J=8.1Hz, 1H), 3.15 (dd, J=11.2,2.4Hz, 1H), 3.04 (dt, J=11.0,2.4Hz, 1H), 2.85 (m, 2H), 2.81 (dt, J=11.0,2.2Hz, 1H), 2.57-2.53 (m, 1H), 2.51-2.47 (m, 1H), 2.24 (s, 3H), 2.21-2.19 (m, 1H), 2.13 (td, J=11.5,3.6Hz, 1H), 1.76 (d, J=12.7Hz, 1H), 1.66 (m, 2H),1.56-1.50(m,1H),1.33-1.22(m,2H).
The synthesis of step 3) 2- (the iodo- 4- aminomethyl phenyls of 2-) octahydro -1H- pyridos [1,2-a] pyrazine
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e. 2- (octahydro -1H- pyrroles Pyridine simultaneously [1,2-a] pyrazine -2 (6H)-yl) -5- methylanilines (1.4g, 5.7mmol) and hydrochloric acid (5mL), sodium nitrite (0.47g, It 6.85mmol) is reacted 40 minutes under the conditions of the in the mixed solvent of acetonitrile (24mL) and water (8mL) is in 0 DEG C, iodate is then added Potassium (1.23g, 7.42mmol) switchs to react at room temperature obtained by overnight preparation.Gained crude product passes through silica gel column chromatography chromatographic column (oil Ether:Ethyl acetate (V:V)=5:1) it is further purified to obtain title compound (yellow oil, 1.46g, 71.8%).
MS(ESI,pos.ion)m/z:246.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.66 (d, J=1.3Hz, 1H), 7.09 (dd, J=8.0,1.3Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 3.13 (dd, J=11.2,2.4Hz, 1H), 3.01 (dt, J=11.0,2.4Hz, 1H), 2.88 (m, 2H), 2.82 (dt, J=11.0,2.2Hz, 1H), 2.56-2.51 (m, 1H), 2.51-2.46 (m, 1H), 2.24 (s, 3H), 2.22-2.19 (m, 1H), 2.14 (td, J=11.5,3.6Hz, 1H), 1.76 (d, J=12.7Hz, 1H), 1.66 (m, 2H),1.56-1.50(m,1H),1.33-1.22(m,2H).
Step 4) 2- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- aminomethyl phenyls) octahydro -1H- pyridos [1,2-a] pyrrole The synthesis of piperazine
Step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e. 2- (the iodo- 4- methylbenzenes of 2- Base) octahydro -1H- pyridos [1,2-a] pyrazine (0.40g, 1.1mmol), 2,4- thiophenol dimethyl benzenes (0.23g, 1.7mmol), Tris(dibenzylideneacetone) dipalladium (52mg, 0.056mmol), bis- (2- diphenylphosphines phenyl) ethers (93mg, 0.17mmol) and uncle Butanol potassium (0.25g, 2.2mmol) reacts under nitrogen protection at 130 DEG C 30 hours in DMSO (12mL) to be prepared.Gained crude product Pass through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=2:1) it is further purified to obtain title compound (yellow oil Shape object, 0.35g, 85.0%).
MS(ESI,pos.ion)m/z:367.35[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.33 (d, J=7.8Hz, 1H), 7.17 (s, 1H), 7.07-7.03 (m, 1H), 7.01 (d, J=8.0Hz, 1H), 6.92 (dd, J=8.0,1.3Hz, 1H), 6.37 (d, J=1.4Hz, 1H), 3.70- 3.63 (m, 2H), 3.36 (m, 2H), 3.25 (m, 2H), 3.11 (s, 1H), 3.01 (dd, J=10.9,4.5Hz, 1H), 2.68 (t, J=11.6Hz, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H), 2.09 (d, J=14.3Hz, 1H), 1.98 (t, J =11.7Hz, 2H), 1.89 (d, J=14.4Hz, 1H), 1.83 (d, J=12.0Hz, 1H), 1.55 (dt, J=13.3,3.7Hz, 1H)；
13C NMR(150MHz,CDCl3)δ(ppm):144.6,141.9,139.3,135.7,135.5,133.8,131.8, 127.9,127.4,127.1,126.8,120.5,64.0,54.8,54.5,54.4,49.0,26.6,22.9,22.2,21.2, 21.0,20.6；
HPLC:97.66%.
Embodiment 3:3- ((2,4- 3,5-dimethylphenyls) is thio) -4- (octahydro -1H- pyridos [1,2-a] pyrazines -2 (6H) - Base) cyanophenyl synthesis
The synthesis of step 1) 4- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) -3- p-nitriles
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e. the fluoro- 3- nitrobenzenes of 4- Nitrile (1.42g, 8.56mmol), octahydro -1H- pyridos [1,2-a] pyrazine (1.0g, 7.13mmol) and N, N- diisopropylethylamine (1.9mL, 10.7mmol) 90 DEG C of reactions are prepared for 4 hours under nitrogen protection in DMF (20mL).Gained crude product passes through layer of silica gel Analyse chromatographic column (petroleum ether:Ethyl acetate (V:V)=1:1) be further purified to obtain title compound (yellow oil, 2.0g, 98.0%).
MS(ESI,pos.ion)m/z:287.25[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.03 (d, J=2.0Hz, 1H), 7.59 (dd, J=8.8,2.1Hz, 1H), 7.07 (d, J=8.8Hz, 1H), 3.26-3.21 (m, 2H), 3.08 (d, J=12.3Hz, 1H), 2.86-2.79 (m, 2H), 2.77 (dt, J=11.5,2.4Hz, 1H), 2.44-2.34 (m, 1H), 2.12-1.06 (m, 2H), 1.76 (d, J=13.1Hz, 1H), 1.66 (d, J=13.2Hz, 1H), 1.62-1.54 (m, 1H), 1.51 (d, J=12.1Hz, 1H), 1.23-1.89 (m, 2H).
The synthesis of step 2) 3- amino -4- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) cyanophenyl
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e. 4- (octahydro -1H- pyrroles Pyridine simultaneously [1,2-a] pyrazine -2 (6H)-yl) -3- p-nitriles (2.0g, 7.0mmol) and 10% palladium carbon (200mg) be in methanol It reacts at room temperature 9 hours and prepares in (30mL), under atmosphere of hydrogen.Gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Acetic acid Ethyl ester (V:V)=5:1) it is further purified to obtain title compound (red oil, 1.5g, 84.0%).
MS(ESI,pos.ion)m/z:257.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.93 (d, J=2.1Hz, 1H), 7.57 (dd, J=8.5,2.1Hz, 1H), 6.95 (d, J=8.3Hz, 1H), 3.29-3.18 (m, 2H), 3.05 (dt, J=12.3,2.5Hz, 1H), 2.88 (d, J= 11.3Hz, 1H), 2.83-2.79 (m, 2H), 2.42 (td, J=11.3,3.9Hz, 1H), 2.13-2.07 (m, 2H), 1.76 (d, J =13.0Hz, 1H), 1.68 (d, J=13.2Hz, 1H), 1.65 (m, 1H), 1.51 (d, J=12.0Hz, 1H), 1.37-1.23 (m,2H).
The synthesis of step 3) 4- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) -3- ioxynil
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e. 3- amino -4- (eight Hydrogen -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) cyanophenyl (1.5g, 5.85mmol) and hydrochloric acid (5mL), sodium nitrite (0.49g, 7.02mmol) reacts 40 minutes under the conditions of the in the mixed solvent of acetonitrile (24mL) and water (8mL) is in 0 DEG C, then adds Enter potassium iodide (1.26g, 7.61mmol), switchs to react at room temperature obtained by overnight preparation.Gained crude product passes through silica gel column chromatography chromatography Column (petroleum ether:Ethyl acetate (V:V)=5:1) it is further purified to obtain title compound (yellow solid, 1.50g, 70%).
MS(ESI,pos.ion)m/z:368.90[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.04 (d, J=1.9Hz, 1H), 7.55 (dd, J=8.3,1.9Hz, 1H), 6.97 (d, J=8.3Hz, 1H), 3.29 (dd, J=11.4,2.6Hz, 1H), 3.17 (dt, J=11.3,2.6Hz, 1H), 2.93 (td, J=11.5,2.6Hz, 1H), 2.88-2.80 (m, 2H), 2.57-2.47 (m, 2H), 2.21 (t, J=10.4Hz, 1H), 2.12 (td, J=11.8,3.1Hz, 1H), 1.80-1.73 (m, 1H), 1.70-1.58 (m, 2H), 1.55-1.51 (m, 1H),1.39-1.18(m,2H).
Step 4) 3- ((2,4- 3,5-dimethylphenyls) is thio) -4- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) The synthesis of cyanophenyl
Step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e. 4- (octahydro -1H- pyridines And [1,2-a] pyrazine -2 (6H)-yl) -3- ioxynil (0.30g, 0.82mmol), 2,4- thiophenol dimethyl benzenes (0.17g, 1.2mmol), tris(dibenzylideneacetone) dipalladium (38mg, 0.041mmol), bis- (2- diphenylphosphines phenyl) ethers (67mg, 0.12mmol) reacts 30 hours and make at 130 DEG C under nitrogen protection in DMSO (12mL) with potassium tert-butoxide (0.18g, 1.6mmol) It is standby.Gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=2:1) it is further purified to obtain title Compound (yellow oil, 0.18g, 58%).
MS(ESI,pos.ion)m/z:378.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.37 (d, J=7.8Hz, 1H), 7.32 (dd, J=8.2,1.9Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=7.7Hz, 1H), 7.02 (d, J=8.2Hz, 1H), 6.65 (d, J=1.9Hz, 1H), 3.42 (dd, J=11.4,2.5Hz, 1H), 3.29 (dt, J=11.3,2.5Hz, 1H), 3.04-2.98 (m, 1H), 2.89 (dd, J =14.3,11.9Hz, 2H), 2.61 (t, J=10.7Hz, 1H), 2.58-2.52 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.26-2.24 (m, 1H), 2.17 (td, J=11.4,3.9Hz, 1H), 1.83-1.75 (m, 1H), 1.72-1.64 (m, 2H), 1.59 (d, J=10.4Hz, 1H), 1.34-1.33 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.6,142.6,140.6,136.7,136.1,132.3,129.4, 128.9,128.4,125.8,119.6,119.2,106.9,61.3,56.9,55.5,55.0,51.0,29.5,25.6,23.9, 21.3,20.5；
HPLC:98.26%.
Embodiment 4:2- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- (trifluoromethyl) phenyl) octahydro -1H- pyridos The synthesis of [1,2-a] pyrazine
The synthesis of step 1) 2- (2- nitros -4- (trifluoromethyl) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e. the fluoro- 2- nitros -4- of 1- (trifluoromethyl) benzene (1.8g, 8.56mmol), octahydro -1H- pyridos [1,2-a] pyrazine (1.0g, 7.13mmol) and N, N- bis- 90 DEG C of reactions are prepared wopropyl ethyl amine (1.9mL, 10.7mmol) for 4 hours under nitrogen protection in DMF (20mL).Gained crude product Pass through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=1:1) it is further purified to obtain title compound (yellow oil Shape object, 2.33g, 95.0%).
MS(ESI,pos.ion)m/z:330.25[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.03 (d, J=1.5Hz, 1H), 7.63 (dd, J=8.8,1.9Hz, 1H), 7.14 (d, J=8.7Hz, 1H), 3.26-3.15 (m, 2H), 3.07 (dt, J=12.1,2.5Hz, 1H), 2.86 (d, J= 11.3Hz, 1H), 2.81-2.74 (m, 2H), 2.44 (td, J=11.3,3.9Hz, 1H), 2.19-2.07 (m, 2H), 1.78 (d, J =13.0Hz, 1H), 1.68 (d, J=13.2Hz, 1H), 1.61 (m, 1H), 1.54 (d, J=12.0Hz, 1H), 1.37-1.19 (m,2H).
The synthesis of step 2) 2- (octahydro -1H- pyridos [1,2-a] pyrazine -2 (6H)-yl) -5- (trifluoromethyl) aniline
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e. 2- (2- nitros -4- (trifluoromethyl) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine (2.23g, 6.77mmol) and 10% palladium carbon (250mg) be in first It reacts at room temperature 9 hours and prepares in alcohol (30mL), under atmosphere of hydrogen.Gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Second Acetoacetic ester (V:V)=5:1) it is further purified to obtain title compound (red oil, 1.85g, 91.3%).
MS(ESI,pos.ion)m/z:300.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05 (d, J=1.6Hz, 1H), 7.51 (dd, J=8.4,1.6Hz, 1H), 7.04 (d, J=8.3Hz, 1H), 3.25-3.19 (m, 1H), 3.05 (dt, J=11.1,2.5Hz, 1H), 2.97 (td, J= 11.4,2.6Hz, 1H), 2.86 (d, J=11.3Hz, 1H), 2.82 (dt, J=11.0,2.3Hz, 1H), 2.51 (m, 2H), 2.27-2.21 (m, 1H), 2.19 (td, J=11.5,3.6Hz, 1H), 1.76 (d, J=12.8Hz, 1H), 1.73-1.65 (m, 3H), 1.51 (dd, J=7.1,6.0Hz, 1H), 1.31-1.23 (m, 3H)
The synthesis of step 3) 2- (2- iodo- 4- (trifluoromethyl) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e. 2- (octahydro -1H- pyrroles Pyridine simultaneously [1,2-a] pyrazine -2 (6H)-yl) -5- (trifluoromethyl) aniline (1.85g, 6.18mmol) and hydrochloric acid (5mL), nitrous acid Sodium (0.52g, 7.42mmol) reacts 40 minutes under the conditions of the in the mixed solvent of acetonitrile (24mL) and water (8mL) is in 0 DEG C, then Potassium iodide (1.33g, 8.04mmol) is added, switchs to react at room temperature obtained by overnight preparation.Gained crude product passes through silica gel column chromatography color Compose column (petroleum ether:Ethyl acetate (V:V)=5:1) be further purified to obtain title compound (yellow oil, 1.90g, 75%).
MS(ESI,pos.ion)m/z:411.90[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07 (d, J=1.6Hz, 1H), 7.56 (dd, J=8.4,1.6Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 3.28 (dd, J=11.3,2.6Hz, 1H), 3.16 (dt, J=11.2,2.5Hz, 1H), 2.96 (td, J=11.4,2.6Hz, 1H), 2.90-2.85 (m, 2H), 2.60-2.52 (m, 1H), 2.29-2.22 (m, 2H), 2.20-2.13 (m, 1H), 1.80 (d, J=12.9Hz, 1H), 1.73-1.60 (m, 2H), 1.60-1.54 (m, 1H), 1.30 (m, 2H).
Step 4) 2- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- (trifluoromethyl) phenyl) octahydro -1H- pyridos [1, 2-a] pyrazine synthesis
Step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e. 2- (iodo- 4- (the trifluoros of 2- Methyl) phenyl) octahydro -1H- pyridos [1,2-a] pyrazine (0.30g, 0.73mmol), 2,4- thiophenol dimethyl benzenes (0.15g, 1.1mmol), tris(dibenzylideneacetone) dipalladium (34mg, 0.037mmol), bis- (2- diphenylphosphines phenyl) ethers (60mg, 0.11mmol) reacts 30 hours and make at 130 DEG C under nitrogen protection in DMSO (12mL) with potassium tert-butoxide (0.16g, 1.5mmol) It is standby.Gained crude product passes through silica gel column chromatography chromatographic column (petroleum ether:Ethyl acetate (V:V)=2:1) it is further purified to obtain title Compound (yellow oil, 0.20g, 70%).
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.33 (d, J=7.8Hz, 2H), 7.19 (s, 1H), 7.15 (d, J= 8.2Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 6.72 (d, J=1.6Hz, 1H), 3.68 (t, J=12.2Hz, 1H), 3.45 (ddd, J=16.3,8.9,2.0Hz, 2H), 3.38 (dd, J=12.5,2.4Hz, 1H), 3.30 (dd, J=12.7,10.5Hz, 1H), 3.17-3.10 (m, 1H), 3.05 (td, J=11.4,4.1Hz, 1H), 2.74-2.60 (m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 2.08 (d, J=14.0Hz, 1H), 2.00-1.98 (m, 2H), 1.91-1.84 (m, 2H), 1.61-1.49 (m, 1H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.4,142.2,140.5,136.1,135.7,132.2,128.3, 127.6,125.5,123.0,122.9,122.9,120.5,63.9,54.9,54.1,53.9,48.4,26.6,22.8,22.1, 21.2,20.4；
HPLC:99.24%.
Biologic test
Embodiment A:Evaluate the affinity of humanization 5-HT transporter of the compound to expression in Chinese hamster ovary celI
Experimental method
Under the conditions of 22 DEG C, to cell membrane homogenate albumen (12 μ g), 2nM [3H] imipramine and buffer solution (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1%BSA) formed mixed system in, be added or be added without survey Compound is tried, is incubated 60 minutes altogether.
And in the mixed system of above-mentioned condition, 10 μM of imipramine are added, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum by pre- dipped Glass fiber filter (GF/B, Packard) fast filtering of 0.3%PEI, and use ice-cold 50mM Tris-HCl and 150mM NaCl is rinsed several times repeatedly.Dry filter membrane uses scintillation solution in scintillation counter (Topcount, Packard) (Microscint 0, Packard) calculates remaining radioactivity.Experimental result is with special relative to control group radioligand Property combine suppression percentage indicate.
Standard reference compound is imipramine, competition linearity curve is obtained by the experiment test of series concentration, to calculate Go out IC50.As a result referring to Table A, Table A is affinity experimental result of the compounds of this invention to humanization 5-HT transporters (SERT).
Affinity measurement result of the Table A the compounds of this invention to people source 5-HT transporters (SERT)
Example No. IC50(nM)
Embodiment 1 13
Embodiment 2 20
Embodiment 3 6.2
Embodiment 4 5.9
Experimental result shows that the compounds of this invention has stronger affinity to people source 5-HT transporters (SERT).
Embodiment B:Rat intravenous or gavage quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses pharmacokinetic of the compounds of this invention in rat body, and animal information refers to Table B.
Table B animal subject information tables of the present invention
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, to animal subject carry out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm from The heart 10 minutes is collected plasma solutions, and is 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 at 3,000 or 4,000rpm, plasma solutions are collected, and protected at -20 DEG C or -70 DEG C It deposits.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analyses.Analysis result shows in rat body The compounds of this invention measured by way of being injected intravenously administration and gastric infusion has exposure magnitude big, and clearance rate is low, raw The preferable pharmacokinetic properties such as object availability height.Illustrate that the compounds of this invention druggability is more preferable, there is better clinic to answer Use foreground.
The experimental results showed that the compounds of this invention has preferable pharmacokinetic property in rat body.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (10)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein：
Q is-O- ,-S- ,-SO- ,-SO2-、-CH2Or-NH-；
M is 0,1,2,3,4 or 5；
Each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-CONH2,-C (=O) NHCH3、- C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or hydroxyl substitution C1-C6Alkyl；
R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6 Halogenated alkoxy；With
R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6 Halogenated alkoxy.
2. compound according to claim 1, wherein each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、- OH、-SH、-COOH、-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkene Base, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or The C of hydroxyl substitution1-C4Alkyl.
3. compound according to claim 1, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogen For alkoxy.
4. compound according to claim 1 or 2, wherein each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、- NH2、-OH、-SH、-COOH、-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, N-propyl oxygroup or isopropyl oxygroup.
5. compound according to claim 1 or 3, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
6. compound according to claim 1, for one of following structure compound or tie with one of following Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of the compound of structure Or its prodrug：
7. a kind of pharmaceutical composition, including the compound described in claim 1-6 any one；With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is arbitrary Combination.
8. pharmaceutical composition according to claim 7 includes further treatment central nervous system dysfunction Drug, the drug of the treatment central nervous system dysfunction is amitriptyline, desipramine, Mirtazapine, Bupropion, auspicious Bo Xiting, Prozac, Trazodone, Sertraline, Duloxetine, Fluvoxamine, Milnacipran, left-handed Milnacipran, first text is gone to draw Method is pungent, vilazodone, Venlafaxine, Dapoxetine hydrochloride, Nefazodone, femoxetine, chlorimipramine, Citalopram, Escitalopram Pulan, Paxil, lithium carbonate, buspirone, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, piperazine sieve Grand, Clozapine, modafinil, Mecamylamine, Cabergoline, adamantane, imipramine, Pramipexole, thyroxine, right U.S. sand Sweet smell, quinindium, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, Pipamperone, dimension are for smooth, sharp It sleeps peaceful, perphenazine or their arbitrary combination.
9. the pharmaceutical composition described in compound or claim 7-8 any one described in claim 1-6 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating central nervous system dysfunction.
10. purposes according to claim 9, the drug is for preventing, treating or mitigating the disturbance of emotion.
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CN106279071A (en) * 2016-08-10 2017-01-04 广东东阳光药业有限公司 Phenylpiperazine derivatives and using method thereof and purposes

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