CN108069937A - Phenylpiperidine derivative and its application method and purposes - Google Patents

Phenylpiperidine derivative and its application method and purposes Download PDF

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Publication number
CN108069937A
CN108069937A CN201610986446.5A CN201610986446A CN108069937A CN 108069937 A CN108069937 A CN 108069937A CN 201610986446 A CN201610986446 A CN 201610986446A CN 108069937 A CN108069937 A CN 108069937A
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alkyl
compound
alkoxy
present
pharmaceutical composition
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CN108069937B (en
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金传飞
易超
张英俊
薛亚萍
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Abstract

The present invention relates to phenylpiperidine derivative and its application methods and purposes, specifically disclose a kind of phenylpiperidine derivative and its pharmaceutical composition for 5 hydroxytryptamine reuptakes of inhibition.The invention further relates to the purposes in the method for preparing this kind of compound and pharmaceutical composition and their pivot nervous system dysfunctions in the treatment, the particularly disturbance of emotion.

Description

Phenylpiperidine derivative and its application method and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating central nervous system dysfunction, be particularly 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 The phenylpiperidine derivative of amine reuptaking inhibitor.
Background technology
Serotonin (5-HT, serotonin), a kind of neurotransmitter that signal is transferred 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, is limited to the non-selective and undesirable side effect of target 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 excessive use, also smaller (Sarko J.Andidepressant, the old and new.A review of toxicity of 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 inhibitory action to 5-HT transporters, It can increase effectively by being combined to inhibit central nervous system presynaptic membrane with 5-HT transporters from synaptic cleft intake 5-HT For the 5-HT actually utilized in gap, so as to achieve the purpose that treatment.
In all and relevant indication of serotonin dysfunction, depression is most important, because being defended according to the world Raw Organization, depression are had become as the fourth-largest burden property disease of the mankind.Expect the year two thousand twenty, the disability adjustment service life of depression 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 Usually it is present with 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.
The present invention provides a kind of noval chemical compounds with serotonin reuptake transporter inhibitory activity, and possessing preferable clinic should Use prospect.Compared with existing similar compound, the compound of the present invention has better drug effect, medicine for property and/or toxicity Learn characteristic.
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 whole.Work as the disclosure of the specification With citation it is variant when, be subject to the disclosure of the specification.
The present invention relates to a kind of novel phenylpiperidine derivatives, have stronger combination with 5-HT transporters (SERT) Affinity can inhibit 5-HT reuptakes, so as to be used to prepare the drug for the treatment of central nervous system (CNS) dysfunction, The drug of the treatment disturbance of emotion is particularly used to prepare, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, society Hand over neurosis, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compounds of this invention property is stablized, good security, has pharmacodynamics and pharmacokinetic advantage, such as good Brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., thus possess compared with Good 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：
Each X1And X2It independently is CRxOr N；
Q is-O- ,-S (O)m-、-CH2- or-NH-；
M is 0,1 or 2；
N is 0,1,2,3,4 or 5；With
Each Rx、R1、R2And R3With meaning of the present invention.
In one embodiment, 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-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, 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-C6Alkyl halide Base, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, each RxIt 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-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R3For D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6 Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, the C of hydroxyl substitution1-C6Alkyl or C1-C6Alkylamino.
In one embodiment, each R1And RxIt 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 one embodiment, 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-C4Alkynyl, C1- C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkane Base.
In one embodiment, 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 one embodiment, each RxIt 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-C4Alkynyl, C1- C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkane Base.
In one embodiment, R3For D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4 Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, the C of hydroxyl substitution1-C4Alkyl or C1-C4Alkylamino.
In one embodiment, each R1And RxIt 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 substituted C1-C4Alkyl.
In one embodiment, 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.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In one embodiment, each RxIt 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.
In one embodiment, R3For D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup, hydroxyl first Base, 2- hydroxyethyls, N- methylaminos, N- ethylaminos, N, N- dimethylaminos or N, N- lignocaine.
Each R1And RxIt 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, just Propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, compound of the present invention, for one of following structure compound or with The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically 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 one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.
In one embodiment, pharmaceutical composition of the present invention, further comprising treatment central nervous system work( The drug of energy obstacle, the drug of the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, as feelings Feel the salts drug of stabilizer, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, alternatively Drug, nervous stimulants, nicotinic antagonists or their any combination of property serotonin reuptake inhibitor.
In another embodiment, the drug of present invention treatment 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 any 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 used to preventing, treat or mitigating central nervous system dysfunction.For example, in one embodiment, the drug is used for Prevention, treatment mitigate mammalian central nervous system dysfunction, and in another embodiment, the drug is for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In one embodiment, the central nervous system dysfunction refers to depression, anxiety disorder, social phobia Disease, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, spirit point Split disease, sleep-disorder, 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 used to preventing, treat or mitigating the disturbance of emotion.
In one embodiment, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, Obsession, 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 used to inhibit 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), because This compound provided by the invention 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 is present with 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 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 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 some 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 for being taken into account in the embodiment in the component of one.
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..
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 that is 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, 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 situation including wherein described event or situation appearance and situation that wherein it does not occur.For example, " optional key " refers to The key may have 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 substituted by one or more substituent groups, such as General formula compound above or a kind of compound included as example, subclass and the present invention special inside embodiment.
Term " optionally by ... substitutes " can exchange use, i.e., with term " unsubstituted or by ... .. substitutes " The structure is unsubstituted or is substituted by one or more substituent groups of the present invention, substituent group bag of the present invention It includes, but is not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, cycloalkyl, heterocycle, Aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and should all be interpreted broadly, both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenced mutually between expressed specific option between same-sign.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " undersaturated " expression part.
In each several part of this specification, the substituent group that the present invention discloses compound is disclosed according to radical species or scope.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 scope.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part 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.If for example, 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 represented respectively 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 " represented containing 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..
Linear chain or branch chain monovalent hydrocarbon of term " alkenyl " expression containing 2-12 carbon atom, wherein at least one carbon- Carbon sp2Double bond, wherein, the alkenyl group can optionally be substituted by one or more substituent groups described in the invention, It includes the positioning of " cis " and " trans " or the positioning of " E " and " Z ".In one embodiment, alkenyl group includes 2-6 A carbon atom；In another embodiment, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but and unlimited In vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2) etc..
Linear chain or branch chain monovalent hydrocarbon of term " alkynyl " expression containing 2-12 carbon atom, wherein at least one carbon- Tri- keys of carbon sp, wherein, the alkynyl group can optionally be substituted by one or more substituent groups described in the invention. In one embodiment, alkynyl group includes 2-6 carbon atom；In another embodiment, it is former to include 2-4 carbon for alkynyl group Son.The example of alkynyl group includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡C-CH3) etc..
Term " alkoxy " represents 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 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 " alkylthio group " represents 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 substituted.
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 substituted 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 Described substituent group is invented to be substituted.
Term " halogenated alkyl " represents that alkyl group is substituted 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 the C of fluorine substitution1-C6Alkyl；In another embodiment, C1- C4Halogenated alkyl includes the C of fluorine substitution1-C4Alkyl；In yet another embodiment, C1-C2Halogenated alkyl includes the C of fluorine substitution1-C2 Alkyl.
Term " halogenated alkoxy " represents that alkoxy base is substituted 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 the C of fluorine substitution1-C6Alkoxy；Another In embodiment, C1-C4Halogenated alkoxy includes the C of fluorine substitution1-C4Alkoxy；In yet another embodiment, C1-C2Alkyl halide Oxygroup includes the C of fluorine substitution1-C2Alkoxy.
When term " blocking group " or " PG " refer to a substituent group with other reacted with functional groups, commonly used to hinder It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for blocking or protecting the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used for blocking or protecting the functionality of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Document is can refer to for the general description of blocking group：Greene et al.,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion by pro-drug is hydrolyzed or influenced in blood or tissue through enzymatic conversion for precursor structure 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 on pro-drug By 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., 2008,51,2328-2345, every document are included herein by reference.
" metabolite " refers to specific compound or its salt in vivo by the obtained product of metabolism.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 reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, 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 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:It is 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 on books document 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 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-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that one or more solvent molecules are formed 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 Acid, ethanolamine 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.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
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, age, weight, gender etc. and change.
Phenylpiperidine derivative of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof, can be with As selective serotonin reuptake inhibitor, to controlling for mankind's central nervous system dysfunction, the particularly disturbance of emotion Treatment has potential purposes, and the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, obsession, frightened Probably breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
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 disclose compound as the present invention and be included in the 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 clearly and is defined with regard to this.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It 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, aoxidize corresponding nitrogen-containing basic substance or pass through Reacted in suitable solvent with peracid, for example, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate or It is reacted in chloroform or dichloromethane with 3- chloroperoxybenzoic acids, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refers to that substance or composition must be with other ingredients comprising preparation and/or using 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 separating 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, alkalescence 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 by making the free alkali forms of these compounds and chemistry 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 is necessary to use non-aqueous media 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, represents 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, except 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 including 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 shown in formula (I) or its individual stereoisomer, 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 include at least one pharmaceutically acceptable carrier, assistant agent or excipient and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, assistant agent and excipient agent 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 some compounds of the present invention can exist to treat or if appropriate in a free form 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 be administered can it is direct or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and to avoid the interaction that the effect of present invention discloses compound can be substantially reduced 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.It 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, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, rectify 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 some 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 well known by persons skilled in the art and method.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, assistant agent, solvent or combination thereof, it is each which includes mixing Kind ingredient.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.
Compound disclosed by the invention is usually formulated as being suitable for the dosage form administered 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, containing 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) suck, 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 with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard shell capsules, 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.
It where appropriate, can be by the dosage unit preparations microencapsulation of oral medication.It can also be prepared into extending or tieing up The composition of release is held, such as by being coated or being embedded in polymer, wax or the like by microparticle material.
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 can 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 with will not to damage other active ingredients of expected therapeutic effect common Prepare or with supplement expected from the substance co-formulation that acts on.
Pharmaceutical composition provided by the invention can be by injecting, being transfused or be implanted into parenteral administration, for local or complete Body is administered.As the parenteral administration 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 administration, including solution, mix 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 known to the technical staff in pharmaceutical science field conventional method 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, can the delivering active ingredients from patch agent be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of local administration 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 mitigate 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 composition of the invention The reuptake of tryptamines, the compound of the present invention can be used as treatment mankind's central nervous system (CNS) dysfunction, particularly feelings Feel the drug of obstacle, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, obsession, 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, and depression, anxiety disorder, are forced at social phobia Disease, panic attack, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, are slept at specific phobias 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 except beneficial in addition to, 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, therapy disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by having The present invention that the patient needed gives safe and effective amount discloses compound or the pharmaceutical composition of compound is disclosed comprising the present invention, To treat the method for disease mentioned above.
In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound It is administered by any suitable administration route, including Formulations for systemic administration and local administration.
In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound Once daily or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.It is for example, every It is administered once, twice, three times or four times.It can be administered until reaching desired therapeutic effect or indefinitely maintaining what is wanted Therapeutic effect.The present invention discloses compound or the appropriate dosage regimen comprising the pharmaceutical composition of the invention for disclosing compound depends on In the pharmacokinetic property of the compound, such as absorption, distribution and half-life period, these can be by determination of technical staff.In addition, The present invention discloses compound or the appropriate dosage regimen of the pharmaceutical composition of compound is disclosed comprising the present invention, including implementing the party The duration of case, depending on treated disease, the severity of disease being treated, the age of patient under consideration and body shape Condition, the property of the medical history of patient under consideration while therapy, desired therapeutic effect etc. are in technical staff's knowledge and experience scope Interior factor.Such technical staff should also be understood that for individual patient to the reaction of dosage regimen or as the time elapses When individual patient needs variation it may require that adjust the dosage regimen of matters.
The present invention discloses compound and can simultaneously or before it or be afterwards administered with one or more other therapeutic agents. The compounds of this invention can be respectively administered by identical or different administration route with other therapeutic agents or therewith with same medicine group Solvate form is administered.
General synthesis step
For the description present invention, embodiment is listed below.But it is to be understood that the present invention is not limited to these Examples, simply The method that the practice present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used to that this to be further illustrated 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 the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is 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 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 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.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 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 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 of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is represented with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level Four bar HPLC-M (pillar models of Agilent： 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, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), it is detected in 210nm/254nm with UV.
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
MeOH methanol
MeCN、CH3CN acetonitriles
HCl hydrogen chloride
NaNO2Sodium nitrite
KI potassium iodide
T-BuOK potassium tert-butoxides
NaHCO3Sodium acid carbonate
Na2S2O3Sodium thiosulfate
Na2SO4Sodium sulphate
10% palladium carbons of Pd/C
Pd2(dba)3Three (dibenzalacetone) two palladium
Double (2- diphenylphosphines) phenylates of DPEPhos
G grams
When h is small
ML, ml milliliters
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention times
TFA trifluoroacetic acids
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
BSA bovine serum albumins
PEI, polyethylenimine polyethyleneimine
Following synthetic schemes describes the step of preparation present invention discloses compound, unless otherwise stated, wherein each R1、R2、 X1、X2There is definition of the present invention with n.
Synthetic schemes
Compound (5) can be prepared by following process：The compound (1) and N, N- diformazan of different substituents substitution Phenylpiperidines -4- amine heats in alkaline conditions is obtained by the reaction compound (2), and compound (2) obtains compound by hydro-reduction (3), compound (3) obtains compound (4) after diazol by being formed with iodo reagent reacting, and compound (4) is under palladium chtalyst Target compound (5) is obtained by the reaction with the thiophenol (6) containing different substituents.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:The synthesis of N, N- dimethyl -1- (2- (pyrimidine -2-base sulfenyl) phenyl) piperidines -4- amine
The synthesis of step 1) N, N- dimethyl -1- (2- nitrobenzophenones) piperidines -4- amine
Successively by the fluoro- 2- nitrobenzenes (1.21g, 8.58mmol) of 1-, N, N- lupetidine -4- amine (1.00g, 7.80mmol) it is added to n,N-diisopropylethylamine (2.02g, 15.60mmol) in anhydrous DMF (15mL), under nitrogen protection, Reaction be warming up to 90 DEG C reaction 12 it is small when.Stop reaction, be cooled to room temperature.Reaction solution adds water (30mL) to dilute, dichloromethane (15mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and vacuum distillation removes solvent, and gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=25/1) and obtains title compound (light yellow solid, 1.40g, 72.0%).
MS(ESI,pos.ion)m/z:250.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.73 (dd, J=8.1,1.5Hz, 1H), 7.45~7.39 (m, 1H), 7.14~7.06 (m, 1H), 6.99~6.92 (m, 1H), 3.30 (d, J=12.4Hz, 2H), 2.80 (td, J=12.1,2.0Hz, 2H), 2.29 (s, 6H), 2.32~2.24 (m, 1H), 1.90~1.82 (m, 2H), 1.68 (qd, J=12.1,3.8Hz, 2H)
The synthesis of step 2) 1- (2- aminophenyls)-N, N- DimethYI-pineridin -4- amine
By N, N- dimethyl -1- (2- nitrobenzophenones) piperidines -4- amine (3.81g, 15.28mmol) is dissolved in absolute methanol In (45mL), 10% palladium carbon (381mg) is then added in, reaction is stirred at room temperature under atmosphere of hydrogen overnight.Stop reaction, filter, receive Collect filtrate, vacuum distillation removes solvent, and gained crude product passes through column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/ 1) title compound (white solid, 2.85g, 85.1%) is obtained.
MS(ESI,pos.ion)m/z:220.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.53 (dd, J=8.1,1.5Hz, 1H), 7.38~7.35 (m, 1H), 7.10~7.00 (m, 1H), 6.97~6.95 (m, 1H), 3.31 (d, J=12.4Hz, 2H), 2.82 (td, J=12.1,2.0Hz, 2H), 2.29 (s, 6H), 2.32~2.26 (m, 1H), 1.90~1.84 (m, 2H), 1.68 (qd, J=12.1,3.8Hz, 2H)
The synthesis of step 3) 1- (2- iodophenyls)-N, N- DimethYI-pineridin -4- amine
1- (2- aminophenyls)-N, N- DimethYI-pineridin -4- amine (2.85g, 13.0mmol) is added to acetonitrile (50mL) With the in the mixed solvent of water (60mL), concentrated hydrochloric acid (12mL) is then added in.Be slowly added at 0 DEG C sodium nitrite (1.08g, 15.65mmol), after addition, continue stirring 1 it is small when.Potassium iodide (3.45g, 20.78mmol) is added at 0 DEG C, addition finishes Afterwards, continue stirring 1 it is small when, following reaction room temperature reaction 4 it is small when.Stop reaction, dichloromethane extraction (20mL × 3), collection has Machine phase is washed successively by saturated sodium bicarbonate, hypo solution, and anhydrous sodium sulfate drying filters, collects filtrate, subtract Solvent is distilled off in pressure, and gained crude product obtains title by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Compound (yellow liquid, 2.06g, 48.0%).
MS(ESI,pos.ion)m/z:331.00[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.80 (dd, J=7.9,1.4Hz, 1H), 7.28 (td, J=7.9, 1.4Hz, 1H), 6.98 (dd, J=8.0,1.4Hz, 1H), 6.79 (td, J=7.7,1.5Hz, 1H), 3.36 (d, J=12.2Hz, 2H), 3.28 (t, J=12.2Hz, 1H), 2.81 (s, 6H), 2.70 (t, J=11.1Hz, 2H), 2.16 (d, J=11.6Hz, 2H), 1.97 (qd, J=11.9,3.8Hz, 2H)
The synthesis of step 4) N, N- dimethyl -1- (2- (pyrimidine -2-base sulfenyl) phenyl) piperidines -4- amine
Successively by 1- (2- iodophenyls)-N, N- DimethYI-pineridin -4- amine (300mg, 0.91mmol), pyrimidine -2- thiophenols Two palladium (41mg, 0.045mmol) of (152mg, 1.36mmol), three (dibenzalacetone), double (2- diphenylphosphines) phenylates (48mg, 0.09mmol) and potassium tert-butoxide (271mg, 2.42mmol) are added in DMSO (10mL), under nitrogen protection, are warming up to 120 DEG C of reactions are overnight.Stopping reaction, reaction solution adds water (30mL) to dilute, and organic phase is collected in dichloromethane (15mL × 3) extraction, Anhydrous sodium sulfate is dried, and is filtered, and collects filtrate, and vacuum distillation removes solvent, and gained crude product passes through column chromatographic isolation and purification (two Chloromethanes/methanol (v/v)=20/1) obtain title compound (yellow liquid, 160mg, 56.01%).
MS(ESI,pos.ion)m/z:315.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.46 (d, J=4.6Hz, 2H), 7.60 (dd, J=7.7,1.3Hz, 1H), 7.36 (td, J=7.9,1.4Hz, 1H), 7.11 (dd, J=10.9,4.2Hz, 1H), 7.07 (d, J=7.9Hz, 1H), 6.98 (t, J=4.7Hz, 1H), 3.38 (d, J=11.5Hz, 2H), 3.14 (t, J=10.9Hz, 1H), 2.70 (d, J= 12.2Hz, 2H), 2.69 (s, 6H), 1.98 (d, J=10.5Hz, 2H), 1.48 (d, J=10.5Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):172.7,157.4,153.4,136.5,130.6,126.2,124.7, 121.1,117.2,63.1,50.5,39.1,22.7；
HPLC:95.37%.
Embodiment 2:1- (2- ((4,6- dimethyl pyrimidine -2- bases) is thio) phenyl)-N, the conjunction of N- lupetidine -4- amine Into
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. and 1- (2- iodophenyls)- N, N- DimethYI-pineridin -4- amine (350mg, 1.06mmol), 4,6- dimethyl pyrimidine -2- thiophenols (222mg, 1.58mmol), three (dibenzalacetone) two palladium (48mg, 0.05mmol), double (2- diphenylphosphines) phenylates (57mg, 0.10mmol) and potassium tert-butoxide (316mg, 2.80mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 120mg, 33.05%).
MS(ESI,pos.ion)m/z:343.35[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.64 (d, J=7.7Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.11 (t, J=7.6Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.74 (s, 1H), 3.38 (d, J=11.9Hz, 2H), 3.20 (t, J=12.2Hz, 1H), 2.73 (d, J=11.8Hz, 2H), 2.70 (s, 6H), 2.33 (s, 6H), 1.98 (d, J=10.4Hz, 2H), 1.56 (qd, J=11.8,3.5Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):171.1,167.3,152.9,135.9,129.9,126.9,124.6, 120.9,116.4,63.1,50.6,38.9,26.1,23.7；
HPLC:99.90%.
Embodiment 3:1- (2- ((4,6- dimethoxypyridin -2- bases) is thio) phenyl)-N, N- lupetidine -4- amine Synthesis
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. and 1- (2- iodophenyls)- N, N- DimethYI-pineridin -4- amine (400mg, 1.21mmol), 4,6- dimethoxypyridin -2- thiophenols (313mg, 1.81mmol), Three (dibenzalacetone) two palladium (55mg, 0.06mmol), double (2- diphenylphosphines) phenylates (65mg, 0.12mmol) and the tert-butyl alcohol For potassium (339mg, 3.00mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column layer Analysis isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 250mg, 55.11%).
MS(ESI,pos.ion)m/z:375.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.61 (dd, J=7.7,1.5Hz, 1H), 7.30 (td, J=7.9, 1.6Hz, 1H), 7.05 (dd, J=8.0,1.1Hz, 1H), 7.02 (td, J=7.5,1.2Hz, 1H), 5.70 (s, 1H), 3.71 (s, 6H), 3.34 (d, J=11.9Hz, 2H), 2.64 (td, J=11.8,1.7Hz, 2H), 2.26 (s, 6H), 2.29~2.23 (m, 1H), 1.78 (d, J=12.1Hz, 2H), 1.52~1.46 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):170.9,170.8,154.9,137.2,129.9,126.1,123.0, 120.1,86.0,62.0,53.9,52.0,41.4,28.4；
HPLC:97.73%.
Embodiment 4:N, N- dimethyl -1- (2- ((4- (trifluoromethyl) pyrimidine -2-base) is thio) phenyl) piperidines -4- amine Synthesis
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. and 1- (2- iodophenyls)- N, N- DimethYI-pineridin -4- amine (300mg, 0.91mmol), 4- (trifluoromethyl) pyrimidine -2- thiophenols (245mg, 1.36mmol), Three (dibenzalacetone) two palladium (41mg, 0.045mmol), double (2- diphenylphosphines) phenylates (48mg, 0.09mmol) and tertiary fourth For potassium alcoholate (271mg, 2.42mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column Chromatography purifying (methylene chloride/methanol (v/v)=20/1) obtains title compound (yellow liquid, 200mg, 57.57%).
MS(ESI,pos.ion)m/z:383.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.66 (d, J=4.9Hz, 1H), 7.58 (dd, J=7.6,1.5Hz, 1H), 7.37 (td, J=7.9,1.5Hz, 1H), 7.24 (d, J=4.9Hz, 1H), 7.12~7.10 (m, 1H), 7.08 (td, J= 7.6,1.2Hz, 1H), 3.30 (d, J=11.9Hz, 2H), 2.62 (td, J=11.7,1.5Hz, 2H), 2.31~2.25 (m, 1H), 2.24 (s, 6H), 1.77 (d, J=12.1Hz, 2H), 1.21 (dd, J=12.0,3.6Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):174.4,159.3,155.7,154.89,136.2,130.8, 125.0,123.9,121.0,119.2,112.1,61.97,51.6,41.1,28.2；
HPLC:95.07%.
Embodiment 5:1- (2- ((2,4- 3,5-dimethylphenyls) is thio) phenyl)-N, the synthesis of N- lupetidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. and 1- (2- iodophenyls)- N, N- DimethYI-pineridin -4- amine (300mg, 0.91mmol), 2,4- thiophenol dimethyl benzenes (188mg, 1.36mmol), three (two Asias Benzylacetone) two palladiums (41mg, 0.045mmol), double (2- diphenylphosphines) phenylates (48mg, 0.09mmol) and potassium tert-butoxide (271mg, 2.42mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 150mg, 55.1%).
MS(ESI,pos.ion)m/z:341.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.37 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.06 (dd, J= 7.9,1.2Hz, 1H), 7.04 (dd, J=3.8,1.4Hz, 1H), 7.02 (d, J=6.7Hz, 1H), 6.87~6.82 (m, 1H), 6.52 (dd, J=7.9,1.1Hz, 1H), 3.45 (d, J=11.9Hz, 2H), 2.71 (t, J=10.9Hz, 2H), 2.57~2.52 (m, 1H), 2.44 (s, 6H), 2.35 (s, 3H), 2.32 (s, 3H), 1.97 (d, J=11.9Hz, 2H), 1.79 (qd, J=12.0, 3.7Hz,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.5,142.3,139.1,136.1,134.6,131.6,128.2, 127.8,126.3,125.4,124.2,119.8,62.5,51.6,41.1,28.2,21.2,20.6；
HPLC:99.01%.
Embodiment 6:The synthesis of N, N- dimethyl -1- (4- methyl -2- (pyrimidine -2-base is thio) phenyl) piperidines -4- amine
The synthesis of step 1) N, N- dimethyl -1- (4- methyl -2- nitrobenzophenones) piperidines -4- amine
This step title compound is prepared with reference to the described method of 1 step 1 of embodiment, i.e. the fluoro- 4- methyl -2- of 1- Nitrobenzene (3.99g, 25.72mmol), N, N- lupetidine -4- amine (3.0g, 23.40mmol) and DIPEA (6.17g, It is prepared when 47.83mmol) 90 DEG C of reactions 12 are small under nitrogen atmosphere in anhydrous DMF (30mL).Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=30/1) and obtains title compound (light yellow solid, 3.55g, 57.6%).
MS(ESI,pos.ion)m/z:264.15[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.53 (d, J=1.2Hz, 1H), 7.24 (dd, J=8.4,1.5Hz, 1H), 7.03 (d, J=8.4Hz, 1H), 3.25 (d, J=12.2Hz, 2H), 2.75 (td, J=12.0,1.8Hz, 2H), 2.30 (s, 3H), 2.29 (s, 6H), 2.28~2.21 (m, 1H), 1.84 (d, J=12.3Hz, 2H), 1.68 (qd, J=12.1, 3.8Hz,2H).
Step 2) 1- (2- amino -4- aminomethyl phenyls)-N, the synthesis of N- lupetidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 2 of embodiment, i.e. N, N- dimethyl -1- (4- methyl -2- nitrobenzophenones) piperidines -4- amine (3.55g, 13.50mmol) in methanol (30mL) through palladium carbon (355mg, 1.35mmol) prepared by catalytic hydrogenation.Gained crude product by column chromatographic isolation and purification (methylene chloride/methanol (v/v)= 20/1) title compound (yellow solid, 2.41g, 76.6%) is obtained.
MS(ESI,pos.ion)m/z:234.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.29 (d, J=1.2Hz, 1H), 7.22 (dd, J=8.4,1.5Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 3.24 (d, J=12.2Hz, 2H), 2.73 (td, J=12.0,1.8Hz, 2H), 2.31 (s, 3H), 2.27 (s, 6H), 2.25~2.20 (m, 1H), 1.84 (d, J=12.3Hz, 2H), 1.68 (qd, J=12.1, 3.8Hz,2H).
Step 3) 1- (the iodo- 4- aminomethyl phenyls of 2-)-N, the synthesis of N- lupetidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 3 of embodiment, i.e. 1- (2- amino -4- first Base phenyl)-N, N- lupetidine -4- amine (2.41g, 10.33mmol) in acetonitrile (50mL) and water (50mL) in the mixed solvent, When at 0 DEG C with concentrated hydrochloric acid (12mL) and small sodium nitrite (855mg, 12.40mmol) reaction 1.Then with potassium iodide (2.74g, When 16.51mmol) reaction 1 is small at 0 DEG C, prepared when reaction 4 is small at room temperature.After reaction, gained crude product passes through column layer Analysis isolates and purifies (methylene chloride/methanol (v/v)=15/1) and obtains title compound (yellow liquid, 1.80g, 50.7%).
MS(ESI,pos.ion)m/z:345.05[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.67 (d, J=1.2Hz, 1H), 7.10 (dd, J=8.0,1.3Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 3.48~3.40 (m, 1H), 3.35 (d, J=12.2Hz, 2H), 2.82 (s, 6H), 2.74 (t, J=11.2Hz, 2H), 2.35 (d, J=11.7Hz, 2H), 2.25 (s, 3H), 2.02 (qd, J=11.9,3.9Hz, 2H)
The synthesis of step 4) N, N- dimethyl -1- (4- methyl -2- (pyrimidine -2-base is thio) phenyl) piperidines -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- methyl of 2- Phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.87mmol), pyrimidine -2- thiophenols (146mg, 1.30mmol), three (two BENZYLIDENE ACETONE) two palladiums (39mg, 0.043mmol), double (2- diphenylphosphines) phenylates (46mg, 0.085mmol) and potassium tert-butoxide (244mg, 2.17mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 150mg, 50.29%).
MS(ESI,pos.ion)m/z:329.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.44 (d, J=4.8Hz, 2H), 7.40 (d, J=1.7Hz, 1H), 7.14 (dd, J=8.1,1.6Hz, 1H), 7.00 (d, J=8.1Hz, 1H), 6.93 (t, J=4.8Hz, 1H), 3.24 (d, J= 11.8Hz, 2H), 2.56 (td, J=11.7,1.6Hz, 2H), 2.31~2.29 (m, 1H), 2.28 (s, 3H), 2.19 (s, 6H), 2.18~2.13 (m, 2H), 1.73~1.66 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):173.1,157.2,152.3,136.5,133.4,131.0,126.0, 120.8,116.8,61.9,51.7,41.4,28.4,20.7；
HPLC:96.47%.
Embodiment 7:1- (2- ((4,6- dimethyl pyrimidine -2- bases) is thio) -4- aminomethyl phenyls)-N, N- lupetidines - The synthesis of 4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- methyl of 2- Phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.87mmol), 4,6- dimethyl pyrimidine -2- thiophenols (183mg, 1.30mmol), three (dibenzalacetone) two palladium (39mg, 0.043mmol), double (2- diphenylphosphines) phenylates (46mg, 0.085mmol) and potassium tert-butoxide (244mg, 2.17mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 155mg, 49.88%).
MS(ESI,pos.ion)m/z:357.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.45 (d, J=1.6Hz, 1H), 7.17 (dd, J=8.1,1.5Hz, 1H), 7.03 (d, J=8.1Hz, 1H), 6.79 (s, 1H), 3.33 (d, J=12.0Hz, 2H), 3.24~3.18 (m, 1H), 2.78 (t, J=11.2Hz, 2H), 2.72 (s, 6H), 2.35 (s, 6H), 2.30 (s, 3H), 1.98 (d, J=10.8Hz, 2H), 1.57 (qd, J=12.1,4.0Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):170.6,167.5,149.8,136.5,135.0,131.1,125.8, 121.0,116.7,63.0,50.8,39.2,26.1,23.4,20.6；
HPLC:96.82%.
Embodiment 8:1- (2- ((4,6- dimethoxypyridin -2- bases) is thio) -4- aminomethyl phenyls)-N, N- dimethyl piperazines The synthesis of pyridine -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- methyl of 2- Phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.87mmol), 4,6- dimethoxypyridin -2- thiophenols (225mg, 1.30mmol), three (dibenzalacetone) two palladium (39mg, 0.043mmol), double (2- diphenylphosphines) phenylates (46mg, 0.085mmol) and potassium tert-butoxide (244mg, 2.17mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 100mg, 29.53%).
MS(ESI,pos.ion)m/z:389.05[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.50 (s, 1H), 7.26 (s, 1H), 7.18 (d, J=6.1Hz, 1H), 7.05 (d, J=6.0Hz, 1H), 3.75 (s, 6H), 3.43 (d, J=6.7Hz, 2H), 3.39~3.33 (m, 1H), 2.93~ 2.81 (m, 2H), 2.78 (s, 6H), 2.32 (s, 3H), 2.05 (dd, J=11.5,5.1Hz, 2H), 1.82~1.77 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):171.0,170.6,137.6,134.6,130.9,126.0,120.4, 114.0,86.0,77.2,54.1,51.0,31.9,29.3,22.7；
HPLC:93.12%.
Embodiment 9:N, N- dimethyl -1- (4- methyl -2- ((4- (trifluoromethyl) pyrimidine -2-base) is thio) phenyl) piperazine The synthesis of pyridine -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- methyl of 2- Phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.87mmol), 4- (trifluoromethyl) pyrimidine -2- thiophenols (235mg, 1.30mmol), three (dibenzalacetone) two palladium (39mg, 0.043mmol), double (2- diphenylphosphines) phenylates (46mg, 0.085mmol) and potassium tert-butoxide (244mg, 2.17mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 120mg, 34.72%).
MS(ESI,pos.ion)m/z:397.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.70 (d, J=4.9Hz, 1H), 7.46 (d, J=1.5Hz, 1H), 7.31 (d, J=5.0Hz, 1H), 7.29~7.21 (m, 1H), 7.12 (d, J=8.2Hz, 1H), 3.39 (d, J=12.1Hz, 2H), 3.30~3.19 (m, 1H), 2.86 (t, J=11.3Hz, 2H), 2.73 (s, 6H), 2.33 (s, 3H), 2.01 (d, J= 11.4Hz, 2H), 1.57 (qd, J=11.9,3.5Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):174.0,159.8,155.9,149.71,137.1,135.8, 132.0,124.6,121.2,120.1,112.5,63.0,51.2,39.5,26.1,20.6；
HPLC:98.73%.
Embodiment 10:1- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- aminomethyl phenyls)-N, N- lupetidine -4- amine Synthesis
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- methyl of 2- Phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.87mmol), 2,4- thiophenol dimethyl benzenes (180mg, 1.30mmol), Three (dibenzalacetone) two palladium (39mg, 0.043mmol), double (2- diphenylphosphines) phenylates (46mg, 0.09mmol) and tertiary fourth For potassium alcoholate (244mg, 2.17mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column Chromatography purifying (methylene chloride/methanol (v/v)=20/1) obtains title compound (yellow liquid, 150mg, 48.53%).
MS(ESI,pos.ion)m/z:355.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.34 (d, J=7.8Hz, 1H), 7.13 (s, 1H), 7.01 (d, J= 7.8Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 6.86 (dd, J=8.0,1.3Hz, 1H), 6.36 (d, J=1.5Hz, 1H), 3.39 (d, J=11.9Hz, 2H), 2.67 (td, J=11.7,1.6Hz, 2H), 2.50~2.42 (m, 1H), 2.39 (s, 6H), 2.36 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H), 1.93 (d, J=11.9Hz, 2H), 1.75 (qd, J=12.0,3.7Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):147.4,142.0,138.8,135.6,134.1,133.8,131.6, 128.4,127.7,127.0,126.2,119.7,62.4,51.8,41.2,28.3,21.2,20.9,20.6；
HPLC:94.63%.
Embodiment 11:The synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- (pyrimidine -2-base is thio) cyanophenyl
The synthesis of step 1) 4- (4- (dimethylamino) piperidin-1-yl) -3- p-nitriles
This step title compound is prepared with reference to the described method of 1 step 1 of embodiment, i.e. the fluoro- 3- nitrobenzenes of 4- Nitrile (4.28g, 25.74mmol), N, N- lupetidine -4- amine (3.0g, 23.40mmol) and DIPEA (6.17g, It is prepared when 47.83mmol) 90 DEG C of reactions 12 are small under nitrogen atmosphere in anhydrous DMF (30mL).Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=30/1) and obtains title compound (light yellow solid, 3.05g, 47.6%).
MS(ESI,pos.ion)m/z:275.15[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.03 (d, J=2.0Hz, 1H), 7.58 (dd, J=8.8,2.0Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 3.46~3.36 (m, 2H), 3.06~2.96 (m, 2H), 2.38~2.31 (m, 1H), 2.28 (s, 6H), 1.90 (d, J=11.8Hz, 2H), 1.65 (qd, J=12.3,3.8Hz, 2H)
The synthesis of step 2) 3- amino -4- (4- (dimethylamino) piperidin-1-yl) cyanophenyl
This step title compound is prepared with reference to the described method of 1 step 2 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- p-nitriles (3.05g, 11.12mmol) in methanol (30mL) through palladium carbon (305mg, 1.11mmol) It is prepared by catalytic hydrogenation.Gained crude product is marked by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Topic compound (yellow solid, 1.40g, 52.0%).
MS(ESI,pos.ion)m/z:245.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.88 (d, J=2.0Hz, 1H), 7.52 (dd, J=8.8,2.0Hz, 1H), 6.98 (d, J=8.8Hz, 1H), 3.44~3.38 (m, 2H), 3.08~2.99 (m, 2H), 2.37~2.31 (m, 1H), 2.26 (s, 6H), 1.92 (d, J=11.8Hz, 2H), 1.66 (qd, J=12.3,3.8Hz, 2H)
The synthesis of step 3) 4- (4- (dimethylamino) piperidin-1-yl) -3- ioxynil
This step title compound is prepared with reference to the described method of 1 step 3 of embodiment, i.e. 3- amino -4- (4- (dimethylamino) piperidin-1-yl) cyanophenyl (1.40g, 5.73mmol) is in acetonitrile (30mL) and water (30mL) in the mixed solvent, and 0 When at DEG C with concentrated hydrochloric acid (8mL) and small sodium nitrite (470mg, 6.81mmol) reaction 1.Then with potassium iodide (1.5g, When 9.04mmol) reaction 1 is small at 0 DEG C, prepared when reaction 4 is small at room temperature.After reaction, gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=15/1) and obtains title compound (yellow liquid, 1.10g, 54.0%).
MS(ESI,pos.ion)m/z:356.95[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05 (d, J=1.9Hz, 1H), 7.56 (dd, J=8.3,1.9Hz, 1H), 7.03~6.96 (m, 1H), 3.44 (d, J=12.2Hz, 2H), 2.95~2.87 (m, 1H), 2.75 (t, J=11.1Hz, 2H), 2.57 (s, 6H), 2.15 (d, J=12.1Hz, 2H), 1.88 (qd, J=12.0,3.7Hz, 2H)
The synthesis of step 4) 4- (4- (dimethylamino) piperidin-1-yl) -3- (pyrimidine -2-base is thio) cyanophenyl
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- ioxynil (300mg, 0.84mmol), pyrimidine -2- thiophenols (142mg, 1.27mmol), three (two benzal Benzylacetone) two palladiums (38mg, 0.04mmol), double (2- diphenylphosphines) phenylates (45mg, 0.084mmol) and potassium tert-butoxide (236mg, 2.1mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 106mg, 36.97%).
MS(ESI,pos.ion)m/z:340.05[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.49 (d, J=4.1Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 7.61 (dd, J=8.3,1.6Hz, 1H), 7.07 (t, J=7.2Hz, 1H), 3.54 (d, J=11.5Hz, 2H), 3.21 (s, 1H), 2.77 (d, J=12.0Hz, 2H), 2.74 (s, 6H), 2.03 (d, J=9.5Hz, 2H), 1.57 (d, J=9.7Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):170.9,157.8,157.1,140.6,134.2,126.4,121.2, 118.3,117.9,107.2,63.1,49.9,39.5,26.2；
HPLC:97.51%.
Embodiment 12:4- (4- (dimethylamino) piperidin-1-yl) -3- ((4,6- dimethyl pyrimidine -2- bases) is thio) benzene The synthesis of nitrile
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- ioxynil (300mg, 0.84mmol), 4,6- dimethyl pyrimidine -2- thiophenols (177mg, 1.26mmol), Three (dibenzalacetone) two palladium (38mg, 0.04mmol), double (2- diphenylphosphines) phenylates (45mg, 0.084mmol) and tertiary fourth For potassium alcoholate (236mg, 2.1mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column Chromatography purifying (methylene chloride/methanol (v/v)=20/1) obtains title compound (yellow liquid, 100mg, 32.22%).
MS(ESI,pos.ion)m/z:368.05[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.96 (d, J=1.9Hz, 1H), 7.59 (dd, J=8.3,1.9Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 3.54 (d, J=12.0Hz, 2H), 3.29 (t, J=12.6Hz, 1H), 2.80 (d, J=11.8Hz, 2H), 2.76 (s, 6H), 2.36 (s, 6H), 2.06 (d, J=9.3Hz, 2H), 1.69 (dd, J= 11.7,3.1Hz,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):169.4,167.8,156.6,140.2,133.5,127.2,120.8, 118.5,117.1,107.1,62.9,50.1,39.1,29.7,23.7；
HPLC:94.25%.
Embodiment 13:4- (4- (dimethylamino) piperidin-1-yl) -3- ((4,6- dimethoxypyridin -2- bases) is thio) The synthesis of cyanophenyl
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- ioxynil (300mg, 0.84mmol), 4,6- dimethoxypyridin -2- thiophenols (218mg, 1.26mmol), three (dibenzalacetone) two palladium (38mg, 0.04mmol), double (2- diphenylphosphines) phenylates (45mg, 0.084mmol) and potassium tert-butoxide (236mg, 2.1mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 140mg, 41.5%).
MS(ESI,pos.ion)m/z:400.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.98 (d, J=2.0Hz, 1H), 7.59 (dd, J=8.4,2.0Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 5.77 (s, 1H), 3.74 (s, 6H), 3.56 (d, J=12.3Hz, 2H), 3.35~3.25 (m, 1H), 2.81 (t, J=11.5Hz, 2H), 2.76 (s, 6H), 2.09 (d, J=11.4Hz, 2H), 1.74 (qd, J=12.0, 3.8Hz,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):171.1,168.9,157.0,141.4,133.6,126.7,120.4, 118.4,106.6,86.7,62.7,54.2,50.3,39.0,25.9；
HPLC:98.61%.
Embodiment 14:4- (4- (dimethylamino) piperidin-1-yl) -3- ((4- (trifluoromethyl) pyrimidine -2-base) is thio) The synthesis of cyanophenyl
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- ioxynil (300mg, 0.84mmol), 4- (trifluoromethyl) pyrimidine -2- thiophenols (228mg, 1.26mmol), three (dibenzalacetone) two palladium (38mg, 0.04mmol), double (2- diphenylphosphines) phenylates (45mg, 0.084mmol) and potassium tert-butoxide (236mg, 2.1mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 103mg, 29.93%).
MS(ESI,pos.ion)m/z:408.00[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.72 (d, J=4.9Hz, 1H), 7.88 (d, J=2.0Hz, 1H), 7.65 (dd, J=8.4,2.0Hz, 1H), 7.35 (d, J=4.9Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 3.53 (d, J= 12.3Hz, 2H), 3.19~3.15 (m, 1H), 2.77 (t, J=11.5Hz, 2H), 2.70 (s, 6H), 2.06 (d, J=11.6Hz, 2H), 1.50 (qd, J=12.0,3.7Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):172.4,160.1,157.4,156.0,140.7,134.7,125.4, 121.2,120.0,118.1,113.1,107.3,62.6,50.1,39.2,26.2；
HPLC:98.64%.
Embodiment 15:The conjunction of 4- (4- (dimethylamino) piperidin-1-yl) -3- ((2,4- 3,5-dimethylphenyls) is thio) cyanophenyl Into
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 4- (4- (dimethylaminos Base) piperidin-1-yl) -3- ioxynil (300mg, 0.84mmol), 2,4- thiophenol dimethyl benzenes (175mg, 1.27mmol), three (two BENZYLIDENE ACETONE) two palladiums (38mg, 0.043mmol), double (2- diphenylphosphines) phenylates (45mg, 0.08mmol) and potassium tert-butoxide (236mg, 2.10mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 105mg, 34.01%).
MS(ESI,pos.ion)m/z:366.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.36~7.34 (m, 1H), 7.34~7.32 (m, 1H), 7.20 (s, 1H), 7.08 (d, J=7.0Hz, 1H), 7.01 (d, J=8.2Hz, 1H), 6.67 (d, J=1.8Hz, 1H), 3.62 (d, J= 12.2Hz, 2H), 3.45~3.37 (m, 1H), 2.86 (s, 6H), 2.81 (t, J=11.4Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.17 (d, J=11.5Hz, 2H), 2.01~1.91 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):151.6,142.5,140.8,136.5,132.4,129.5,129.1, 128.5,125.2,120.1,118.9,108.0,63.2,49.8,39.4,26.1,21.2,20.5；
HPLC:94.26%.
Embodiment 16:N, N- dimethyl -1- (2- (pyrimidine -2-base is thio) -4- (trifluoromethyl)-phenyl) piperidines -4- amine Synthesis
The synthesis of step 1) N, N- dimethyl -1- (2- nitros -4- (trifluoromethyl) phenyl) piperidines -4- amine
This step title compound is prepared with reference to the described method of 1 step 1 of embodiment, i.e. the fluoro- 2- nitros -4- of 1- (trifluoromethyl) benzene (1.8g, 8.58mmol), N, N- lupetidine -4- amine (1.0g, 7.80mmol) and DIPEA (2.02g, It is prepared when 15.60mmol) 90 DEG C of reactions 12 are small under nitrogen atmosphere in anhydrous DMF (15mL).Gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=30/1) and obtains title compound (light yellow solid, 1.64g, 66.2%).
MS(ESI,pos.ion)m/z:318.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.00 (s, 1H), 7.58 (dd, J=8.8,1.7Hz, 1H), 7.13 (d, J=8.8Hz, 1H), 3.37 (d, J=12.7Hz, 2H), 2.92 (dd, J=17.9,6.4Hz, 2H), 2.32 (ddd, J=14.9, 7.4,3.8Hz, 1H), 2.28 (s, 6H), 1.88 (d, J=12.2Hz, 2H), 1.68~1.62 (m, 2H)
Step 2) 1- (the synthesis of 2- amino -4- (trifluoromethyl) phenyl-N, N- lupetidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 2 of embodiment, i.e. N, N- dimethyl -1- (2- nitros -4- (trifluoromethyl) phenyl) piperidines -4- amine (1.50g, 4.73mmol) in methanol (15mL) through palladium carbon (150mg, 0.47mmol) prepared by catalytic hydrogenation.Gained crude product by column chromatographic isolation and purification (methylene chloride/methanol (v/v)= 20/1) title compound (yellow solid, 1.19g, 87.5%) is obtained.
MS(ESI,pos.ion)m/z:288.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.04 (s, 1H), 7.60 (dd, J=8.8,1.7Hz, 1H), 7.15 (d, J=8.8Hz, 1H), 3.35 (d, J=12.7Hz, 2H), 2.90 (dd, J=17.9,6.4Hz, 2H), 2.30 (ddd, J=14.9, 7.4,3.8Hz, 1H), 2.27 (s, 6H), 1.84 (d, J=12.2Hz, 2H), 1.70~1.64 (m, 2H)
Step 3) 1- (the synthesis of 2- iodo- 4- (trifluoromethyl) phenyl-N, N- lupetidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 3 of embodiment, i.e. 1- (2- amino -4- (trifluoromethyl) phenyl-N, N- lupetidine -4- amine (0.30g, 1.04mmol) is molten in acetonitrile (15mL) and water (6mL) mixing In agent, at 0 DEG C with concentrated hydrochloric acid (3mL) and sodium nitrite (86mg, 1.25mmol) reaction 1 it is small when.Then with potassium iodide (276mg, When 1.66mmol) reaction 1 is small at 0 DEG C, prepared when reaction 4 is small at room temperature.After reaction, gained crude product passes through column chromatography It isolates and purifies (methylene chloride/methanol (v/v)=15/1) and obtains title compound (yellow liquid, 0.18g, 43.5%).
MS(ESI,pos.ion)m/z:399.00[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05 (s, 1H), 7.55 (d, J=8.1Hz, 1H), 7.04 (d, J= 8.3Hz, 1H), 3.42 (d, J=11.6Hz, 2H), 2.90 (t, J=11.6Hz, 1H), 2.74 (t, J=11.5Hz, 2H), 2.59 (s, 6H), 2.15 (d, J=11.5Hz, 2H), 1.94~1.88 (m, 2H)
The conjunction of step 4) N, N- dimethyl -1- (2- (pyrimidine -2-base is thio) -4- (trifluoromethyl)-phenyl) piperidines -4- amine Into
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- (three of 2- Methyl fluoride) phenyl)-N, N- lupetidine -4- amine (400mg, 1.00mmol), pyrimidine -2- thiophenols (169mg, 1.50mmol), Three (dibenzalacetone) two palladium (45mg, 0.05mmol), double (2- diphenylphosphines) phenylates (54mg, 0.10mmol) and the tert-butyl alcohol For potassium (299mg, 2.50mmol) in DMSO (10mL), nitrogen protects 120 DEG C of reactions to prepare overnight.Gained crude product passes through column layer Analysis isolates and purifies (methylene chloride/methanol (v/v)=20/1) and obtains title compound (yellow liquid, 150mg, 39.05%).
MS(ESI,pos.ion)m/z:383.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.52 (s, 2H), 7.89 (s, 1H), 7.62 (d, J=5.8Hz, 1H), 7.19~7.04 (m, 2H), 3.50 (d, J=8.1Hz, 2H), 3.23 (s, 1H), 2.84 (s, 2H), 2.76 (s, 6H), 2.02 (d, J=6.2Hz, 2H), 1.55 (d, J=8.4Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):171.4,157.6,156.2,133.8,127.7,126.4,126.2, 123.8,121.0,117.7,63.2,50.1,39.5,29.7；
HPLC:97.05%.
Embodiment 17:1- (2- ((4,6- dimethyl pyrimidine -2- bases) is thio) -4- (trifluoromethyl)-phenyl)-N, N- diformazans The synthesis of phenylpiperidines -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- (three of 2- Methyl fluoride) phenyl)-N, N- lupetidine -4- amine (400mg, 1.00mmol), 4,6- dimethyl pyrimidine -2- thiophenols (211mg, 1.50mmol), three (dibenzalacetone) two palladium (45mg, 0.05mmol), double (2- diphenylphosphines) phenylates (54mg, 0.10mmol) and potassium tert-butoxide (299mg, 2.50mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 120mg, 29.10%).
MS(ESI,pos.ion)m/z:411.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.00 (d, J=1.6Hz, 1H), 7.56 (dd, J=8.4,1.7Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 6.79 (s, 1H), 3.47 (d, J=12.2Hz, 2H), 3.31~3.23 (m, 1H), 2.78 (d, J=11.6Hz, 2H), 2.75 (s, 6H), 2.36 (s, 6H), 2.04 (d, J=10.2Hz, 2H), 1.71~1.65 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):169.7,167.6,155.4,133.1,127.2,126.6,126.1, 123.9,120.5,116.9,63.0,50.4,39.1,26.0,23.6；
HPLC:98.21%.
Embodiment 18:1- (2- ((4,6- dimethoxypyridin -2- bases) is thio) -4- (trifluoromethyl)-phenyl)-N, N- bis- The synthesis of methyl piperidine -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- (three of 2- Methyl fluoride) phenyl)-N, N- lupetidine -4- amine (400mg, 1.00mmol), 4,6- dimethoxypyridin -2- thiophenols Two palladium (45mg, 0.05mmol) of (259mg, 1.50mmol), three (dibenzalacetone), double (2- diphenylphosphines) phenylates (54mg, 0.10mmol) and potassium tert-butoxide (299mg, 2.50mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 100mg, 22.50%).
MS(ESI,pos.ion)m/z:443.10[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.01 (d, J=1.5Hz, 1H), 7.55 (dd, J=8.4,1.6Hz, 1H), 7.10 (d, J=8.3Hz, 1H), 5.76 (s, 1H), 3.74 (s, 6H), 3.49 (d, J=11.9Hz, 2H), 3.32 (t, J= 11.9Hz, 1H), 2.81 (s, 2H), 2.78 (s, 6H), 2.08 (d, J=11.1Hz, 2H), 1.82~1.76 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):171.0,169.3,155.7,126.8,125.7,124.8,123.7, 123.0,120.1,86.6,63.0,54.1,50.5,39.1,26.0；
HPLC:97.15%.
Embodiment 19:N, N- dimethyl -1- (4- (trifluoromethyl) -2 ((4- (trifluoromethyl) pyrimidine -2-base) is thio) benzene Base) piperidines -4- amine synthesis
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- (three of 2- Methyl fluoride) phenyl)-N, N- lupetidine -4- amine (400mg, 1.00mmol), 4- (trifluoromethyl) pyrimidine -2- thiophenols Two palladium (45mg, 0.05mmol) of (271mg, 1.50mmol), three (dibenzalacetone), double (2- diphenylphosphines) phenylates (54mg, 0.10mmol) and potassium tert-butoxide (299mg, 2.50mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight. Gained crude product obtains title compound (yellow liquid by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) Body, 150mg, 45.24%).
MS(ESI,pos.ion)m/z:451.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.70 (d, J=4.9Hz, 1H), 7.86 (d, J=1.8Hz, 1H), 7.61 (dd, J=8.4,1.9Hz, 1H), 7.31 (d, J=4.9Hz, 1H), 7.14 (d, J=8.4Hz, 1H), 3.43 (d, J= 9.2Hz, 2H), 2.77~2.74 (m, 1H), 2.71 (t, J=11.1Hz, 2H), 2.47 (s, 6H), 1.92 (d, J=10.7Hz, 2H), 1.42~1.35 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):173.0,159.8,157.0,155.9,133.6,127.8,125.8, 125.2,123.8,120.8,116.8,112.7,62.2,50.8,45.7,27.1；
HPLC:99.45%.
Embodiment 20:1- (2- ((2,4- 3,5-dimethylphenyls) is thio) -4- (trifluoromethyl) phenyl)-N, N- dimethyl piperazines The synthesis of pyridine -4- amine
This step title compound is prepared with reference to the described method of 1 step 4 of embodiment, i.e. 1- (the iodo- 4- (three of 2- Methyl fluoride) phenyl)-N, N- DimethYI-pineridin -4- amine (300mg, 0.75mmol), 2,4- thiophenol dimethyl benzenes (156mg, 1.13mmol), three (dibenzalacetone) two palladium (34mg, 0.04mmol), double (2- diphenylphosphines) phenylates (40mg, 0.07mmol) and potassium tert-butoxide (224mg, 2.0mmol) is in DMSO (10mL), and nitrogen protects 120 DEG C of reactions to prepare overnight.Institute Crude product by column chromatographic isolation and purification (methylene chloride/methanol (v/v)=20/1) obtain title compound (yellow liquid, 220mg, 70.05%).
MS(ESI,pos.ion)m/z:409.30[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.34~7.29 (m, 2H), 7.17 (s, 1H), 7.05 (d, J= 8.3Hz, 2H), 6.75 (d, J=1.8Hz, 1H), 3.59 (d, J=12.2Hz, 2H), 3.35 (ddd, J=12.2,9.0, 3.6Hz, 1H), 2.82 (s, 6H), 2.79 (d, J=11.6Hz, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 2.17 (d, J= 11.6Hz, 2H), 1.97~1.91 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):151.0,142.1,140.1,135.9,135.5,132.0,128.2, 126.8,126.1,123.9,123.2,122.7,119.9,62.9,50.2,39.0,26.1,21.2,20.4；
HPLC:99.00%.
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, add in 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 in, 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, in scintillation counter (Topcount, Packard), uses scintillation solution (Microscint 0, Packard) calculates remaining radioactivity.Experimental result is with special compared with control group radioligand Property combine suppression percentage represent.
Standard reference compound is imipramine, competition linearity curve is obtained by the experiment test of series concentration, so as to calculate Go out IC50.As a result referring to Table A, Table A is the compounds of this invention to the affinity experimental result of humanization 5-HT transporters (SERT).
Table A the compounds of this invention is to the affinity measurement result of people source 5-HT transporters (SERT)
Example No. IC50(nM)
Embodiment 2 15.6
Embodiment 3 10.1
Embodiment 7 14.4
Embodiment 8 16.3
Embodiment 12 8.1
Embodiment 13 7.2
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 the compounds of this invention in the in vivo pharmacokinetic of rat, 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, animal subject is carried out to Medicine.For being injected intravenously administration group, dosage is 1mg/kg or 2mg/kg, then time point upon administration for 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 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 under 3,000 or 4,000rpm, plasma solutions are collected, and are protected at -20 DEG C or -70 DEG C It deposits.
The plasma solutions obtained are collected to above-mentioned each group and carry 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 is big with exposure magnitude, 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 preferably clinical answer Use prospect.
The experimental results showed that the compounds of this invention has preferable pharmacokinetic property in rat body.
In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", " specific example " or " some examples " etc. means to combine the specific spy that the embodiment, embodiment or example describe Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms is necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by the difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined and combine.
Although the embodiment of the present invention has 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, those of ordinary skill 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：
Each X1And X2It independently is CRxOr N；
Q is-O- ,-S (O)m-、-CH2- or-NH-；
M is 0,1 or 2；
N is 0,1,2,3,4 or 5；
Each R1And RxIt 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-C6Alkene Base, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or The C of hydroxyl substitution1-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 D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, the C of hydroxyl substitution1-C6Alkyl or C1-C6Alkylamino.
2. compound according to claim 1, wherein, each R1And RxIt 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-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkane ammonia Base 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 R1And RxIndependently be 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. the 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 the compound with one of following structure or with one of following knot Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of the compound of structure Or its prodrug：
7. a kind of pharmaceutical composition includes 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, further comprising 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, go first text 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 any 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 used to preventing, treat or mitigating central nervous system dysfunction.
10. purposes according to claim 9, the drug is used to preventing, treat or mitigating the disturbance of emotion.
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