CN105294554B - Phenylpiperazine derivatives and its application method and purposes - Google Patents

Phenylpiperazine derivatives and its application method and purposes Download PDF

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CN105294554B
CN105294554B CN201510794724.2A CN201510794724A CN105294554B CN 105294554 B CN105294554 B CN 105294554B CN 201510794724 A CN201510794724 A CN 201510794724A CN 105294554 B CN105294554 B CN 105294554B
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piperazine
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CN105294554A (en
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金传飞
梁海平
张英俊
张
亢宁
李勇
刘言萍
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Guangdong HEC Pharmaceutical
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Ruyuan Yao Autonomous County Dazhong Drug Trading Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

The invention discloses Phenylpiperazine derivatives and its application method and purposes, specifically, pharmaceutical composition the present invention relates to novel (2 (heteroaryl epoxide) phenyl) bridged piperazine derivatives of a class and comprising such compound, they can be used for suppressing 5 hydroxytryptamine reuptakes.The invention further relates to prepare the method for this kind of compound and pharmaceutical composition, and their purposes in the treatment in pivot nervous system dysfunction, the particularly disturbance of emotion.

Description

Phenylpiperazine derivatives 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, particularly feelings Feel the compound and composition of obstacle, and its application method and purposes.Especially, it is of the present invention be can be as 5- hydroxyl colors The Phenylpiperazine derivatives of amine reuptaking inhibitor.
Background technology
Serotonin (5-HT, serotonin), a kind of neurotransmitter that signal is transmitted 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, and it reuptakes serotonin into presynaptic god from nerve synapse gap 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 MAOI (MAOIs), these medicines are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl colors Amine) blocking effect play curative effect.However, the non-selective and undesirable side effect to target limits making for they With.To in the 1980s, selective serotonin reuptake inhibitor (selective serotonin reuptake Inhibitors, SSRIs) appearance, change this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect It is small, even if 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 produces inhibitory action to 5-HT transporters, Central nervous system presynaptic membrane can effectively be suppressed by being combined with 5-HT transporters and absorb 5-HT, increase from synaptic cleft The 5-HT actually utilized is available in gap, so as to reach the purpose for the treatment of.
In all indications related to serotonin dysfunction, depression is most important, because being defended according to the world Raw Organization, depression has turned into the fourth-largest burden property disease of the mankind.Expect the year two thousand twenty, the disability adjustment life-span 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 clinical research about depression shows that the phenomenon not responded to known SSRIs is protruded very much, another Delay generally occurs through the therapeutic action that commonly overlooked factor is SSRIs in anti depressant therapy, symptom is in treatment 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 It is enough to improve treatment depression and the compound of other serotonin relevant diseases.
The invention provides the noval chemical compound that a class has serotonin reuptake transporter inhibitory activity, possess preferably clinical answer Use prospect.Compared with existing similar compound, compound of the invention has more preferable drug effect, and medicine is 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 overall.Work as the disclosure of the specification With citation it is variant when, be defined by the disclosure of the specification.
The present invention relates to novel (2- (heteroaryl epoxide) phenyl) bridged piperazine derivatives of a class, itself and 5-HT transporters (SERT) there is stronger binding affinity, 5-HT reuptakes can be suppressed, so as to for preparing treatment central nervous system (CNS) medicine of dysfunction, particularly for the medicine for preparing the treatment disturbance of emotion, the disturbance of emotion includes but not limited In depression, anxiety disorder, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, terrified barrier Hinder and posttraumatic stress disorder.
The compounds of this invention property is stable, and such as security is good, good with pharmacodynamics and pharmacokinetic advantage Brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., thus possess compared with Good potential applicability in clinical practice.
The present invention, which is also provided, prepares the method for this kind of compound and the pharmaceutical composition containing such compound.
On the one hand, the present invention relates to a kind of compound, its compound shown in the compound or formula (I) shown in formula (I) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein,X、Y、R1、R2、R3、R4、R5、R6And R7With implication as described in the present invention.
In one embodiment,For singly-bound or double bond.
In one embodiment, X is-CHRx- or CRx；With each RxWith implication as described in the present invention.
In one embodiment, Y is-CHRy- or CRy；With each RyWith implication as described in the present invention.
In one embodiment,For-O- ,-S- or-NH-.
In one embodiment, R1For 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-C6Haloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R2For 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-C6Haloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
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-C6Haloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, each RyIt 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-C6Haloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, R3、R5And R6Each stand alone as H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkane Epoxide), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, R7For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Haloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R1For 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-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R2For 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-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
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- C4Haloalkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkane Base.
In one embodiment, each RyIt 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- C4Haloalkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkane Base.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
In one embodiment, R3、R5And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4Halogen For alkoxy.
In one embodiment, R1For 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, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl epoxide or isopropyl epoxide.
In one embodiment, R2For 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, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl epoxide or isopropyl epoxide.
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 epoxide or isopropyl epoxide.
In one embodiment, each RyIt 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 epoxide or isopropyl epoxide.
In one embodiment, R4For 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, R3、R5And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
Each R of the present invention1、R2、Rx、Ry、R3、R4、R5、R6And R7Individually optionally by one or more RwReplaced；With
Each RwIt independently is H, D, F, Cl, Br, I ,-NO2、-CN、-N3、-NH2,-OH ,-SH, oxo (=O), C1-C4Alkane Base, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylamino, C1-C4 Alkylthio group, NH2-(C1-C4Alkylidene)-, HO- (C1-C4Alkylidene)-, HS- (C1-C4Alkylidene)-, (C1-C4Alkoxy)-(C1- C4Alkylidene)-, (C1-C4Alkylamino)-(C1-C4Alkylidene)-, (C1-C4Alkylthio group)-(C1-C4Alkylidene)-, C3-C6Cycloalkyl, (C3-C6Cycloalkyl)-(C1-C4Alkylidene)-, the heterocyclic radical of 3-7 annular atom composition, (heterocycle that 3-7 annular atom is constituted Base)-(C1-C4Alkylidene)-, phenyl, phenyl-(C1-C4Alkylidene)-, the heteroaryl or (5-6 ring of 5-6 annular atom composition Former molecular heteroaryl)-(C1-C4Alkylidene)-.
In one embodiment, compound of the present invention, it is the compound with one of following structure or has The stereoisomer of the compound of one of following structure, dynamic isomer, 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 Thing.
In one embodiment, pharmaceutical composition of the present invention, further comprising 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 medicine of energy obstacle, the medicine of the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, is used as feelings Feel the salts medicine of stabilizer, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, alternatively Medicine, nervous stimulants, nicotinic antagonists or their any combination of property serotonin reuptake inhibitor.
In another embodiment, the medicine 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 disclosed by the invention or composition in medicine is prepared, described Medicine is used to preventing, treat or mitigating central nervous system dysfunction.For example, in one embodiment, the medicine is used for Prevention, treatment mitigate mammalian central nervous system dysfunction, in another embodiment, and the medicine is used for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In one embodiment, described 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 disclosed by the invention or composition in medicine is prepared, described Medicine is used to preventing, treat or mitigating the disturbance of emotion.
In one embodiment, the described 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 disclosed by the invention or composition in medicine is prepared, described Medicine is used to suppress serotonin reuptake transporter.
On the other hand, the present invention relates to the method for the preparation of compound shown in formula (I), separation and purifying.
Biological results show that the compounds of this invention has strong affinity to people source 5-HT transporters (SERT), because The compound that this present invention is provided 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 suppress Property synergy, other of the invention compounds have serotonin reuptake transporter inhibition and dopamine reuptake inhibition There are synergy, other compound of the invention serotonin, norepinephrine and the triple reuptakes of dopamine to suppress to make With.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its 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 enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material The practice present invention.The present invention is not limited to method of the present invention and material.In the document combined, patent and similar material One or more or contradict in the case of (include but is not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, 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 obvious conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have many Use or use in the embodiment that the component of one is taken into account in the embodiment.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.It is different that stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometry Structure body (cis/trans) isomers, atropisomer, etc..
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face is rotated.When describing optically active compound, represent molecule on one using prefix D and L or R and S Individual or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are to be used to linearly polarized light caused by appointed compound revolve The symbol turned, wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for (+) or d compound.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or three-dimensional special When different in nature, such case may occur in which.
Term " dynamic isomer " or " tautomeric form " refer to that (low can be built by low energy with different-energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), it can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases that is carried out by proton migration, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to such some compounds, raw material, composition and/or formulation, and they are cured rationally Learn judge in the range of, it is adaptable to patient tissue contacts without excessive toxicity, excitant, allergy or with rational profit The symmetrical other problemses of benefit/Hazard ratio and complication, and effective for given application.
Term " optional " or " optionally " refer to the event or situation that then describe can with but not necessarily occur, and this is retouched State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.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 compound described in the invention, of the invention optionally can be replaced by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass and the class compound of the invention included.
Term " optionally by ... replaces ", can be exchanged with term " unsubstituted or by ... .. replaces " makes With that is, described structure is unsubstituted or replaced by one or more substituents of the present invention, of the present invention to take Dai Ji includes, but are not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, cycloalkyl, Heterocyclic radical, aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, it 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 influenceed mutually between expressed specific option between same-sign.
Term "comprising" is open language, i.e., including 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 that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including 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 for being 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 " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", are represented containing 1-20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention Substitution.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 Individual carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group is included, but is not limited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substituent stated is replaced, and it includes " cis " and " trans " positioning, or " E " and " Z " positioning.In an embodiment In, alkenyl group includes 2-6 carbon atom；In another embodiment, alkenyl group includes 2-4 carbon atom.Alkenyl group Example include, but is not limited to, vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2) etc..
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a key of carbon-to-carbon sp tri-, wherein, the alkynyl group can be retouched optionally by one or more present invention The substituent stated is replaced.In one embodiment, alkynyl group includes 2-6 carbon atom；In another embodiment, alkynyl Group includes 2-4 carbon atom.The example of alkynyl group is included, 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 remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent that the present invention is described is replaced.
The example of alkoxy base is included, 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 " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.Close Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example is included, 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 The described substituent of invention is replaced.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, alkenyl or alkoxy base by one Individual or multiple halogen atoms are replaced, and wherein alkyl, alkenyl and alkoxy base have implication as described in the present invention, such Example is included, but is not limited to, trifluoromethyl, trifluoromethoxy etc..In one embodiment, C1-C6Haloalkyl takes comprising fluorine The C in generation1-C6Alkyl；In another embodiment, C1-C4Haloalkyl includes the C that fluorine replaces1-C4Alkyl；In another embodiment party In case, C1-C4Haloalkyl includes the C that fluorine replaces1-C2Alkyl.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or the feature 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 be used for blocking or protecting the feature of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent of carboxyl is used for blocking or protect the feature 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 referred 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 compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, in existing invention ester can as pro-drug the phenyl ester class that has, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug begging for completely 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., this is incorporated herein by reference in 2008,51,2328-2345, every document.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt and experimentally characterized as stating.Such product can be by, by aoxidizing, being reduced, water to drug compound Solution, amidated, desamido- effect is esterified, degreasing, and enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention is fully contacted to the metabolite produced by a period of time with mammal.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, 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, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali is obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of included N group is formed.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation of quaternary ammonium salt and gegenions formation, such as halide, hydroxide, carboxylate, sulfuric acid Compound, 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 the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, monoethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " treatment " any disease or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent or 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 and (for example stablizes perceptible symptom) or physiologically (for example stablize body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay disease or disease Breaking-out, generation or the deterioration of disease.
Term " therapeutically effective amount " refers to that when delivering medicine to main body to treat disease the component of compound is enough to this disease The treatment of disease works." therapeutically effective amount " can be with compound, disease and the order of severity, and has the bar of main body to be treated Part, age, body weight, sex etc. and change.
Phenylpiperazine derivatives of the present invention, its 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 changes of compound of the invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, 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 when wedge shape line (solid wedge) or dotted line are indicated in fact of particular configuration, 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.Can be by an elevated temperature using normal With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, corresponding nitrogen-containing basic material is aoxidized, or pass through With crossing acid reaction in suitable solvent, such as reacted in dichloromethane, ethyl acetate or methyl acetate with peracetic acid, or Reacted in chloroform or dichloromethane with 3- chloroperoxybenzoic acids, prepare the nitrogen oxides of the compounds of this invention.
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 material or composition must be with other compositions 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, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds It is prepared by the suitable acid reaction of metered amount.Such reaction is generally carried 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, ethanol, isopropanol or acetonitrile. For example " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
Any structural formula that the present invention is provided is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to the intermediate 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 combinations 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 single stereoisomer, isomery The racemic or non-racemic mixture or its pharmaceutically acceptable salt or solvate of body.In one embodiment of the present invention In formula, described pharmaceutical composition is further comprising at least one pharmaceutically acceptable carrier, assistant agent or excipient, and optionally Ground, others treatment and/or prevention composition.
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 is used to treat it will also be appreciated that some compounds of the present invention can exist in a free form, or it is if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some nonrestrictive implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need 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.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and the interaction of effect of the invention for disclosing compound can be substantially reduced during avoiding that patient is administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, with sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably Agent, surfactant and buffer.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 in the presence of which other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, it is each that the technique includes mixing Plant composition.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 the formulation for being suitable for that patient is administered by required approach.Example Such as, formulation includes the formulation that those are suitable for following method of administration：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and 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) it is local administration, such as cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration formulation.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.
The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are provided.
The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate is tieed up to prepare.
The pharmaceutical composition that the present invention is provided can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tieing up The composition of release is held, such as by the way that microparticle material to be coated or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention is provided can also be carried in the form of liposome, micella, microballoon or nanometer system For.
The pharmaceutical composition that the present invention is provided 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 be wrapped Include organic acid and carbon dioxide source.
Colouring agent and flavor enhancement can be used in all above-mentioned formulations.
Compound disclosed in this invention can also be combined with as the soluble polymer of target medicine carrier.
The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention is provided can with will not to damage other active components of expected therapeutic action common Prepare, or the material co-formulation with the expected effect of supplement.
The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention is provided can be configured to any formulation suitable for parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method preparing (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 to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.
Discontinuous paster agent can be prepared into by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as General description in Pharmaceutical Research, 3 (6), 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.
The purposes of the compounds of this invention and composition
The compound and pharmaceutical composition that the present invention is provided, which can be used for preparing, to be used to preventing, treat or mitigating mammal, The medicine of central nervous system dysfunction including the mankind, can be used for preparing the medicine for being used for suppressing serotonin reuptake transporter Product.
Specifically, the amount of compound effectively detectably can optionally suppress 5- hydroxyls in composition of the invention The reuptake of tryptamines, compound of the invention can be used as treatment mankind's central nervous system (CNS) dysfunction, particularly feelings Feel the medicine of obstacle, the disturbance of emotion includes but is not limited to, it is 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 apply to, but be not limited to, and use the effective of compound or composition of the invention Central nervous system dysfunction disease is prevented, treats or mitigated to amount to patient's administration.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, social phobia, forces Disease, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, sleep 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 and pharmaceutical composition of the present invention applies also for veterinary treatment and doted in addition to beneficial to human treatment Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, compound of the invention includes its pharmaceutically acceptable derivates.
In one embodiment, treatment method 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, Method to treat 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 method of administration, 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, in different time interval administrations several times.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 for the pharmaceutical composition for disclosing compound comprising the present invention depends on In the pharmacokinetic property of the compound, for example, absorb, be distributed 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 implements the party The duration of case, depending on treated disease, the order of severity of disease being treated, the age of patient under consideration and body shape Condition, the medical history of patient under consideration, while the property of therapy, desired therapeutic effect etc. are in technical staff's knowledge and experience scope Interior factor.Such technical staff should also be understood that the reaction to dosage regimen for individual patient, or elapse over time When individual patient needs change, in order to be sufficiently accurate it may be desired to adjust the dosage regimen of matters.
The present invention, which discloses compound, to be administered simultaneously, or before it or afterwards with one or more other therapeutic agents. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different method of administration, or therewith with 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 invention is not restricted to these embodiments, simply The method that the practice present invention is provided.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be for suitably preparing perhaps Other compounds of many present invention, and be considered as preparing other methods of compound of the invention in model of the invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, 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 is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
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 with 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 condition determination of Algorithm (MS) data is：Level Four bar HPLC-M (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase：5%-95% (contains 0.1% first The CH of acid3CN) (H of 0.1% formic acid is being contained2O the ratio in), using electron spray ionisation (ESI), under 210nm/254nm, is used UV is detected.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.
The use of brief word below is through the present invention：
BOC, Boc tert-butoxycarbonyl
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
EDTA ethylenediamine tetra-acetic acids
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
MeOH methanol
G grams
H hours
HCl hydrogen chloride
NH3Ammonia
KCl potassium chloride
MgSO4Magnesium sulfate
K2CO3Potassium carbonate
MeCN、CH3CN acetonitriles
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
Boc2O di-tert-butyl dicarbonates
Following synthetic schemes describes the step of preparation present invention discloses compound, unless otherwise indicated, wherein each R1、R2、 Ry、R4And RxWith definition of the present invention.
Synthetic schemes 1
Formula (4) shown in compound can be prepared by synthetic schemes 1：Compound (1) and compound (2) with carbonic acid Potassium is alkali, reaction generation compound (3).Compound (3) sloughed in the ethyl acetate solution of hydrogen chloride after Boc protection groups, then Alkalization obtain target compound (4)。
Synthetic schemes 2
Formula (10) shown in compound can be prepared by synthetic schemes 2：First, compound (5) replaced by piperazine Generation compound (6)；Then, compound (6) protected with tertbutyloxycarbonyl after again catalytic hydrogenation take off benzyl and obtain compound (8)；Compound (8) and compound (2) using potassium carbonate as alkali, reaction generation compound (9)；Finally, compound (9) in hydrogen chloride Ethyl acetate solution in slough after Boc protection groups, Re-boostering test obtain target compound (10)。
Synthetic schemes 3
Formula (14) shown in compound can be prepared by synthetic schemes 3：Compound (11) and compound (2) with carbon Sour potassium be alkali, reaction generation compound (12)；Compound (12) obtain chemical combination with the generation substitution reaction of piperazine -1- t-butyl formates Thing (13)；Compound (13) sloughed in the ethyl acetate solution of hydrogen chloride after Boc protection groups, Re-boostering test obtains target compound (14)。
Synthetic schemes 4
Formula (20) shown in compound can be prepared by synthetic schemes 4：First, compound (8) and compound (18) using potassium carbonate as alkali, reaction generation compound (19)；Then compound (19) in the acetic acid second of trifluoroacetic acid or hydrogen chloride Sloughed in ester solution after Boc protection groups, Re-boostering test obtain target compound (20)。
Synthetic schemes 5
Formula (22) shown in compound can be prepared by synthetic schemes 5：Compound (1) and compound (18) with carbon Sour potassium be alkali, reaction generation compound (21), compound (21) sloughed in the ethyl acetate solution of trifluoroacetic acid or hydrogen chloride After Boc protection groups, Re-boostering test obtain target compound (22)。
Synthetic schemes 6
Formula (25) shown in compound can be prepared by synthetic schemes 6：Compound (11) and compound (18) with Potassium carbonate is alkali, reaction generation compound (23)；Then compound (23) occur substitution reaction life with piperazine -1- t-butyl formates Into compound (24)；Final compound (24) sloughed in the ethyl acetate solution of trifluoroacetic acid or hydrogen chloride after Boc protection groups, Re-boostering test obtain target compound (25)。
Compound, pharmaceutical composition and its application provided with reference to embodiments the present invention is further described.
Embodiment
The 2- of embodiment 1 (2- (piperazine -1- bases) phenoxy group) niacinamide
Step 1) 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates synthesis
By 4- (2- hydroxy phenyls) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chloro-nicotinamides (0.25g, 1.58mmol) it is added sequentially to potassium carbonate (0.42g, 3.02mmol) in DMSO (10mL), then reaction solution is warming up to 110 DEG C Reaction 20 hours.After reaction terminates, reaction solution is cooled to room temperature, and adds water (20mL) washing, ethyl acetate is then used (20mL × 3) are extracted.The organic phase of merging is through anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Residue is pure through silicagel column Change (petrol ether/ethyl acetate (v/v)=2/1) and obtain title compound for faint yellow solid (0.42g, 69.9%).
MS(ESI,pos.ion)m/z:399.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.63 (dd, J=7.6,2.0Hz, 1H), 8.24 (dd, J=4.8, 2.0Hz,1H),7.95(brs,1H),7.30-7.25(m,2H),7.22-7.15(m,3H),6.07(brs,1H),3.24-3.22 (m,4H),2.85-2.82(m,4H),1.45(s,9H).
Step 2) 2- (2- (piperazine -1- bases) phenoxy group) niacinamide synthesis
By 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.28g, 0.70mmol) it is dissolved in dichloromethane in (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reacts Liquid reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is passed through successively Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for dark brown solid (0.20g, 95.4%).
MS(ESI,pos.ion)m/z:299.3[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.13-8.11(m,2H),7.94(s,1H),7.77(s,1H), 7.19-7.17(m,5H),3.12-3.10(m,4H),2.83-2.81(m,4H).
The 1- of embodiment 2 (2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine
Step 1) 4- (2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chloro- 4- (trifluoromethyl) pyridine (0.29g, 1.58mmol) reacted in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol) and prepare crude product, crude product is through silicon Glue post purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.25g, 39.1%).
MS(ESI,pos.ion)m/z:424.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.33 (d, J=5.2Hz, 1H), 7.24-7.22 (m, 1H), 7.19- 7.16(m,2H),7.14-7.12(m,1H),7.07-7.04(m,1H),6.95(m,1H),3.20-3.17(m,4H),2.93- 2.91(m,4H),1.43(s,9H).
Step 2) 1- (2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine synthesis
By 4- (2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.30g, 0.71mmol) it is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution React 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water (15mL) is added into gained residue, And be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium is dried, filtering, and filtrate decompression is concentrated to give title compound for yellow solid (0.22g, 96.1%).
MS(ESI,pos.ion)m/z:324.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.35(s,1H),7.45(s,1H),7.36(s,1H),7.22- 7.13(m,4H),3.13-3.11(m,4H),2.79-2.77(m,4H).
The 1- of embodiment 3 (2- ((5- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine
Step 1) 4- (2- ((5- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chloro- 5- (trifluoromethyl) pyridine (0.29g, 1.58mmol) reacted in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol) and prepare crude product, crude product is through silicon Title compound is obtained after glue post purifying (petrol ether/ethyl acetate (v/v)=2/1) for white solid (0.35g, 54.8%).
MS(ESI,pos.ion)m/z:424.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.24 (s, 1H), 7.85 (dd, J=8.4,2.4Hz, 1H), 7.26- 7.21 (m, 1H), 7.15 (dd, J=7.6,1.6Hz, 1H), 7.12 (dd, J=7.2,1.2Hz, 1H), 7.07-7.05 (m, 1H), (s, the 9H) of 6.87 (d, J=8.8Hz, 1H), 3.25-3.23 (m, 4H), 2.95-2.92 (m, 4H), 1.44
Step 2) 1- (2- ((5- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine synthesis
By 4- (2- ((5- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.30g, 0.71mmol) it is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution React 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water (15mL) is added into gained residue, And be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium is dried, filtering, and filtrate decompression is concentrated to give title compound for faint yellow solid (0.22g, 96.1%).
MS(ESI,pos.ion)m/z:324.3[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.47(s,1H),8.15(s,1H),7.13-7.11(m,5H), 3.12-3.10(m,4H),2.79-2.77(m,4H).
The 2- of embodiment 4 (2- (piperazine -1- bases) phenoxy group) nicotinic acid nitrile
Step 1) 4- (2- ((nicotinonitrile -2- bases) epoxide) phenyl) piperazine -1- carboxylates synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chlorine nicotinic acid nitrile (0.22g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL) prepares crude product, and crude product purifies (petroleum ether/second through silicagel column Acetoacetic ester (v/v)=2/1) after obtain title compound for faint yellow solid (0.28g, 48.8%).
MS(ESI,pos.ion)m/z:381.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.27 (dd, J=4.8,2.0Hz, 1H), 8.00 (dd, J=7.6, 2.0Hz,1H),7.28-7.21(m,2H),7.18-7.13(m,2H),7.10-7.06(m,1H),3.24-3.22(m,4H), 2.92-2.89(m,4H),1.47(s,9H).
Step 2) 2- (2- (piperazine -1- bases) phenoxy group) nicotinic acid nitrile synthesis
By 4- (2- ((nicotinonitrile -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.27g, 0.71mmol) It is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution is anti-at room temperature Answer 2 hours.After reaction terminates, the solvent in reaction solution is evaporated off.Water (15mL) is added into gained residue, and uses sodium carbonate Solid regulation pH is 7, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sodium sulfate drying, mistake Filter, filtrate decompression is concentrated to give title compound for faint yellow solid (0.15g, 92.6%).
MS(ESI,pos.ion)m/z:281.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.43 (d, J=5.2Hz, 1H), 8.34 (s, 1H), 7.31-7.18 (m,5H),3.13-3.11(m,4H),2.90-2.88(m,4H).
The 1- of embodiment 5 (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine
Step 1) 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- formic acid The synthesis of tertiary butyl ester
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- chloro- 4- (trifluoromethyl) pyridine The reaction in DMSO (10mL) of (0.29g, 1.58mmol) and potassium carbonate (0.41g, 3.00mmol) prepares crude product, thick production Product obtained after purifying (petrol ether/ethyl acetate (v/v)=2/1) through silicagel column title compound for faint yellow solid (0.34g, 46.0%).
MS(ESI,pos.ion)m/z:492.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.32 (d, J=5.2Hz, 1H), 7.49 (dd, J=8.4Hz, 1.5Hz, 1H), 7.40 (d, J=1.9Hz, 1H), 7.24 (d, J=5.1Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 3.26-3.23(m,4H),3.02-3.00(m,4H),1.44(s,9H).
Step 2) 1- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine synthesis
By 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) the tertiary fourth of piperazine -1- formic acid Ester (0.34g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, so Reaction solution reacts 2 hours at room temperature afterwards.After reaction terminates, the solvent in reaction solution is evaporated off.Added into gained residue Water (15mL), and be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively Through anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.25g, 92.3%).
MS(ESI,pos.ion)m/z:392.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.38 (d, J=5.2Hz, 1H), 7.60-7.58 (m, 3H), 7.54 (d, J=4.9Hz, 1H), 7.32 (d, J=8.2Hz, 1H), 3.28-3.25 (m, 4H), 2.89 (brs, 4H)
The 2- of embodiment 6 (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) niacinamide
Step 1) 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid uncles The synthesis of butyl ester
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.5mmol), 2- chloro-nicotinamides (0.25g, 1.58mmol) reacted in DMSO (10mL) with potassium carbonate (0.41g, 3.00mmol) and prepare crude product, crude product is through silicon Glue post purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.35g, 50.0%).
MS(ESI,pos.ion)m/z:467.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.62 (dd, J=7.6,2.0Hz, 1H), 8.22 (dd, J=4.8, 2.0Hz, 1H), 7.74 (s, 1H), 7.50 (d, J=8.6Hz, 1H), 7.48 (s, 1H), 7.20 (dd, J=7.6,4.8Hz, 1H), (s, the 9H) of 7.15 (d, J=8.2Hz, 1H), 6.02 (s, 1H), 3.25-3.22 (m, 4H), 2.92-2.90 (m, 4H), 1.43
Step 2) 2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) niacinamide synthesis
By 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.33g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is passed through successively Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.25g, 96.5%).
MS(ESI,pos.ion)m/z:367.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.16-8.12(m,2H),7.97(s,1H),7.77(s,1H), 7.57-7.54 (m, 2H), 7.30 (d, J=8.1Hz, 1H), 7.23 (dd, J=6.8,1.9Hz, 1H), 3.27 (brs, 4H), 2.87(brs,4H).
The 2- of embodiment 7 (5- cyano group -2- (piperazine -1- bases) phenoxy group) niacinamide
Step 1) 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) -4- cyano-phenyls) piperazine -1- t-butyl formates Synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), 2- chloro-nicotinamides (0.25g, 1.59mmol) and Potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL) prepares crude product, and crude product purifies (stone through silicagel column Oily ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.25g, 38.9%).
MS(ESI,pos.ion)m/z:424.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):12.07 (s, 1H), 11.65 (s, 1H), 8.90 (d, J=1.8Hz, 1H), 8.69 (dd, J=7.2,2.1Hz, 1H), 7.56 (dd, J=6.0,1.4Hz, 1H), 7.36 (dd, J=8.2,1.8Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 6.56 (t, J=6.8Hz, 1H), 3.69 (brs, 4H), 2.90 (brs, 4H), 1.44 (s, 9H).
Step 2) 2- (5- cyano group -2- (piperazine -1- bases) phenoxy group) niacinamide synthesis
By 4- (2- ((3- carbamyl pyridine -2- bases) epoxide) -4- cyano-phenyls) piperazine -1- t-butyl formates (0.30g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is passed through successively Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.18g, 78.6%).
MS(ESI,pos.ion)m/z:324.1[M+H]+；
1H NMR(CD3OD,600MHz)δ(ppm):8.80 (d, J=1.6Hz, 1H), 8.56 (dd, J=7.2,1.9Hz, 1H), 7.73 (dd, J=6.2,1.9Hz, 1H), 7.43 (dd, J=8.2,1.5Hz, 1H), 7.30 (d, J=8.3Hz, 1H), 6.58 (t, J=6.8Hz, 1H), 3.19 (brs, 4H), 2.96-2.95 (m, 4H)
The 4- of embodiment 8 (piperazine -1- bases) -3- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) benzonitrile
Step 1) 4- (4- cyano group -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates Synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 1 is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), 2- chloro- 4- (trifluoromethyl) pyridine (0.29g, 1.59mmol) reacted in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol) and prepare crude product, crude product is through silicon Glue post purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.33g, 48.5%).
MS(ESI,pos.ion)m/z:449.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.30 (d, J=5.0Hz, 1H), 7.51 (dd, J=8.4,1.6Hz, 1H), 7.39 (d, J=1.6Hz, 1H), 7.22 (d, J=5.0Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=8.4Hz, 1H), 3.24(brs,4H),3.05(brs,4H),1.42(s,9H).
Step 2) 4- (piperazine -1- bases) -3- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) benzonitrile synthesis
By 4- (4- cyano group -2- ((4- (trifluoromethyl) pyridine -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.31g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is passed through successively Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.13g, 53.9%).
MS(ESI,pos.ion)m/z:349.1[M+H]+；
1H NMR(CD3OD,600MHz)δ(ppm):8.32 (d, J=5.2Hz, 1H), 7.59 (dd, J=8.4,1.1Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=5.1Hz, 1H), 7.30 (s, 1H), 7.19 (d, J=8.5Hz, 1H), 3.08-3.06 (m,4H),2.60-2.57(m,4H).
4- methyl-the 2- of embodiment 9 (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) thiazole -5- Ethyl formates
Step 1) 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) -4- methylthiazols - The synthesis of 5- Ethyl formates
4- (2- hydroxyls -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- is bromo- 4- methylthiazole-5-carboxylates (0.39g, 1.58mmol) and potassium carbonate (0.42g, 3.00mmol) are added to DMSO (10mL) In, then reaction solution is warming up to 110 DEG C and reacted 20 hours.After reaction terminates, reaction solution is cooled to room temperature, and add thereto Water (20mL), is then extracted with ethyl acetate (20mL × 3).The organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate subtracts Pressure concentration.Gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying Faint yellow solid (0.35g, 45.2%).
MS(ESI,pos.ion)m/z:516.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.49 (d, J=8.6Hz, 1H), 7.47 (s, 1H), 7.09 (d, J= 8.4Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 3.41-3.38 (m, 4H), 3.07-3.04 (m, 4H), 2.58 (s, 3H), 1.44 (s, 9H), 1.29 (t, J=7.1Hz, 3H)
Step 2) 4- methyl -2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) thiazole -5- Ethyl formates conjunction Into
By 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) -4- methylthiazol -5- first Acetoacetic ester (0.36g, 0.70mmol) is dissolved in dichloromethane (5mL), and add hydrogen chloride ethyl acetate solution (2mL, 4M), then reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.To gained residue Middle addition water (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).Merge Organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression be concentrated to give title compound for faint yellow solid (0.12g, 41.4%).
MS(ESI,pos.ion)m/z:416.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.56 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.16 (d, J= 8.4Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 3.44 (brs, 4H), 3.24 (brs, 4H), 2.59 (s, 3H), 1.32 (t, J= 7.1Hz,3H).
4- methyl-the 2- of embodiment 10 (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) thiazole -5- formamides
Step 1) 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- (trifluoromethyl) phenyl) piperazine - The synthesis of 1- t-butyl formates
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), the bromo- 4- methylthiazols -5- formyls of 2- The reaction in DMSO (10mL) of amine (0.35g, 1.58mmol) and potassium carbonate (0.42g, 3.00mmol) prepares crude product, slightly Product obtains title compound for faint yellow solid after purification through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) (0.37g, 50.7%).
MS(ESI,pos.ion)m/z:387.1[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.49 (d, J=8.4Hz, 1H), 7.46 (s, 1H), 7.08 (d, J= 8.4Hz,1H),5.99(s,2H),3.40(brs,4H),3.05(brs,4H),2.54(s,3H),1.44(s,9H).
Step 2) 4- methyl -2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) thiazole -5- formamides synthesis
By 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- (trifluoromethyl) phenyl) piperazine -1- first Tert-butyl acrylate (0.34g, 0.70mmol) is dissolved in dichloromethane (5mL), and add hydrogen chloride ethyl acetate solution (2mL, 4M), then reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.To gained residue Middle addition water (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).Merge Organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression be concentrated to give title compound for faint yellow solid (0.16g, 59.2%).
MS(ESI,pos.ion)m/z:387.1[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.51 (d, J=8.2Hz, 1H), 7.46 (s, 1H), 7.11 (d, J= 8.4Hz,1H),5.86(s,2H),3.14-3.11(m,4H),2.90-2.87(m,4H),2.57(s,3H).
The 2- of embodiment 11 (5- cyano group -2- (piperazine -1- bases) phenoxy group) -4- methylthiazol -5- formamides
Step 1) 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- cyano-phenyls) piperazine -1- formic acid The synthesis of the tert-butyl ester
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), the bromo- 4- methylthiazols -5- formamides of 2- The reaction in DMSO (10mL) of (0.35g, 1.59mmol) and potassium carbonate (0.42g, 3.02mmol) prepares crude product, thick production Product obtain title compound for faint yellow solid after purification through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) (0.34g, 50.5%).
MS(ESI,pos.ion)m/z:344.1[M+H-Boc]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.52 (dd, J=8.4,1.8Hz, 1H), 7.50 (d, J=1.8Hz, 1H), 7.03 (d, J=8.5Hz, 1H), 5.87 (s, 2H), 3.43-3.40 (m, 4H), 3.12-3.10 (m, 4H), 2.55 (s, 3H),1.44(s,9H).
Step 2) 2- (5- cyano group -2- (piperazine -1- bases) phenoxy group) -4- methylthiazol -5- formamides synthesis
By 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- cyano-phenyls) the tertiary fourth of piperazine -1- formic acid Ester (0.31g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, so Reaction solution reacts 2 hours at room temperature afterwards.After reaction terminates, the solvent in reaction solution is evaporated off.Added into gained residue Water (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging With anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.18g, 75.0%).
MS(ESI,pos.ion)m/z:344.1[M+H]+；
1H NMR(CD3OD,600MHz)δ(ppm):7.69 (s, 1H), 7.66 (dd, J=8.5,1.4Hz, 1H), 7.25 (d, J=8.5Hz, 1H), 3.18-3.15 (m, 4H), 2.83-2.80 (m, 4H), 2.51 (s, 3H)
The 2- of embodiment 12 (5- cyano group -2- (piperazine -1- bases) phenoxy group) -4- methylthiazole-5-carboxylates
Step 1) 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- cyano-benzene oxygens) -4- methylthiazol-5-formic acids The synthesis of ethyl ester
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), the bromo- 4- methylthiazole-5-carboxylates of 2- The reaction in DMSO (10mL) of (0.40g, 1.59mmol) and potassium carbonate (0.42g, 3.02mmol) prepares crude product, thick production Product obtain title compound for faint yellow solid after purification through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) (0.38g, 53.0%).
MS(ESI,pos.ion)m/z:373.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.53 (d, J=8.6Hz, 1H), 7.51 (s, 1H), 7.04 (d, J= 8.4Hz, 1H), 4.27 (q, J=7.1Hz, 2H), 3.43-3.40 (m, 4H), 3.13-3.10 (m, 4H), 2.59 (s, 3H), 1.45 (s, 9H), 1.33 (t, J=7.1Hz, 3H)
Step 2) 2- (5- cyano group -2- (piperazine -1- bases) phenoxy group) -4- methylthiazole-5-carboxylates synthesis
By 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- cyano-benzene oxygens) -4- methylthiazole-5-carboxylates (0.33g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is used Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.15g, 58.0%).
MS(ESI,pos.ion)m/z:391.1[M+H+H2O]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):7.85 (dd, J=8.4,2.0Hz, 1H), 7.80 (d, J=2.0Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 4.20 (q, J=7.1Hz, 2H), 2.99 (t, J=4.8Hz, 4H), 2.67 (t, J= 4.8Hz, 4H), 2.52 (s, 3H), 1.23 (t, J=7.1Hz, 3H)
4- methyl-the 2- of embodiment 13 (2- piperazine -1- bases) phenoxy group) thiazole -5- formamides
Step 1) 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates Synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), the bromo- 4- methylthiazols -5- formamides of 2- (0.35g, 1.58mmol) reacted in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol) and prepare crude product, crude product is through silicon Plastic column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain after purification title compound for faint yellow solid (0.37g, 58.6%).
MS(ESI,pos.ion)m/z:319.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.32 (dd, J=8.4,1.8Hz, 1H), 7.20-7.18 (m, 1H), 7.07-7.03 (m, 2H), 5.88 (s, 2H), 3.22 (brs, 4H), 3.11 (t, J=4.8Hz, 4H), 2.53 (s, 3H), 1.44 (s,9H).
Step 2) 4- methyl -2- (2- piperazine -1- bases) phenoxy group) thiazole -5- formamides synthesis
By 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.35g, 0.84mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is used Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.23g, 86.5%).
MS(ESI,pos.ion)m/z:319.1[M+H]+；
1H NMR(CD3OD,600MHz)δ(ppm):7.44-7.40 (m, 1H), 7.33 (dd, J=8.4,1.4Hz, 1H), (s, the 3H) of 7.25-7.20 (m, 2H), 3.26 (t, J=4.8Hz, 4H), 2.82 (t, J=4.8Hz, 4H), 2.51
4- methyl-the 2- of embodiment 14 (2- (piperazine -1- bases) phenoxy group) thiazole -5- Ethyl formates
Step 1) 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) phenoxy group) -4- methylthiazole-5-carboxylates conjunction Into
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.40g, 1.44mmol), the bromo- 4- methylthiazole-5-carboxylates of 2- (0.38g, 1.51mmol) reacted in DMSO (10mL) with potassium carbonate (0.40g, 2.87mmol) and prepare crude product, crude product is through silicon Plastic column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain after purification title compound for faint yellow solid (0.44g, 68.4%).
MS(ESI,pos.ion)m/z:348.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.33 (dd, J=8.6,1.8Hz, 1H), 7.21-7.15 (m, 2H), 7.02 (d, J=8.4Hz, 1H), 4.25 (q, J=7.2Hz, 2H), 3.32-3.29 (m, 4H), 3.13-3.10 (m, 4H), 2.55 (s, 3H), 1.44 (s, 9H), 1.32 (t, J=7.2Hz, 3H)
Step 2) 4- methyl -2- (2- (piperazine -1- bases) phenoxy group) thiazole -5- Ethyl formates synthesis
By 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) phenoxy group) -4- methylthiazole-5-carboxylates (0.40g, 0.89mmol) it is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution React 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water (15mL) is added into gained residue, And be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase anhydrous slufuric acid of merging Sodium is dried, filtering, and filtrate decompression is concentrated to give title compound for faint yellow solid (0.25g, 80.5%).
MS(ESI,pos.ion)m/z:348.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.35 (dd, J=8.4,2.0Hz, 1H), 7.20-7.15 (m, 2H), 7.04 (d, J=8.4Hz, 1H), 4.21 (q, J=7.2Hz, 2H), 3.39 (t, J=4.8Hz, 4H), 2.67 (t, J=4.8Hz, 4H), 2.52 (s, 3H), 1.24 (t, J=7.2Hz, 3H)
4- methyl-the 2- of embodiment 15 (2- (piperazine -1- bases) phenoxy group) thiazole -5- formonitrile HCNs
Step 1) 4- (2- ((5- cyano group -4- methylthiazol -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), the bromo- 4- methylthiazols -5- formonitrile HCNs of 2- (0.32g, 1.59mmol) reacted in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol) and prepare crude product, crude product is through silicon Plastic column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain after purification title compound for faint yellow solid (0.33g, 54.6%).
MS(ESI,pos.ion)m/z:301.1[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.32 (dd, J=8.4,2.0Hz, 1H), 7.21-7.15 (m, 2H), (s, the 9H) of 7.02 (d, J=8.4Hz, 1H), 3.30 (brs, 4H), 3.13-3.10 (m, 4H), 2.54 (s, 3H), 1.44
Step 2) 4- methyl -2- (2- (piperazine -1- bases) phenoxy group) thiazole -5- formonitrile HCNs synthesis
By 4- (2- ((5- cyano group -4- methylthiazol -2- bases) epoxide) phenyl) piperazine -1- t-butyl formates (0.30g, 0.75mmol) it is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution React 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water (15mL) is added into gained residue, And be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase anhydrous slufuric acid of merging Sodium is dried, filtering, and filtrate decompression is concentrated to give title compound for faint yellow solid (0.19g, 84.4%).
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.34 (dd, J=8.4,2.0Hz, 1H), 7.20-7.14 (m, 2H), (s, the 3H) of 7.03 (d, J=8.4Hz, 1H), 3.38 (t, J=4.8Hz, 4H), 2.88 (t, J=4.8Hz, 4H), 2.51
4- methyl-the 2- of embodiment 16 (5- nitros -2- (piperazine -1- bases) phenoxy group) thiazole -5- formamides
Step 1) 2- (the fluoro- 5- nitro-phenoxies of 2-) -4- methylthiazol -5- formamides synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by the fluoro- 5- of 2- The bromo- 4- methylthiazols -5- formamides (0.69g, 3.14mmol) of nitrophenol (0.47g, 2.99mmol), 2- and potassium carbonate (0.83g, 5.98mmol) reaction in DMSO (10mL) prepares crude product, and crude product is through silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=20/1) title compound is obtained after purification for white solid (0.65g, 73.1%).
MS(ESI,pos.ion)m/z:298.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.17 (dd, J=8.8,2.8Hz, 1H), 8.15-8.11 (m, 1H), 7.22-7.18(m,1H),5.84(s,2H),2.54(s,3H).
Step 2) 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- nitrobenzophenones) piperazine -1- formic acid The synthesis of the tert-butyl ester
By 2- (the fluoro- 5- nitro-phenoxies of 2-) -4- methylthiazol -5- formamides (0.64g, 2.15mmol), piperazine -1- first Tert-butyl acrylate (0.37g, 4.31mmol) and potassium carbonate (0.33g, 2.37mmol) are added in DMSO (10mL), then reaction solution 110 DEG C are warming up to react 20 hours.After reaction terminates, reaction solution is cooled to room temperature, and adds water (20mL) thereto, then Extracted with ethyl acetate (20mL × 3).The organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate decompression concentration.Gained is residual Thing is stayed to obtain title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying for red solid (0.35g, 35.1%).
MS(ESI,pos.ion)m/z:464.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.20 (dd, J=8.8,2.8Hz, 1H), 8.01 (d, J=2.8Hz, 1H), 6.99 (d, J=8.8Hz, 1H), 5.85 (s, 2H), 3.28 (brs, 4H), 3.14 (brs, 4H), 2.53 (s, 3H), 1.45 (s,9H).
Step 3) 4- methyl -2- (5- nitros -2- (piperazine -1- bases) phenoxy group) thiazole -5- formamides synthesis
By 4- (2- ((5- carbamyl -4- methylthiazol -2- bases) epoxide) -4- nitrobenzophenones) the tertiary fourth of piperazine -1- formic acid Ester (0.33g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, so Reaction solution reacts 2 hours at room temperature afterwards.After reaction terminates, the solvent in reaction solution is evaporated off.Added into gained residue Water (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging With anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.15g, 57.9%).
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.18 (dd, J=8.8,2.4Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.20 (d, J=8.8Hz, 1H), 5.84 (s, 2H), 3.35 (t, J=4.8Hz, 4H), 2.87 (t, J=4.8Hz, 4H), 2.53(s,3H).
4- methyl-the 2- of embodiment 17 (5- nitros -2- (piperazine -1- bases) phenoxy group) thiazole -5- Ethyl formates
Step 1) 2- (the fluoro- 5- nitro-phenoxies of 2-) -4- methylthiazole-5-carboxylates synthesis
The method that this step title compound is referred to described by the step 1 of embodiment 9 is prepared, i.e., by the fluoro- 5- of 2- The bromo- 4- methylthiazole-5-carboxylates (0.79g, 3.14mmol) of nitrophenol (0.47g, 2.99mmol), 2- and potassium carbonate (0.83g, 5.98mmol) reaction in DMSO (10mL) prepares crude product, and crude product purifies (oil through silica gel column chromatography Ether/ethyl acetate (v/v)=20/1) after obtain title compound for white solid (0.57g, 58.4%).
MS(ESI,pos.ion)m/z:327.0[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.16 (dd, J=8.8,2.8Hz, 1H), 8.14-8.10 (m, 1H), (t, J=7.2Hz, the 3H) of 7.22-7.19 (m, 1H), 4.22 (q, J=7.2Hz, 2H), 2.52 (s, 3H), 1.25
Step 2) 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- nitro-phenoxies) -4- methylthiazol-5-formic acids The synthesis of ethyl ester
The method that this step title compound is referred to described by the step 2 of embodiment 16 is prepared, i.e., by 2- (2- Fluoro- 5- nitro-phenoxies) -4- methylthiazole-5-carboxylates (0.56g, 1.72mmol), piperazine -1- t-butyl formates (0.30g, 3.43mmol) and potassium carbonate (0.26g, 1.89mmol) prepare crude product, crude product in DMSO (10mL) reactions Through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) obtain after purification title compound for red solid (0.35g, 41.4%).
MS(ESI,pos.ion)m/z:393.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.16 (dd, J=8.8,2.8Hz, 1H), 8.14-8.10 (m, 1H), 7.22-7.19 (m, 1H), 4.22 (q, J=7.2Hz, 2H), 3.36-3.33 (m, 4H), 3.16-3.14 (m, 4H), 2.52 (s, 3H), 1.45 (s, 9H), 1.25 (t, J=7.2Hz, 3H)
Step 3) 4- methyl -2- (5- nitros -2- (piperazine -1- bases) phenoxy group) thiazole -5- Ethyl formates synthesis
By 2- (2- (4- (tertbutyloxycarbonyl) piperazine -1- bases) -5- nitro-phenoxies) -4- methylthiazole-5-carboxylates (0.34g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction terminates, the solvent in reaction solution is evaporated off.Water is added into gained residue (15mL), and be 7~8 with sodium carbonate solid regulation pH, then extracted with dichloromethane (15mL × 3).The organic phase of merging is used Anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title compound for faint yellow solid (0.20g, 73.8%).
MS(ESI,pos.ion)m/z:393.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.10 (dd, J=8.4,2.0Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 4.21 (q, J=7.2Hz, 2H), 3.43 (brs, 4H), 2.82 (t, J=4.8Hz, 4H), 2.51 (s, 3H), 1.24 (t, J=7.2Hz, 3H)
Biologic test
Embodiment A：Compound is evaluated to expressing the affinity of the humanization 5-HT transporters 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 or be added without survey Compound is tried, is incubated 60 minutes altogether.
And in the mixed system of above-mentioned condition, 10 μM of imipramine are added, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum by pre- dipped 0.3%PEI glass fiber filter (GF/B, Packard) fast filtering, and use ice-cold 50mM Tris-HCl and 150mM NaCl is rinsed several times repeatedly.Filter membrane is dried, in scintillation counter (Topcount, Packard), scintillation solution is used (Microscint 0, Packard) calculates the radioactivity of residual.Experimental result is with special relative to 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 affinity experimental result of the compounds of this invention to humanization 5-HT transporters (SERT).
Affinity measurement result of the Table A the compounds of this invention to people source 5-HT transporters (SERT)
Experimental result shows that the compounds of this invention has stronger affinity to people source 5-HT transporters (SERT).
Pharmacokinetic Evaluation after embodiment B rats intravenous or the quantitative the compounds of this invention of gavage
The present invention is assessed pharmacokinetic of the compounds of this invention in rat body, and animal information is referred to Table B.
Table B animal subject information tables of the present invention
Test method
By the compounds of this invention with 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline salt The form of the aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, gives to animal subject Medicine.For intravenous injection administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25th, 0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours when venous blood sampling (0.3mL), and under 3,000 or 4,000rpm from The heart 10 minutes, collects plasma solutions, and in preservation at -20 DEG C or -70 DEG C.For gastric infusion group, dosage is 2.5mg/ Kg or 5mg/kg, then time point upon administration be 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours when vein take Blood (0.3mL), and centrifuged 10 minutes under 3,000 or 4,000rpm, plasma solutions are collected, and in guarantor at -20 DEG C or -70 DEG C Deposit.
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 determined by way of being injected intravenously administration and gastric infusion is big with exposure value, and clearance rate is low, raw The preferably pharmacokinetic property such as thing availability height.Illustrate the compounds of this invention druggability more preferably, should with more preferable clinic Use prospect.
Test result indicates 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 are described Levy, structure, material or feature are contained at least one embodiment, embodiment or the example of the present invention.In this specification In, identical embodiment, embodiment or example are necessarily directed to the schematic representation of above-mentioned term.Moreover, description Specific features, structure, material or feature can be in any one or more embodiments, embodiment or example with suitable Mode is combined.In addition, in the case of not conflicting, those skilled in the art can be by the difference described in this specification The feature of embodiment, embodiment or example and non-be the same as Example, embodiment or example is combined and combined.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (8)

1. a kind of compound, stereoisomer, the tautomerism of its compound shown in the compound or formula (I) shown in formula (I) Body or pharmaceutically acceptable salt,
Wherein：
For double bond；
X is CRx；
Y is CRy；
Each R1、R2、RxAnd RyIt independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4 Halogenated alkoxy；
R4For H, D, F, Cl, Br, I ,-CN ,-NO2、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4 Alkoxy or C1-C4Halogenated alkoxy；
R3、R5And R6It is each independently H, D, F, Cl, Br, I or C1-C4Alkyl；With
R7For H, D, F, Cl, Br, I or C1-C4Alkyl.
2. compound according to claim 1, wherein each R1、R2、RxAnd RyIndependently be H, D, F, Cl, Br, I ,-CN ,- NO2、-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 epoxide or isopropyl oxygen Base.
3. compound according to claim 1, wherein R4For H, D, F, Cl, Br, I ,-CN ,-NO2, methyl, ethyl, positive third Base, isopropyl ,-CF3Or-CH2CF3；
R3、R5And R6It is each independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl.
4. compound according to claim 1, it is for the compound with one of following structure or with one of following knot Stereoisomer, dynamic isomer or the pharmaceutically acceptable salt of the compound of structure：
5. a kind of pharmaceutical composition, includes the compound described in claim 1-4 any one；With
Described pharmaceutical composition is optionally further comprising pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.
6. pharmaceutical composition according to claim 5, it is further comprising treatment central nervous system dysfunction Medicine, the medicine 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 drawing 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 replace a smooth, profit Sleep peaceful, perphenazine or their any combination.
7. the pharmaceutical composition described in compound or claim 5-6 any one described in claim 1-4 any one exists The purposes in medicine is prepared, the medicine is used to preventing, treat or mitigating central nervous system dysfunction.
8. purposes according to claim 7, the medicine is used to preventing, treat or mitigating the disturbance of emotion.
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