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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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Publication number
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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ethyl
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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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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, methods of use, and uses thereof
Technical Field
The present invention is in the field of pharmaceutical technology and specifically relates to compounds and compositions for the treatment of central nervous system disorders, particularly affective disorders, and methods of use and uses thereof. In particular, the present invention relates to phenylpiperazine derivatives which are 5-hydroxytryptamine reuptake inhibitors.
Background
5-hydroxytryptamine (5-HT), a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. The serotonin transporter (5-HT transporter,5-HTT/serotonin transporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes serotonin from the synaptic cleft into presynaptic neurons, directly affecting the concentration of serotonin in the synaptic cleft.
Historically, the medical treatment of affective disorders began in the 50's of the 20 th century and included tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) which were mainly effective by blocking the neurotransmitters dopamine, norepinephrine and 5-hydroxytryptamine. However, non-selective and undesirable side effects on targets limit their use. By the 80's of the 20 th century, the appearance of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) changed this situation. Such drugs are of comparable efficacy to TCAs, but have fewer side effects and less toxicity even when taken in excess (Sarko J. Anddidepressant, old and new. A review of the same additive effects and toxicity in excess. Embedded Med. Clin North Am, 2000; 18(4): 637-54). The selective 5-hydroxytryptamine reuptake inhibitor mainly has an inhibitory effect on 5-HT transporters, can effectively inhibit the presynaptic membrane of the central nervous system from absorbing 5-HT from synaptic clefts by combining with the 5-HT transporters, and increases the 5-HT which can be practically utilized in the gaps, thereby achieving the purpose of treatment.
Of all indications associated with 5-hydroxytryptamine dysfunction, depression is of prime importance, as it has been reported by the world health organization as the fourth most burdensome disease in humans. It is expected that disability from depression will jump to the second place in all diseases by the year 2020. (Bromet E, Andlade LH, Hwang I, et al, Cross-national epidemiology of DSM-IV major depression epsilon. BMC Med.2011,9: 90).
However, clinical studies on depression have shown that the lack of response to known SSRIs is prominent, and another factor that is often overlooked in antidepressant therapy is that the therapeutic effects of SSRIs are often delayed and sometimes the symptoms worsen within the first few weeks of treatment. Furthermore, sexual dysfunction is a common side effect for SSRIs. Therefore, there is a need to develop compounds that can improve the treatment of depression and other 5-hydroxytryptamine related disorders.
The invention provides a new compound with 5-hydroxytryptamine reuptake inhibition activity, and the new compound has good clinical application prospect. Compared with the existing similar compounds, the compound of the invention has better drug effect, pharmacological property and/or toxicological property.
Disclosure of Invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The present invention relates to a novel class of (2- (heteroaryloxy) phenyl) piperazine derivatives having a strong binding affinity to the 5-HT transporter (SERT) which inhibit 5-HT reuptake and are therefore useful in the manufacture of a medicament for the treatment of Central Nervous System (CNS) disorders, in particular for the treatment of affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder and post-traumatic stress disorder.
The compound has stable property and good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like, so the compound has good clinical application prospect.
The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
wherein,X、Y、R1、R2、R3、R4、R5、R6and R7Have the meaning as described in the present invention.
In one embodiment of the process of the present invention,is a single bond or a double bond.
In one embodiment, X is-CHRx-or CRx(ii) a And each RxHave the meaning as described in the present invention.
In one embodiment, Y is-CHRy-or CRy(ii) a And each RyHave the meaning as described in the present invention.
In one embodiment of the process of the present invention,is-O-, -S-or-NH-.
In one embodiment, R1Is 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino or hydroxy substituted C1-C6An alkyl group.
In one implementationIn the scheme, R2Is 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino or hydroxy substituted C1-C6An alkyl group.
In one embodiment, each R isxIndependently 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino or hydroxy substituted C1-C6An alkyl group.
In one embodiment, each R isyIndependently 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino or hydroxy substituted C1-C6An alkyl group.
In one embodiment, R4Is 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6A haloalkoxy group.
In one embodiment, R3、R5And R6Each independently is 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) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6A haloalkoxy group.
In one embodiment, R7Is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-COOH、-C(＝O)NH2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy or hydroxy substituted C1-C6An alkyl group.
In one embodiment, R1Is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In one embodiment, R2Is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In one embodiment, each R isxIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In one embodiment, each R isyIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In one embodiment, R4Is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-COOH、-C(＝O)NH2、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4A haloalkoxy group.
In one embodiment, R3、R5And R6Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-COOH、-C(＝O)NH2、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4A haloalkoxy group.
In one embodiment, R1Is 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)2Methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R2Is 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)2Methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, each R isxIndependently 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)2Methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, each R isyIndependently 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)2Methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R4Is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-COOH、-C(＝O)NH2Methyl, ethyl, n-propyl, isopropyl, -CF3or-CH2CF3。
In one embodiment, R3、R5And R6Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-COOH、-C(＝O)NH2Methyl, ethyl, n-propyl, isopropyl, -CF3or-CH2CF3。
Each R in the invention1、R2、Rx、Ry、R3、R4、R5、R6And R7Independently optionally substituted by one or more RwSubstituted; and
each RwIndependently H, D, F, Cl, Br, I, -NO2、-CN、-N3、-NH2-OH, -SH, oxo (═ O), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylamino radical, C1-C4Alkylthio, NH2-(C1-C4Alkylene) -, HO- (C1-C4Alkylene) -, HS- (C)1-C4Alkylene) -, (C)1-C4Alkoxy group) - (C1-C4Alkylene) -, (C)1-C4Alkylamino) - (C1-C4Alkylene) -, (C)1-C4Alkylthio) - (C1-C4Alkylene) -, C3-C6Cycloalkyl group, (C)3-C6Cycloalkyl) - (C)1-C4Alkylene) -, heterocyclic group consisting of 3 to 7 ring atoms, (heterocyclic group consisting of 3 to 7 ring atoms) - (C)1-C4Alkylene) -, phenyl- (C)1-C4Alkylene) -, heteroaryl of 5 to 6 ring atoms or heteroaryl of 5 to 6 ring atoms) - (C1-C4Alkylene) -.
In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound having one of the following structures:
in another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In one embodiment, the pharmaceutical composition of the present invention further comprises a drug for treating central nervous system dysfunction, wherein the drug for treating central nervous system dysfunction is an antidepressant, an anxiolytic, a lithium salt drug as an affective stabilizer, an atypical antipsychotic, an antiepileptic, an antiparkinsonian, a drug as a selective 5-hydroxytryptamine reuptake inhibitor, a central nervous stimulant, a nicotine antagonist, or any combination thereof.
In another embodiment, the drug of the present invention to treat a dysfunction of the central nervous system is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, samidorphan, buprenorphine, melatonine, alprazolam, pipamperone, vestpitant, chlordiazeparate, perphenazine or any combination thereof.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction. For example, in one embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a mammal, and in another embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a human.
In one embodiment, the central nervous system disorder is depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, and premenstrual tension syndrome.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the preparation of a medicament for the prevention, treatment or alleviation of affective disorders.
In one embodiment, the affective disorder includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, and post-traumatic stress disorder.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for inhibiting 5-hydroxytryptamine reuptake.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound has strong affinity to human 5-HT transporters (SERT), so that the compound provided by the invention can be used as a better selective 5-hydroxytryptamine reuptake inhibitor.
In addition, some of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and norepinephrine reuptake inhibition, others of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and dopamine reuptake inhibition, and still other compounds of the present invention have triple reuptake inhibition of 5-hydroxytryptamine, norepinephrine and dopamine.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples.
The term "optionally substituted", is used interchangeably with the term "unsubstituted or substituted", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, N3，-CN，-OH，-SH，-NH2Alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Butyl to isobutylRadical (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) And so on.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 6 carbon atoms; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-6 carbon atoms; in another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Alkoxy radicalExamples of (A) include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) And so on.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" mean alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, wherein alkyl, alkenyl and alkoxy groups have the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like. In one embodiment, C1-C6The haloalkyl group containing a fluorine-substituted C1-C6An alkyl group; in another embodiment, C1-C4The haloalkyl group containing a fluorine-substituted C1-C4An alkyl group; in yet another embodiment, C1-C4The haloalkyl group containing a fluorine-substituted C1-C2An alkyl group.
The term "protecting group" or "PG" means that a substituent is initiated with another functional groupWhen reacting, it is usually used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, Protective Groups in organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, ed., Bioreversible Cariers in drug design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews Drug Discovery,2008,7,255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoatesSalts, caproates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
The phenylpiperazine derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof according to the present invention can be used as selective 5-hydroxytryptamine reuptake inhibitors, and have potential use in the treatment of central nervous system disorders, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder and post-traumatic stress disorder in humans.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipient agents are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include 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).
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups.
Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system.
The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers.
The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Use of the Compounds and compositions of the invention
The compounds and pharmaceutical compositions provided by the present invention can be used for preparing medicines for preventing, treating or relieving central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicines for inhibiting reuptake of 5-hydroxytryptamine.
In particular, the amount of compound in the compositions of the invention is effective to detectably and selectively inhibit 5-hydroxytryptamine reuptake, and the compounds of the invention are useful as medicaments for the treatment of Central Nervous System (CNS) disorders in humans, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorders, panic attacks, specific phobias, agoraphobia, mania, panic disorders, and post-traumatic stress disorders.
The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of central nervous system dysfunctional disorders by administering to a patient an effective amount of a compound or composition of the present invention. The central nervous system dysfunction responsive to 5-hydroxytryptamine regulation further includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive-compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms of drug addiction, premenstrual tension syndrome, and the like.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.
In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration.
In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.
The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or together with them in pharmaceutical compositions.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following acronyms are used throughout the invention:
BOC, Boc tert-butoxycarbonyl
CH2Cl2DCM dichloromethane
CDC13Deuterated chloroform
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylene diamine tetraacetic acid
Et3N, TEA Triethylamine
EtOAc, EA ethyl acetate
MeOH methanol
g
h hours
HCl hydrogen chloride
NH3Ammonia gas
KCl potassium chloride
MgSO4Magnesium sulfate
K2CO3Potassium carbonate
MeCN、CH3CN acetonitrile
mL, mL
PE Petroleum ether (60-90 deg.C)
RT, RT, r.t. Room temperature
Rt Retention time
TFA trifluoroacetic acid
Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid
BSA bovine serum albumin
Boc2Di-tert-butyl O dicarbonate
The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicated1、R2、Ry、R4And RxHaving the definitions set out in the present invention.
Synthesis scheme 1
Formula (A), (B) and4) The compounds shown can be prepared by synthesis scheme 1: compound (A) to (B)1) And a compound of (A)2) Potassium carbonate is used as alkali to react to generate a compound (A)3). Compound (A) to (B)3) Removing Boc protecting group in ethyl acetate solution of hydrogen chloride, and alkalifying to obtain target compound (4)。
Synthesis scheme 2
Formula (A), (B) and10) The compounds shown can be prepared by synthesis scheme 2: first, a compound (A)5) Formation of a compound substituted by piperazine (6) (ii) a Then, the compound (A), (B), (C6) Protecting with tert-butyloxycarbonyl group, catalytic hydrogenating to remove benzyl group to obtain compound (B)8) (ii) a Compound (A) to (B)8) And a compound of (A)2) Potassium carbonate is used as alkali to react to generate a compound (A)9) (ii) a Finally, the compound (A)9) In the presence of chlorineRemoving Boc protecting group from hydrogen chloride in ethyl acetate solution, alkalifying to obtain target compound (10)。
Synthesis scheme 3
Formula (A), (B) and14) The compounds shown can be prepared by synthesis scheme 3: compound (A) to (B)11) And a compound of (A)2) Potassium carbonate is used as alkali to react to generate a compound (A)12) (ii) a Compound (A) to (B)12) Carrying out substitution reaction with piperazine-1-tert-butyl formate to obtain a compound (I)13) (ii) a Compound (A) to (B)13) Removing Boc protecting group in ethyl acetate solution of hydrogen chloride, and alkalifying to obtain target compound (14)。
Synthesis scheme 4
Formula (A), (B) and20) The compounds shown can be prepared by synthesis scheme 4: first, a compound (A)8) And a compound of (A)18) Potassium carbonate is used as alkali to react to generate a compound (A)19) (ii) a Then the compound (A), (B), (C19) Removing Boc protecting group in ethyl acetate solution of trifluoroacetic acid or hydrogen chloride, and alkalifying to obtain target compound (20)。
Synthesis scheme 5
Formula (A), (B) and22) The compounds shown can be prepared by synthesis scheme 5: compound (A) to (B)1) And a compound of (A)18) Potassium carbonate is used as alkali to react to generate a compound (A)21) Compound (A) to (B)21) Removing Boc protecting group in ethyl acetate solution of trifluoroacetic acid or hydrogen chloride, and alkalifying to obtain target compoundArticle (A), (B), (C), (22)。
Synthesis scheme 6
Formula (A), (B) and25) The compounds shown can be prepared by synthesis scheme 6: compound (A) to (B)11) And a compound of (A)18) Potassium carbonate is used as alkali to react to generate a compound (A)23) (ii) a Then the compound (A), (B), (C23) Carrying out substitution reaction with piperazine-1-carboxylic acid tert-butyl ester to generate a compound (A)24) (ii) a Finally the compound (A)24) Removing Boc protecting group in ethyl acetate solution of trifluoroacetic acid or hydrogen chloride, and alkalifying to obtain target compound (25)。
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 12- (2- (piperazin-1-yl) phenoxy) nicotinamide
Step 1) Synthesis of tert-butyl 4- (2- ((3-carbamoylpyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate
Tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-chloronicotinamide (0.25g,1.58mmol) and potassium carbonate (0.42g,3.02mmol) were added to DMSO (10mL) in that order, and the reaction was warmed to 110 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with water (20mL), and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.42g, 69.9%).
MS(ESI,pos.ion)m/z:399.1[M+H]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of 2- (2- (piperazin-1-yl) phenoxy) nicotinamide
Tert-butyl 4- (2- ((3-carbamoylpyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.28g,0.70mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a dark brown solid (0.20g, 95.4%).
MS(ESI,pos.ion)m/z:299.3[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 21- (2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Step 1) Synthesis of tert-butyl 4- (2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-chloro-4- (trifluoromethyl) pyridine (0.29g,1.58mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.25g, 39.1%).
MS(ESI,pos.ion)m/z:424.1[M+H]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of 1- (2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Tert-butyl 4- (2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.30g,0.71mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.22g, 96.1%).
MS(ESI,pos.ion)m/z:324.2[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 31- (2- ((5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Step 1) Synthesis of tert-butyl 4- (2- ((5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-chloro-5- (trifluoromethyl) pyridine (0.29g,1.58mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (0.35g, 54.8%).
MS(ESI,pos.ion)m/z:424.1[M+H]+；
1H NMR(CDCl3,400MHz)(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),6.87(d,J＝8.8Hz,1H),3.25-3.23(m,4H),2.95-2.92(m,4H),1.44(s,9H).
Step 2) Synthesis of 1- (2- ((5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Tert-butyl 4- (2- ((5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.30g,0.71mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.22g, 96.1%).
MS(ESI,pos.ion)m/z:324.3[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 42- (2- (piperazin-1-yl) phenoxy) nicotinonitrile
Step 1) Synthesis of tert-butyl 4- (2- ((3-cyanopyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate
The title compound of this step was prepared as described in example 1, step 1, by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-chloronicotinonitrile (0.22g,1.58mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.28g, 48.8%).
MS(ESI,pos.ion)m/z:381.1[M+H]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of 2- (2- (piperazin-1-yl) phenoxy) nicotinonitrile
Tert-butyl 4- (2- ((3-cyanopyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.27g,0.71mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.15g, 92.6%).
MS(ESI,pos.ion)m/z:281.2[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 51- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Step 1)4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylic acid Synthesis of tert-butyl esters
The title compound of this step may be prepared as described in example 1, step 1, by reacting tert-butyl 4- (2-hydroxy-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.52g,1.50mmol), 2-chloro-4- (trifluoromethyl) pyridine (0.29g,1.58mmol) and potassium carbonate (0.41g,3.00mmol) in DMSO (10mL) to give a crude product which, after purification on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1), gives the title compound as a pale yellow solid (0.34g, 46.0%).
MS(ESI,pos.ion)m/z:492.2[M+H]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of 1- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine
Tert-butyl 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.34g,0.69mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.25g, 92.3%).
MS(ESI,pos.ion)m/z:392.1[M+H]+；
1H NMR(DMSO-d6,600MHz)(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).
Example 62- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenoxy) nicotinamide
Step 1) tert-4- (2- ((3-carbamoylpyridin-2-yl) oxy) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid Synthesis of butyl ester
The title compound of this step may be prepared as described in example 1, step 1, by reacting tert-butyl 4- (2-hydroxy-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.52g,1.5mmol), 2-chloronicotinamide (0.25g,1.58mmol) and potassium carbonate (0.41g,3.00mmol) in DMSO (10mL) to afford a crude product which, after purification on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1), gives the title compound as a light yellow solid (0.35g, 50.0%).
MS(ESI,pos.ion)m/z:467.2[M+H]+；
1H NMR(CDCl3,400MHz)(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),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(s,9H).
Step 2) Synthesis of 2- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenoxy) nicotinamide
Tert-butyl 4- (2- ((3-carbamoylpyridin-2-yl) oxy) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.33g,0.71mmol) was dissolved in dichloromethane (5mL) and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.25g, 96.5%).
MS(ESI,pos.ion)m/z:367.1[M+H]+；
1H NMR(DMSO-d6,600MHz)(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).
Example 72- (5-cyano-2- (piperazin-1-yl) phenoxy) nicotinamide
Step 1) preparation of tert-butyl 4- (2- ((3-carbamoylpyridin-2-yl) oxy) -4-cyanophenyl) piperazine-1-carboxylate Synthesis of
The title compound of this step may be prepared as described in example 1, step 1, by reacting tert-butyl 4- (4-cyano-2-hydroxyphenyl) piperazine-1-carboxylate (0.46g,1.52mmol), 2-chloronicotinamide (0.25g,1.59mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to afford a crude product which, after purification on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1), gives the title compound as a light yellow solid (0.25g, 38.9%).
MS(ESI,pos.ion)m/z:424.2[M+H]+；
1H NMR(CDCl3,600MHz)(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) Synthesis of 2- (5-cyano-2- (piperazin-1-yl) phenoxy) nicotinamide
Tert-butyl 4- (2- ((3-carbamoylpyridin-2-yl) oxy) -4-cyanophenyl) piperazine-1-carboxylate (0.30g,0.71mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.18g, 78.6%).
MS(ESI,pos.ion)m/z:324.1[M+H]+；
1H NMR(CD3OD,600MHz)(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).
Example 84- (piperazin-1-yl) -3- ((4- (trifluoromethyl) pyridin-2-yl) oxy) benzonitrile
Step 1)4- (4-cyano-2- ((4- (trifluoro)Methyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylic acid tert-butyl ester Synthesis of (2)
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 4- (4-cyano-2-hydroxyphenyl) piperazine-1-carboxylate (0.46g,1.52mmol), 2-chloro-4- (trifluoromethyl) pyridine (0.29g,1.59mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.33g, 48.5%).
MS(ESI,pos.ion)m/z:449.2[M+H]+；
1H NMR(CDCl3,600MHz)(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) Synthesis of 4- (piperazin-1-yl) -3- ((4- (trifluoromethyl) pyridin-2-yl) oxy) benzonitrile
Tert-butyl 4- (4-cyano-2- ((4- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.31g,0.69mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL) and the pH was adjusted to 7 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.13g, 53.9%).
MS(ESI,pos.ion)m/z:349.1[M+H]+；
1H NMR(CD3OD,600MHz)(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).
Example 94-methyl-2- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenoxy) thiazole-5-carboxylic acid ethyl ester
Step 1)2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5- (trifluoromethyl) phenoxy) -4-methylthiazole- Synthesis of ethyl 5-carboxylate
Tert-butyl 4- (2-hydroxy-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.52g,1.50mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.39g,1.58mmol) and potassium carbonate (0.42g,3.00mmol) were added to DMSO (10mL), and the reaction was warmed to 110 ℃ for 20 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water (20mL) was added thereto, followed by extraction with ethyl acetate (20 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a light yellow solid (0.35g, 45.2%).
MS(ESI,pos.ion)m/z:516.2[M+H]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of ethyl 4-methyl-2- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenoxy) thiazole-5-carboxylate Become into
Ethyl 2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5- (trifluoromethyl) phenoxy) -4-methylthiazole-5-carboxylate (0.36g,0.70mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.12g, 41.4%).
MS(ESI,pos.ion)m/z:416.1[M+H]+；
1H NMR(CDCl3,400MHz)(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).
Example 104-methyl-2- (2- (piperazin-1-yl) -5- (trifluoromethyl) phenoxy) thiazole-5-carboxamide
Step 1)4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) -4- (trifluoromethyl) phenyl) piperazine- Synthesis of tert-butyl 1-carboxylate
The title compound of this step may be prepared as described in example 9, step 1, by reacting tert-butyl 4- (2-hydroxy-4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.52g,1.50mmol), 2-bromo-4-methylthiazole-5-carboxamide (0.35g,1.58mmol) and potassium carbonate (0.42g,3.00mmol) in DMSO (10mL) to give a crude product which is purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.37g, 50.7%).
MS(ESI,pos.ion)m/z:387.1[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(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- (piperazin-1-yl) -5- (trifluoromethyl)) Synthesis of phenoxy) thiazole-5-carboxamide
Tert-butyl 4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) -4- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.34g,0.70mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.16g, 59.2%).
MS(ESI,pos.ion)m/z:387.1[M+H]+；
1H NMR(CDCl3,600MHz)(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).
Example 112- (5-cyano-2- (piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxamide
Step 1)4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) -4-cyanophenyl) piperazine-1-carboxylic acid Synthesis of tert-butyl ester
The title compound of this step may be prepared as described in example 9, step 1, by reacting tert-butyl 4- (4-cyano-2-hydroxyphenyl) piperazine-1-carboxylate (0.46g,1.52mmol), 2-bromo-4-methylthiazole-5-carboxamide (0.35g,1.59mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to afford a crude product which, after purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1), gives the title compound as a pale yellow solid (0.34g, 50.5%).
MS(ESI,pos.ion)m/z:344.1[M+H-Boc]+；
1H NMR(CDCl3,600MHz)(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) Synthesis of 2- (5-cyano-2- (piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxamide
Tert-butyl 4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) -4-cyanophenyl) piperazine-1-carboxylate (0.31g,0.70mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.18g, 75.0%).
MS(ESI,pos.ion)m/z:344.1[M+H]+；
1H NMR(CD3OD,600MHz)(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).
Example 122- (5-cyano-2- (piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxylic acid ethyl ester
Step 1)2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5-cyanophenoxy) -4-methylthiazole-5-carboxylic acid Synthesis of Ethyl ester
The title compound of this step may be prepared as described in example 9, step 1, by reacting tert-butyl 4- (4-cyano-2-hydroxyphenyl) piperazine-1-carboxylate (0.46g,1.52mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.40g,1.59mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to afford a crude product which, after purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1), gives the title compound as a pale yellow solid (0.38g, 53.0%).
MS(ESI,pos.ion)m/z:373.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of ethyl 2- (5-cyano-2- (piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxylate
Ethyl 2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5-cyanophenoxy) -4-methylthiazole-5-carboxylate (0.33g,0.70mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.15g, 58.0%).
MS(ESI,pos.ion)m/z:391.1[M+H+H2O]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 134-methyl-2- (2-piperazin-1-yl) phenoxy) thiazole-5-carboxamide
Step 1) preparation of tert-butyl 4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) phenyl) piperazine-1-carboxylate Synthesis of
The title compound was prepared as described in example 9, step 1 by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-bromo-4-methylthiazole-5-carboxamide (0.35g,1.58mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.37g, 58.6%).
MS(ESI,pos.ion)m/z:319.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of 4-methyl-2- (2-piperazin-1-yl) phenoxy) thiazole-5-carboxamide
Tert-butyl 4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.35g,0.84mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.23g, 86.5%).
MS(ESI,pos.ion)m/z:319.1[M+H]+；
1H NMR(CD3OD,600MHz)(ppm):7.44-7.40(m,1H),7.33(dd,J＝8.4,1.4Hz,1H),7.25-7.20(m,2H),3.26(t,J＝4.8Hz,4H),2.82(t,J＝4.8Hz,4H),2.51(s,3H).
Example 144-methyl-2- (2- (piperazin-1-yl) phenoxy) thiazole-5-carboxylic acid ethyl ester
Step 1) Synthesis of ethyl 2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxylate Become into
The title compound was prepared as described in example 9, step 1 by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.40g,1.44mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.38g,1.51mmol) and potassium carbonate (0.40g,2.87mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.44g, 68.4%).
MS(ESI,pos.ion)m/z:348.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of ethyl 4-methyl-2- (2- (piperazin-1-yl) phenoxy) thiazole-5-carboxylate
Ethyl 2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenoxy) -4-methylthiazole-5-carboxylate (0.40g,0.89mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.25g, 80.5%).
MS(ESI,pos.ion)m/z:348.1[M+H]+；
1H NMR(DMSO-d6,600MHz)(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).
Example 154-methyl-2- (2- (piperazin-1-yl) phenoxy) thiazole-5-carbonitrile
Step 1) Synthesis of tert-butyl 4- (2- ((5-cyano-4-methylthiazol-2-yl) oxy) phenyl) piperazine-1-carboxylate
The title compound was prepared as described in example 9, step 1 by reacting tert-butyl 4- (2-hydroxyphenyl) piperazine-1-carboxylate (0.42g,1.51mmol), 2-bromo-4-methylthiazole-5-carbonitrile (0.32g,1.59mmol) and potassium carbonate (0.42g,3.02mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a pale yellow solid (0.33g, 54.6%).
MS(ESI,pos.ion)m/z:301.1[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(ppm):7.32(dd,J＝8.4,2.0Hz,1H),7.21-7.15(m,2H),7.02(d,J＝8.4Hz,1H),3.30(brs,4H),3.13-3.10(m,4H),2.54(s,3H),1.44(s,9H).
Step 2) Synthesis of 4-methyl-2- (2- (piperazin-1-yl) phenoxy) thiazole-5-carbonitrile
Tert-butyl 4- (2- ((5-cyano-4-methylthiazol-2-yl) oxy) phenyl) piperazine-1-carboxylate (0.30g,0.75mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.19g, 84.4%).
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(DMSO-d6,600MHz)(ppm):7.34(dd,J＝8.4,2.0Hz,1H),7.20-7.14(m,2H),7.03(d,J＝8.4Hz,1H),3.38(t,J＝4.8Hz,4H),2.88(t,J＝4.8Hz,4H),2.51(s,3H).
Example 164-methyl-2- (5-nitro-2- (piperazin-1-yl) phenoxy) thiazole-5-carboxamide
Step 1) Synthesis of 2- (2-fluoro-5-nitrophenoxy) -4-methylthiazole-5-carboxamide
The title compound was prepared as described in example 9, step 1 by reacting 2-fluoro-5-nitrophenol (0.47g,2.99mmol), 2-bromo-4-methylthiazole-5-carboxamide (0.69g,3.14mmol) and potassium carbonate (0.83g,5.98mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give the title compound as a white solid (0.65g, 73.1%).
MS(ESI,pos.ion)m/z:298.2[M+H]+；
1H NMR(CDCl3,400MHz)(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-carbamoyl-4-methylthiazol-2-yl) oxy) -4-nitrophenyl) piperazine-1-carboxylic acid Synthesis of tert-butyl ester
2- (2-fluoro-5-nitrophenoxy) -4-methylthiazole-5-carboxamide (0.64g,2.15mmol), piperazine-1-carboxylic acid tert-butyl ester (0.37g,4.31mmol) and potassium carbonate (0.33g,2.37mmol) were added to DMSO (10mL), and the reaction was warmed to 110 ℃ for 20 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water (20mL) was added thereto, followed by extraction with ethyl acetate (20 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a red solid (0.35g, 35.1%).
MS(ESI,pos.ion)m/z:464.2[M+H]+；
1H NMR(CDCl3,600MHz)(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) Synthesis of 4-methyl-2- (5-nitro-2- (piperazin-1-yl) phenoxy) thiazole-5-carboxamide
Tert-butyl 4- (2- ((5-carbamoyl-4-methylthiazol-2-yl) oxy) -4-nitrophenyl) piperazine-1-carboxylate (0.33g,0.71mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction solution was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.15g, 57.9%).
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Example 174-methyl-2- (5-nitro-2- (piperazin-1-yl) phenoxy) thiazole-5-carboxylic acid ethyl ester
Step 1) Synthesis of ethyl 2- (2-fluoro-5-nitrophenoxy) -4-methylthiazole-5-carboxylate
The title compound was prepared as described in example 9, step 1 by reacting 2-fluoro-5-nitrophenol (0.47g,2.99mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.79g,3.14mmol) and potassium carbonate (0.83g,5.98mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give the title compound as a white solid (0.57g, 58.4%).
MS(ESI,pos.ion)m/z:327.0[M+H]+；
1H NMR(CDCl3,400MHz)(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),2.52(s,3H),1.25(t,J＝7.2Hz,3H).
Step 2)2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5-nitrophenoxy) -4-methylthiazole-5-carboxylic acid Synthesis of Ethyl ester
The title compound was prepared as described in example 16, step 2 by reacting ethyl 2- (2-fluoro-5-nitrophenoxy) -4-methylthiazole-5-carboxylate (0.56g,1.72mmol), piperazine-1-carboxylic acid tert-butyl ester (0.30g,3.43mmol) and potassium carbonate (0.26g,1.89mmol) in DMSO (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a red solid (0.35g, 41.4%).
MS(ESI,pos.ion)m/z:393.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)(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) Synthesis of ethyl 4-methyl-2- (5-nitro-2- (piperazin-1-yl) phenoxy) thiazole-5-carboxylate
Ethyl 2- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5-nitrophenoxy) -4-methylthiazole-5-carboxylate (0.34g,0.69mmol) was dissolved in dichloromethane (5mL), and a solution of hydrogen chloride in ethyl acetate (2mL,4M) was added, and then the reaction was reacted at room temperature for 2 hours. After the reaction, the solvent in the reaction solution was distilled off. To the resulting residue was added water (15mL), and the pH was adjusted to 7-8 with sodium carbonate solid, followed by extraction with dichloromethane (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.20g, 73.8%).
MS(ESI,pos.ion)m/z:393.1[M+H]+；
1H NMR(DMSO-d6,400MHz)(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).
Biological assay
Example A: evaluation of the affinity of Compounds for humanized 5-HT transporters expressed in CHO cells
Experimental methods
Homogenizing protein (12. mu.g), 2nM [ mu.g ] to the cell membrane at 22 ℃, [3H]Imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1% BSA) were incubated for 60 minutes with or without test compound.
And in the mixed system of the above conditions, 10 μ M imipramine was added for measuring the non-specific binding value.
The incubated samples were rapidly filtered through a glass fiber filter (GF/B, Packard) pre-soaked with 0.3% PEI under vacuum using a 96-sample cell harvester (Unifilter, Packard) and washed several times with ice-cold 50mM Tris-HCl and 150mM NaCl. The filters were dried and the residual radioactivity was counted in scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The results of the experiment are expressed as the percentage inhibition of the specific binding of the radioligand relative to the control.
The standard reference compound is imipramine, and IC is calculated by obtaining competitive curves through experimental tests of series of concentrations50. See Table A for the results of affinity experiments for humanized 5-HT transporters (SERTs) for compounds of the invention.
TABLE A affinity assay for human 5-HT transporters (SERT) for the Compounds of the invention
The experimental result shows that the compound has stronger affinity to human 5-HT transporters (SERT).
Example B pharmacokinetic evaluation of rats following intravenous or intragastric dosing of a Compound of the invention
The present invention evaluates the pharmacokinetic studies of the compounds of the invention in rats and the animal information is detailed in table B.
Table B information sheet of the subject animals of the present invention
Test method
The compounds of the invention were administered to the test animals as 5% DMSO + 5% Kolliphor HS 15+ 2% (2% HCl) + 88% Saline solution or 10% DMSO + 10% Kolliphor HS 15+ 80% physiological Saline solution. For the group administered by intravenous injection, the dose was 1mg/kg or 2mg/kg, followed by intravenous blood (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration and centrifugation at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage administration group, the dose was 2.5mg/kg or 5mg/kg, and then blood was taken intravenously (0.3mL) at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.
The plasma solutions collected from the above groups were analyzed by LC/MS/MS. The analysis result shows that the compound of the invention measured by intravenous injection administration and intragastric administration in rat body has better pharmacokinetic properties of large exposure value, low clearance rate, high bioavailability and the like. The compound of the invention has better drugability and better clinical application prospect.
The experimental result shows that the compound has better pharmacokinetic property in the rat body.
In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (8)

1. A compound which is a compound represented by formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound represented by formula (I),
wherein:
is a double bond;
x is CRx；
Y is CRy；
Each R1、R2、RxAnd RyIndependently H, D, F, Cl, Br, I, -CN, -NO2、-CONH2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4A haloalkoxy group;
R4is H, D, F, Cl, Br, I, -CN, -NO2、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4A haloalkoxy group;
R3、R5and R6Each independently is H, D, F, Cl, Br, I or C1-C4An alkyl group; and
R7is H, D, F, Cl, Br, I or C1-C4An alkyl group.
2. The compound of claim 1, wherein each R1、R2、RxAnd RyIndependently 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)2Methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3Methoxy, ethoxy, n-propyloxy or isopropyloxy.
3. The compound of claim 1, wherein R4H, D, F, Cl is,Br、I、-CN、-NO2Methyl, ethyl, n-propyl, isopropyl, -CF3or-CH2CF3；
R3、R5And R6Each independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl.
4. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:
5. a pharmaceutical composition comprising a compound of any one of claims 1-4; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
6. The pharmaceutical composition of claim 5, further comprising a central nervous system dysfunction treating agent that is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, pipiprepin, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramipexole, pramipexole, dextromethorphan, quinidine, naltrexone, and, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, vertetipitan, chlordiazepoxide, perphenazine, or any combination thereof.
7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 6 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.
8. Use according to claim 7, for the prevention, treatment or alleviation of affective disorders.
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