CN108069937B - Phenyl piperidine derivatives, methods of use and uses thereof - Google Patents

Phenyl piperidine derivatives, methods of use and uses thereof Download PDF

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

Abstract

The invention relates to a phenyl piperidine derivative, a using method and application thereof, and particularly discloses a phenyl piperidine derivative for inhibiting reuptake of 5-hydroxytryptamine and a pharmaceutical composition thereof. The invention also relates to processes for preparing such compounds and pharmaceutical compositions, and their use in the treatment of central nervous system disorders, in particular affective disorders.

Description

Phenyl piperidine derivatives, methods of use and uses thereof
Technical Field
The present invention is in the field of pharmaceutical technology, and in particular 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 phenylpiperidine derivatives which are useful as 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 have comparable therapeutic effects but less side effects than TCAs, and produce less toxicity even when taken in excess (Sarko J. Anddepressant, old and new. A review of the ir additive effects and toxicity in overdose. Emerg 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 presynaptic membranes 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 related to 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 epidemic of DSM-IV major de-pressing epimode. 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, pharmacokinetic property and/or toxicological property.
Disclosure of Invention
The following is merely a summary of some aspects of the invention 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 phenylpiperidine derivatives having a strong binding affinity to the 5-HT transporter (SERT) and inhibiting 5-HT reuptake, which are useful in the preparation of medicaments 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 disorders and post-traumatic stress disorders.
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, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0001149217270000021
wherein:
each X 1 And X 2 Independently is CR x Or N;
q is-O-, -S (O) m -、-CH 2 -or-NH-;
m is 0, 1 or 2;
n is 0, 1,2, 3, 4 or 5; and
each R x 、R 1 、R 2 And R 3 Have the meaning described in the present invention.
In one embodiment, each R is 1 Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (═ O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio radical, C 1 -C 6 Alkylamino or hydroxy substituted C 1 -C 6 An alkyl group.
In one embodiment, R 2 Is H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (═ O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group.
In one embodiment, each R is x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (═ O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio radical, C 1 -C 6 Alkylamino or hydroxy substituted C 1 -C 6 An alkyl group.
In one embodiment, R 3 Is D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, hydroxy-substituted C 1 -C 6 Alkyl or C 1 -C 6 An alkylamino group.
In one embodiment, each R is 1 And R x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、-C(＝O)-(C 1 -C 6 Alkyl), -C (═ O) - (C) 1 -C 6 Alkoxy group), C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio radical, C 1 -C 6 Alkylamino or hydroxy substituted C 1 -C 6 An alkyl group.
In one embodiment, each R is 1 Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (═ O) - (C) 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylamino or hydroxy substituted C 1 -C 4 An alkyl group.
In one embodiment, R 2 Is H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
In one embodiment, each R is x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (═ O) - (C) 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylamino or hydroxy substituted C 1 -C 4 An alkyl group.
In one embodiment, R 3 Is D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 、C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, hydroxy-substituted C 1 -C 4 Alkyl or C 1 -C 4 An alkylamino group.
In one embodiment, each R is 1 And R x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)-(C 1 -C 4 Alkyl), -C (═ O) - (C) 1 -C 4 Alkoxy group), C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylamino or hydroxy substituted C 1 -C 4 An alkyl group.
In one embodiment, each R is 1 Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)CH 3 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OCH 2 CH 2 CH 3 、-C(＝O)OCH(CH 3 ) 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 2 Is H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 or-CH 2 CF 3 。
In one embodiment, each R is x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)CH 3 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OCH 2 CH 2 CH 3 、-C(＝O)OCH(CH 3 ) 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
In one embodiment, R 3 Is D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-COOH、-C(＝O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, N-propyloxy, isopropyloxy, hydroxymethyl, 2-hydroxyethyl, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.
Each R 1 And R x Independently H, D, F, Cl, Br, I, -CN, -NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(＝O)CH 3 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OCH 2 CH 2 CH 3 、-C(＝O)OCH(CH 3 ) 2 Methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
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 a compound having one of the following structures:
Figure BDA0001149217270000031
Figure BDA0001149217270000041
in another aspect, the 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 agent for treating a central nervous system dysfunction of the present invention is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), bupropion (bupipion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), milnacipran (milnacipran), levomilnacipran (levomilnacipran), desvenlafaxine (desvenlafaxine), vilazodone (vilazodone), venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), nonsexitin (femoxetine), chlorpromazine (chlorpromazine), ziprasidone (fluazine), sulbazine (fluazine), sultoprazone (fluazine), sulpirtine (piperazinone), sulpridone (piperazinone), sulpridone (piperazinone), sulpridone (piperacillin), sulpridone (piperazinone), sulprizone (piperazinone), sulprizone (piperazinone (sulprizone), sulpridinone (sulprizone), sulpridone (sulpridinone (sulprizone), sulpridinone (sulpridinone), sulpridinone (sulprine), sulpridinone (sulprine (sulpridinone), sulprine (sulpridinone), sulpridinone (sulpridinone) or (sulpridinone), sulpridinone (sulpridinone), sulpridinone (sulpridinone) or (sulpridinone), sulpridinone (sulpridinone), sulpridinone (sulpride) or (sulpridinone), sulpride) or (sulpri, Perospirone (perospirone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), cabergoline (cabergoline), adamantane (amantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dexamethorphan), quinidine (quinidine), naltrexone (naltrexone), samindoorphan (buprenorphine), melatonin (meonilon), alprazolam (alprazolam), pipamperone (pimperone), vetepitant (vestitant), chlordiazepoxide (chloridizime), perphenazine (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 preventing, treating or reducing 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 is selected from the group consisting of, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders, and post-traumatic stress disorders.
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 referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York: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 "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 term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy 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 with … …" is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, N 3 ，-CN，-OH，-SH，-NH 2 Alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl and the like.
In addition, unless otherwise explicitly stated, the description "… is" independently "and" … is "independently" and "… is" independently "used in the present invention are to be construed broadly, which means that the specific items expressed between the same symbols in different groups are not affected by each other, or that the specific items expressed between the same symbols in the same groups are not affected by each other.
The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
In each part of this specification, substituents for 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 "C 1 -C 6 Alkyl "in particular denotes independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An 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 chain or branched chain containing from 1 to 20 carbon atomsBranched monovalent hydrocarbyl groups wherein the alkyl group may be optionally substituted with one or more substituents 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 (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) 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 at least one carbon-carbon sp 2 A 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, alkenyl groups contain 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) 2 CH＝CH 2 ) 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 carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally 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 ≡ CH), propargyl (-CH) 2 C.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 groups contain 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.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) And so on.
The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.
Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH) 3 ) Ethylthio (EtS, -SCH) 2 CH 3 ) 1-propylthio (n-PrS, n-propylthio, -SCH) 2 CH 2 CH 3 ) 2-propylthio (i-PrS, i-propylthio, -SCH (CH) 3 ) 2 ) 1-butylthio (n-BuS, n-butylthio, -SCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH) 2 CH(CH 3 ) 2 ) 2-butylthio (s-BuS, s-butylthio, -SCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC (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 term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, and such examples include, but are not limited to, -CF 3 、-CH 2 CF 3 、-CHFCH 3 、-CH 2 CH 2 F、CF 2 CH 3 And so on. In one embodiment, C 1 -C 6 The haloalkyl group containing a fluorine-substituted C 1 -C 6 An alkyl group; in another embodiment, C 1 -C 4 The haloalkyl group containing a fluorine-substituted C 1 -C 4 An alkyl group; in yet another embodiment, C 1 -C 2 Haloalkyl comprises fluorine-substituted C 1 -C 2 An alkyl group.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCF 3 、-OCH 2 CF 3 、-OCHFCH 3 、-OCH 2 CH 2 F、-OCF 2 CH 3 And so on. In one embodiment, C 1 -C 6 Haloalkoxy comprises fluorine substituted C 1 -C 6 An alkoxy group; in thatIn another embodiment, C 1 -C 4 Haloalkoxy comprises fluorine substituted C 1 -C 4 An alkoxy group; in yet another embodiment, C 1 -C 2 Haloalkoxy comprises fluorine substituted C 1 -C 2 An alkoxy group.
The term "protecting group" or "PG" refers to a substituent which, when reacted with other functional groups, is generally 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-CH 2 CH 2 SO 2 Ph, 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 Carriers 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, description of the scientific 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, aspartatesExamples of suitable organic solvents include, but are not limited to, salts of hydrochloric, sulfuric, benzoic, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A 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, C 1 -C 8 Sulfonates 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 mitigating 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 the 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 such 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 phenyl piperidine derivatives, pharmaceutically acceptable salts thereof, pharmaceutical formulations and compositions thereof according to the present invention are useful as selective 5-hydroxytryptamine reuptake inhibitors, and have potential use in the treatment of disorders of the central nervous system including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders and post-traumatic stress disorders 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 substances using a common oxidizing agent (e.g. hydrogen peroxide) at elevated temperature in the presence of an acid such as acetic acid, 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 salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) and/or in the isolation of an enantiomer of a compound 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 generally carried out in water or an organic solvent or a mixture of the two. 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 pharmaceutical salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), may find a list of additional 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 as 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 31 P、 32 P、 35 S、 36 Cl and 125 I。
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 a 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 must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and interactions that 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 much of the excipient is 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, for example, by mixing 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, such as 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 can be formulated into 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 can 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 in 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 herein 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 invention can be used for preparing medicaments for preventing, treating or relieving central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicaments for inhibiting reuptake of 5-hydroxytryptamine.
In particular, the amount of the compound in the compositions of the invention is effective to detectably and selectively inhibit reuptake of 5-hydroxytryptamine and the compounds of the invention are useful as medicaments for the treatment of disorders of the Central Nervous System (CNS) in humans, in particular affective disorders, including but not limited to depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders, and post-traumatic stress disorder.
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 disorder, obsessive compulsive disorder, 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. Other examples of 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 presently disclosed compounds or pharmaceutical compositions comprising the presently 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 can be carried out until the desired therapeutic effect is achieved or 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 skilled persons will also appreciate that adjustments to the appropriate dosage regimen may be required for an individual patient's response to the dosage regimen, or as the individual patient needs to change over time.
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 in the same pharmaceutical composition.
General synthetic procedure
To describe the invention, examples are set forth below. 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, all temperatures are 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 plant, Guangdong Guanghua chemical plant, Guangzhou chemical plant, Tianjin Haojiuyu Chemicals Co., Ltd, Tianjin Shuichun chemical plant, Wuhan Xin Huayuan science and technology development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao maritime chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. 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 a positive pressure of nitrogen or argon or by placing a drying tube over an anhydrous solvent (unless otherwise indicated), the reaction vial is stoppered with a suitable rubber stopper and the substrate is driven in by syringe. Glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic chemical plants.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 H NMR spectrum expressed in CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0ppm) or chloroform (7.26ppm) were used as reference standards 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-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) 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:
CH 2 Cl 2 DCM dichloromethane
CDC1 3 Deuterated chloroform
DMF N, N-dimethylformamide
DIPEA N, N-diisopropylethylamine
DMSO dimethyl sulfoxide
MeOH methanol
MeCN、CH 3 CN acetonitrile
HCl hydrogen chloride
NaNO 2 Sodium nitrite
KI potassium iodide
t-BuOK Potassium tert-Butanol
NaHCO 3 Sodium bicarbonate
Na 2 S 2 O 3 Sodium thiosulfate
Na 2 SO 4 Sodium sulfate
Pd/C10% palladium on carbon
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium
DPEPhos bis (2-diphenylphosphino) phenyl ether
g
h hours
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
PEI and polyethylenimine polyethyleneimine
The following synthetic schemes describe the procedures for preparing the compounds disclosed herein, except as otherwise indicated, wherein each R is 1 、R 2 、X 1 、X 2 And n has the definitions set forth herein.
Synthetic schemes
Figure BDA0001149217270000141
The compound (5) can be prepared by the following process: heating a compound (1) substituted by different substituents and N, N-dimethylpiperidine-4-amine to react under the alkaline condition to obtain a compound (2), hydrogenating and reducing the compound (2) to obtain a compound (3), reacting the compound (3) with an iodo reagent after forming a diazonium salt to obtain a compound (4), and reacting the compound (4) with thiophenol (6) containing different substituents under the catalysis of palladium to obtain a target compound (5).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated in the following examples.
Examples
EXAMPLE 1 Synthesis of N, N-dimethyl-1- (2- (pyrimidin-2-ylthio) phenyl) piperidin-4-amine
Figure BDA0001149217270000142
Step 1) Synthesis of N, N-dimethyl-1- (2-nitrophenyl) piperidin-4-amine
1-fluoro-2-nitrobenzene (1.21g,8.58mmol), N-dimethylpiperidin-4-amine (1.00g,7.80mmol) and N, N-diisopropylethylamine (2.02g,15.60mmol) were added in this order to anhydrous DMF (15mL), and the reaction was allowed to warm to 90 ℃ for 12 hours under nitrogen. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with water (30mL), extracted with dichloromethane (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound (pale yellow solid, 1.40g, 72.0%).
MS(ESI,pos.ion)m/z:250.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.73(dd,J＝8.1,1.5Hz,1H),7.45～7.39(m,1H),7.14～7.06(m,1H),6.99～6.92(m,1H),3.30(d,J＝12.4Hz,2H),2.80(td,J＝12.1,2.0Hz,2H),2.29(s,6H),2.32～2.24(m,1H),1.90～1.82(m,2H),1.68(qd,J＝12.1,3.8Hz,2H).
Step 2) Synthesis of 1- (2-aminophenyl) -N, N-dimethyl-piperidin-4-amine
N, N-dimethyl-1- (2-nitrophenyl) piperidin-4-amine (3.81g,15.28mmol) was dissolved in anhydrous methanol (45mL), followed by the addition of 10% palladium on carbon (381mg), and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. The reaction was stopped, suction filtered, the filtrate was collected, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (white solid, 2.85g, 85.1%).
MS(ESI,pos.ion)m/z:220.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.53(dd,J＝8.1,1.5Hz,1H),7.38～7.35(m,1H),7.10～7.00(m,1H),6.97～6.95(m,1H),3.31(d,J＝12.4Hz,2H),2.82(td,J＝12.1,2.0Hz,2H),2.29(s,6H),2.32～2.26(m,1H),1.90～1.84(m,2H),1.68(qd,J＝12.1,3.8Hz,2H).
Step 3) Synthesis of 1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine
1- (2-aminophenyl) -N, N-dimethyl-piperidin-4-amine (2.85g,13.0mmol) was added to a mixed solvent of acetonitrile (50mL) and water (60mL), followed by addition of concentrated hydrochloric acid (12 mL). Sodium nitrite (1.08g,15.65mmol) was added slowly at 0 ℃ and after the addition was complete stirring was continued for 1 hour. Potassium iodide (3.45g,20.78mmol) was added at 0 ℃ and, after completion of the addition, stirring was continued for 1 hour, followed by reaction at room temperature for 4 hours. The reaction was stopped, extracted with dichloromethane (20mL × 3), the organic phase was collected, washed successively with saturated sodium bicarbonate and sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was collected, the solvent was removed by distillation under reduced pressure, and the resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 2.06g, 48.0%).
MS(ESI,pos.ion)m/z:331.00[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.80(dd,J＝7.9,1.4Hz,1H),7.28(td,J＝7.9,1.4Hz,1H),6.98(dd,J＝8.0,1.4Hz,1H),6.79(td,J＝7.7,1.5Hz,1H),3.36(d,J＝12.2Hz,2H),3.28(t,J＝12.2Hz,1H),2.81(s,6H),2.70(t,J＝11.1Hz,2H),2.16(d,J＝11.6Hz,2H),1.97(qd,J＝11.9,3.8Hz,2H).
Step 4) Synthesis of N, N-dimethyl-1- (2- (pyrimidin-2-ylthio) phenyl) piperidin-4-amine
1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.91mmol), pyrimidine-2-thiophenol (152mg,1.36mmol), tris (dibenzylideneacetone) dipalladium (41mg,0.045mmol), bis (2-diphenylphosphino) phenyl ether (48mg,0.09mmol) and potassium tert-butoxide (271mg,2.42mmol) were added in this order to DMSO (10mL), and the mixture was heated to 120 ℃ under nitrogen protection overnight. The reaction was stopped, the reaction solution was diluted with water (30mL), dichloromethane (15mL × 3) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, the filtrate was collected, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 160mg, 56.01%).
MS(ESI,pos.ion)m/z:315.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.46(d,J＝4.6Hz,2H),7.60(dd,J＝7.7,1.3Hz,1H),7.36(td,J＝7.9,1.4Hz,1H),7.11(dd,J＝10.9,4.2Hz,1H),7.07(d,J＝7.9Hz,1H),6.98(t,J＝4.7Hz,1H),3.38(d,J＝11.5Hz,2H),3.14(t,J＝10.9Hz,1H),2.70(d,J＝12.2Hz,2H),2.69(s,6H),1.98(d,J＝10.5Hz,2H),1.48(d,J＝10.5Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):172.7,157.4,153.4,136.5,130.6,126.2,124.7,121.1,117.2,63.1,50.5,39.1,22.7；
HPLC:95.37％.
Example 2 Synthesis of 1- (2- ((4, 6-dimethylpyrimidin-2-yl) thio) phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000161
The title compound was prepared as described in example 1, step 4, namely 1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine (350mg,1.06mmol), 4, 6-dimethylpyrimidine-2-thiol (222mg,1.58mmol), tris (dibenzylideneacetone) dipalladium (48mg,0.05mmol), bis (2-diphenylphosphino) phenyl ether (57mg,0.10mmol) and potassium tert-butoxide (316mg,2.80mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 120mg, 33.05%).
MS(ESI,pos.ion)m/z:343.35[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.64(d,J＝7.7Hz,1H),7.33(t,J＝7.6Hz,1H),7.11(t,J＝7.6Hz,1H),7.06(d,J＝8.0Hz,1H),6.74(s,1H),3.38(d,J＝11.9Hz,2H),3.20(t,J＝12.2Hz,1H),2.73(d,J＝11.8Hz,2H),2.70(s,6H),2.33(s,6H),1.98(d,J＝10.4Hz,2H),1.56(qd,J＝11.8,3.5Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):171.1,167.3,152.9,135.9,129.9,126.9,124.6,120.9,116.4,63.1,50.6,38.9,26.1,23.7；
HPLC:99.90％.
EXAMPLE 3 Synthesis of 1- (2- ((4, 6-Dimethoxypyrimidin-2-yl) thio) phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000162
The title compound of this step was prepared by the method described in example 1, step 4, namely 1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine (400mg,1.21mmol), 4, 6-dimethoxypyrimidin-2-thiol (313mg,1.81mmol), tris (dibenzylideneacetone) dipalladium (55mg,0.06mmol), bis (2-diphenylphosphino) phenyl ether (65mg,0.12mmol) and potassium tert-butoxide (339mg,3.00mmol) in DMSO (10mL) overnight at 120 ℃ under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 250mg, 55.11%).
MS(ESI,pos.ion)m/z:375.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.61(dd,J＝7.7,1.5Hz,1H),7.30(td,J＝7.9,1.6Hz,1H),7.05(dd,J＝8.0,1.1Hz,1H),7.02(td,J＝7.5,1.2Hz,1H),5.70(s,1H),3.71(s,6H),3.34(d,J＝11.9Hz,2H),2.64(td,J＝11.8,1.7Hz,2H),2.26(s,6H),2.29～2.23(m,1H),1.78(d,J＝12.1Hz,2H),1.52～1.46(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):170.9,170.8,154.9,137.2,129.9,126.1,123.0,120.1,86.0,62.0,53.9,52.0,41.4,28.4；
HPLC:97.73％.
Example 4 Synthesis of N, N-dimethyl-1- (2- ((4- (trifluoromethyl) pyrimidin-2-yl) thio) phenyl) piperidin-4-amine
Figure BDA0001149217270000171
The title compound of this step was prepared by the method described in example 1, step 4, namely 1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.91mmol), 4- (trifluoromethyl) pyrimidin-2-thiol (245mg,1.36mmol), tris (dibenzylideneacetone) dipalladium (41mg,0.045mmol), bis (2-diphenylphosphino) phenyl ether (48mg,0.09mmol) and potassium tert-butoxide (271mg,2.42mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen protection. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 200mg, 57.57%).
MS(ESI,pos.ion)m/z:383.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.66(d,J＝4.9Hz,1H),7.58(dd,J＝7.6,1.5Hz,1H),7.37(td,J＝7.9,1.5Hz,1H),7.24(d,J＝4.9Hz,1H),7.12～7.10(m,1H),7.08(td,J＝7.6,1.2Hz,1H),3.30(d,J＝11.9Hz,2H),2.62(td,J＝11.7,1.5Hz,2H),2.31～2.25(m,1H),2.24(s,6H),1.77(d,J＝12.1Hz,2H),1.21(dd,J＝12.0,3.6Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):174.4,159.3,155.7,154.89,136.2,130.8,125.0,123.9,121.0,119.2,112.1,61.97,51.6,41.1,28.2；
HPLC:95.07％.
EXAMPLE 5 Synthesis of 1- (2- ((2, 4-dimethylphenyl) thio) phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000172
The title compound of this step was prepared by the method described in example 1, step 4, i.e. 1- (2-iodophenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.91mmol), 2, 4-dimethylthiophenol (188mg,1.36mmol), tris (dibenzylideneacetone) dipalladium (41mg,0.045mmol), bis (2-diphenylphosphino) phenyl ether (48mg,0.09mmol) and potassium tert-butoxide (271mg,2.42mmol) in DMSO (10mL) overnight under nitrogen protection at 120 ℃. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 150mg, 55.1%).
MS(ESI,pos.ion)m/z:341.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.37(d,J＝7.8Hz,1H),7.14(s,1H),7.06(dd,J＝7.9,1.2Hz,1H),7.04(dd,J＝3.8,1.4Hz,1H),7.02(d,J＝6.7Hz,1H),6.87～6.82(m,1H),6.52(dd,J＝7.9,1.1Hz,1H),3.45(d,J＝11.9Hz,2H),2.71(t,J＝10.9Hz,2H),2.57～2.52(m,1H),2.44(s,6H),2.35(s,3H),2.32(s,3H),1.97(d,J＝11.9Hz,2H),1.79(qd,J＝12.0,3.7Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):149.5,142.3,139.1,136.1,134.6,131.6,128.2,127.8,126.3,125.4,124.2,119.8,62.5,51.6,41.1,28.2,21.2,20.6；
HPLC:99.01％.
EXAMPLE 6 Synthesis of N, N-dimethyl-1- (4-methyl-2- (pyrimidin-2-ylthio) phenyl) piperidin-4-amine
Figure BDA0001149217270000181
Step 1) Synthesis of N, N-dimethyl-1- (4-methyl-2-nitrophenyl) piperidin-4-amine
The title compound was prepared as described in example 1, step 1, by reacting 1-fluoro-4-methyl-2-nitrobenzene (3.99g,25.72mmol), N-dimethylpiperidin-4-amine (3.0g,23.40mmol) and DIPEA (6.17g,47.83mmol) in dry DMF (30mL) under nitrogen at 90 ℃ for 12 hours. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound (pale yellow solid, 3.55g, 57.6%).
MS(ESI,pos.ion)m/z:264.15[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.53(d,J＝1.2Hz,1H),7.24(dd,J＝8.4,1.5Hz,1H),7.03(d,J＝8.4Hz,1H),3.25(d,J＝12.2Hz,2H),2.75(td,J＝12.0,1.8Hz,2H),2.30(s,3H),2.29(s,6H),2.28～2.21(m,1H),1.84(d,J＝12.3Hz,2H),1.68(qd,J＝12.1,3.8Hz,2H).
Step 2) preparation of 1- (2-amino-4-methylphenyl) -N, N-dimethylpiperidin-4-amineSynthesis of
The title compound of this step was prepared as described in example 1, step 2, by catalytic hydrogenation of N, N-dimethyl-1- (4-methyl-2-nitrophenyl) piperidin-4-amine (3.55g,13.50mmol) over palladium on carbon (355mg,1.35mmol) in methanol (30 mL). The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow solid, 2.41g, 76.6%).
MS(ESI,pos.ion)m/z:234.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.29(d,J＝1.2Hz,1H),7.22(dd,J＝8.4,1.5Hz,1H),7.01(d,J＝8.4Hz,1H),3.24(d,J＝12.2Hz,2H),2.73(td,J＝12.0,1.8Hz,2H),2.31(s,3H),2.27(s,6H),2.25～2.20(m,1H),1.84(d,J＝12.3Hz,2H),1.68(qd,J＝12.1,3.8Hz,2H).
Step 3) Synthesis of 1- (2-iodo-4-methylphenyl) -N, N-dimethylpiperidine-4-amine
The title compound of this step was prepared by the method described in example 1, step 3, i.e., 1- (2-amino-4-methylphenyl) -N, N-dimethylpiperidin-4-amine (2.41g,10.33mmol) was reacted with concentrated hydrochloric acid (12mL) and sodium nitrite (855mg,12.40mmol) at 0 ℃ for 1 hour in a mixed solvent of acetonitrile (50mL) and water (50 mL). Followed by reaction with potassium iodide (2.74g,16.51mmol) at 0 ℃ for 1 hour and at room temperature for 4 hours. After the reaction was completed, the obtained crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound (yellow liquid, 1.80g, 50.7%).
MS(ESI,pos.ion)m/z:345.05[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.67(d,J＝1.2Hz,1H),7.10(dd,J＝8.0,1.3Hz,1H),6.90(d,J＝8.1Hz,1H),3.48～3.40(m,1H),3.35(d,J＝12.2Hz,2H),2.82(s,6H),2.74(t,J＝11.2Hz,2H),2.35(d,J＝11.7Hz,2H),2.25(s,3H),2.02(qd,J＝11.9,3.9Hz,2H).
Step 4) Synthesis of N, N-dimethyl-1- (4-methyl-2- (pyrimidin-2-ylthio) phenyl) piperidin-4-amine
The title compound was prepared as described in example 1, step 4, namely 1- (2-iodo-4-methylphenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.87mmol), pyrimidine-2-thiophenol (146mg,1.30mmol), tris (dibenzylideneacetone) dipalladium (39mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (46mg,0.085mmol) and potassium tert-butoxide (244mg,2.17mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 150mg, 50.29%).
MS(ESI,pos.ion)m/z:329.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.44(d,J＝4.8Hz,2H),7.40(d,J＝1.7Hz,1H),7.14(dd,J＝8.1,1.6Hz,1H),7.00(d,J＝8.1Hz,1H),6.93(t,J＝4.8Hz,1H),3.24(d,J＝11.8Hz,2H),2.56(td,J＝11.7,1.6Hz,2H),2.31～2.29(m,1H),2.28(s,3H),2.19(s,6H),2.18～2.13(m,2H),1.73～1.66(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):173.1,157.2,152.3,136.5,133.4,131.0,126.0,120.8,116.8,61.9,51.7,41.4,28.4,20.7；
HPLC:96.47％.
EXAMPLE 7 Synthesis of 1- (2- ((4, 6-dimethylpyrimidin-2-yl) thio) -4-methylphenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000191
The title compound was prepared as described in example 1, step 4, namely 1- (2-iodo-4-methylphenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.87mmol), 4, 6-dimethylpyrimidine-2-thiophenol (183mg,1.30mmol), tris (dibenzylideneacetone) dipalladium (39mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (46mg,0.085mmol) and potassium tert-butoxide (244mg,2.17mmol) in DMSO (10mL) at 120 ℃ under nitrogen protection overnight. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 155mg, 49.88%).
MS(ESI,pos.ion)m/z:357.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.45(d,J＝1.6Hz,1H),7.17(dd,J＝8.1,1.5Hz,1H),7.03(d,J＝8.1Hz,1H),6.79(s,1H),3.33(d,J＝12.0Hz,2H),3.24～3.18(m,1H),2.78(t,J＝11.2Hz,2H),2.72(s,6H),2.35(s,6H),2.30(s,3H),1.98(d,J＝10.8Hz,2H),1.57(qd,J＝12.1,4.0Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):170.6,167.5,149.8,136.5,135.0,131.1,125.8,121.0,116.7,63.0,50.8,39.2,26.1,23.4,20.6；
HPLC:96.82％.
EXAMPLE 8 Synthesis of 1- (2- ((4, 6-dimethoxypyrimidin-2-yl) thio) -4-methylphenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000201
The title compound of this step was prepared by the method described in example 1, step 4, namely 1- (2-iodo-4-methylphenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.87mmol), 4, 6-dimethoxypyrimidine-2-thiol (225mg,1.30mmol), tris (dibenzylideneacetone) dipalladium (39mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (46mg,0.085mmol) and potassium tert-butoxide (244mg,2.17mmol) in DMSO (10mL) at 120 ℃ under nitrogen protection overnight. The obtained crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 100mg, 29.53%).
MS(ESI,pos.ion)m/z:389.05[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.50(s,1H),7.26(s,1H),7.18(d,J＝6.1Hz,1H),7.05(d,J＝6.0Hz,1H),3.75(s,6H),3.43(d,J＝6.7Hz,2H),3.39～3.33(m,1H),2.93～2.81(m,2H),2.78(s,6H),2.32(s,3H),2.05(dd,J＝11.5,5.1Hz,2H),1.82～1.77(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):171.0,170.6,137.6,134.6,130.9,126.0,120.4,114.0,86.0,77.2,54.1,51.0,31.9,29.3,22.7；
HPLC:93.12％.
EXAMPLE 9 Synthesis of N, N-dimethyl-1- (4-methyl-2- ((4- (trifluoromethyl) pyrimidin-2-yl) thio) phenyl) piperidin-4-amine
Figure BDA0001149217270000202
The title compound of this step was prepared by the method described in example 1, step 4, namely 1- (2-iodo-4-methylphenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.87mmol), 4- (trifluoromethyl) pyrimidin-2-thiol (235mg,1.30mmol), tris (dibenzylideneacetone) dipalladium (39mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (46mg,0.085mmol) and potassium tert-butoxide (244mg,2.17mmol) in DMSO (10mL) at 120 ℃ under nitrogen protection overnight. The obtained crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 120mg, 34.72%).
MS(ESI,pos.ion)m/z:397.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.70(d,J＝4.9Hz,1H),7.46(d,J＝1.5Hz,1H),7.31(d,J＝5.0Hz,1H),7.29～7.21(m,1H),7.12(d,J＝8.2Hz,1H),3.39(d,J＝12.1Hz,2H),3.30～3.19(m,1H),2.86(t,J＝11.3Hz,2H),2.73(s,6H),2.33(s,3H),2.01(d,J＝11.4Hz,2H),1.57(qd,J＝11.9,3.5Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):174.0,159.8,155.9,149.71,137.1,135.8,132.0,124.6,121.2,120.1,112.5,63.0,51.2,39.5,26.1,20.6；
HPLC:98.73％.
EXAMPLE 10 Synthesis of 1- (2- ((2, 4-dimethylphenyl) thio) -4-methylphenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000211
The title compound of this step was prepared by the method described in reference to example 1, step 4, namely 1- (2-iodo-4-methylphenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.87mmol), 2, 4-dimethylthiophenol (180mg,1.30mmol), tris (dibenzylideneacetone) dipalladium (39mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (46mg,0.09mmol) and potassium tert-butoxide (244mg,2.17mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 150mg, 48.53%).
MS(ESI,pos.ion)m/z:355.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.34(d,J＝7.8Hz,1H),7.13(s,1H),7.01(d,J＝7.8Hz,1H),6.94(d,J＝8.0Hz,1H),6.86(dd,J＝8.0,1.3Hz,1H),6.36(d,J＝1.5Hz,1H),3.39(d,J＝11.9Hz,2H),2.67(td,J＝11.7,1.6Hz,2H),2.50～2.42(m,1H),2.39(s,6H),2.36(s,3H),2.33(s,3H),2.11(s,3H),1.93(d,J＝11.9Hz,2H),1.75(qd,J＝12.0,3.7Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):147.4,142.0,138.8,135.6,134.1,133.8,131.6,128.4,127.7,127.0,126.2,119.7,62.4,51.8,41.2,28.3,21.2,20.9,20.6；
HPLC:94.63％.
EXAMPLE 11 Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- (pyrimidin-2-ylthio) benzonitrile
Figure BDA0001149217270000212
Step 1) Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3-nitrobenzonitrile
The title compound of this step was prepared by the method described in example 1, step 1, and reacting 4-fluoro-3-nitrobenzonitrile (4.28g,25.74mmol), N-dimethylpiperidin-4-amine (3.0g,23.40mmol), and DIPEA (6.17g,47.83mmol) in dry DMF (30mL) under nitrogen at 90 ℃ for 12 hours. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound (pale yellow solid, 3.05g, 47.6%).
MS(ESI,pos.ion)m/z:275.15[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.03(d,J＝2.0Hz,1H),7.58(dd,J＝8.8,2.0Hz,1H),7.08(d,J＝8.8Hz,1H),3.46～3.36(m,2H),3.06～2.96(m,2H),2.38～2.31(m,1H),2.28(s,6H),1.90(d,J＝11.8Hz,2H),1.65(qd,J＝12.3,3.8Hz,2H).
Step 2) Synthesis of 3-amino-4- (4- (dimethylamino) piperidin-1-yl) benzonitrile
The title compound was prepared as described in example 1, step 2, using 4- (4- (dimethylamino) piperidin-1-yl) -3-nitrobenzonitrile (3.05g,11.12mmol) in methanol (30mL) via catalytic hydrogenation on palladium on carbon (305mg,1.11 mmol). The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow solid, 1.40g, 52.0%).
MS(ESI,pos.ion)m/z:245.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.88(d,J＝2.0Hz,1H),7.52(dd,J＝8.8,2.0Hz,1H),6.98(d,J＝8.8Hz,1H),3.44～3.38(m,2H),3.08～2.99(m,2H),2.37～2.31(m,1H),2.26(s,6H),1.92(d,J＝11.8Hz,2H),1.66(qd,J＝12.3,3.8Hz,2H).
Step 3) Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile
The title compound of this step was prepared by the method described in example 1, step 3, i.e. 3-amino-4- (4- (dimethylamino) piperidin-1-yl) benzonitrile (1.40g,5.73mmol) was reacted with concentrated hydrochloric acid (8mL) and sodium nitrite (470mg,6.81mmol) in a mixed solvent of acetonitrile (30mL) and water (30mL) at 0 ℃ for 1 hour. Followed by reaction with potassium iodide (1.5g,9.04mmol) at 0 ℃ for 1 hour and at room temperature for 4 hours. After the reaction was completed, the obtained crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound (yellow liquid, 1.10g, 54.0%).
MS(ESI,pos.ion)m/z:356.95[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.05(d,J＝1.9Hz,1H),7.56(dd,J＝8.3,1.9Hz,1H),7.03～6.96(m,1H),3.44(d,J＝12.2Hz,2H),2.95～2.87(m,1H),2.75(t,J＝11.1Hz,2H),2.57(s,6H),2.15(d,J＝12.1Hz,2H),1.88(qd,J＝12.0,3.7Hz,2H).
Step 4) Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- (pyrimidin-2-ylthio) benzonitrile
The title compound was prepared by the method described in example 1, step 4, namely 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile (300mg,0.84mmol), pyrimidine-2-thiophenol (142mg,1.27mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.04mmol), bis (2-diphenylphosphino) phenyl ether (45mg,0.084mmol) and potassium tert-butoxide (236mg,2.1mmol) in DMSO (10mL) overnight under nitrogen at 120 ℃. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 106mg, 36.97%).
MS(ESI,pos.ion)m/z:340.05[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.49(d,J＝4.1Hz,1H),7.88(d,J＝1.8Hz,1H),7.61(dd,J＝8.3,1.6Hz,1H),7.07(t,J＝7.2Hz,1H),3.54(d,J＝11.5Hz,2H),3.21(s,1H),2.77(d,J＝12.0Hz,2H),2.74(s,6H),2.03(d,J＝9.5Hz,2H),1.57(d,J＝9.7Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):170.9,157.8,157.1,140.6,134.2,126.4,121.2,118.3,117.9,107.2,63.1,49.9,39.5,26.2；
HPLC:97.51％.
EXAMPLE 12 Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- ((4, 6-dimethylpyrimidin-2-yl) thio) benzonitrile
Figure BDA0001149217270000231
The title compound was prepared as described in example 1, step 4, namely 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile (300mg,0.84mmol), 4, 6-dimethylpyrimidine-2-thiophenol (177mg,1.26mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.04mmol), bis (2-diphenylphosphino) phenyl ether (45mg,0.084mmol) and potassium tert-butoxide (236mg,2.1mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 100mg, 32.22%).
MS(ESI,pos.ion)m/z:368.05[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.96(d,J＝1.9Hz,1H),7.59(dd,J＝8.3,1.9Hz,1H),7.07(d,J＝8.4Hz,1H),6.80(s,1H),3.54(d,J＝12.0Hz,2H),3.29(t,J＝12.6Hz,1H),2.80(d,J＝11.8Hz,2H),2.76(s,6H),2.36(s,6H),2.06(d,J＝9.3Hz,2H),1.69(dd,J＝11.7,3.1Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):169.4,167.8,156.6,140.2,133.5,127.2,120.8,118.5,117.1,107.1,62.9,50.1,39.1,29.7,23.7；
HPLC:94.25％.
EXAMPLE 13 Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- ((4, 6-dimethoxypyrimidin-2-yl) thio) benzonitrile
Figure BDA0001149217270000232
The title compound of this step was prepared by the method described in example 1, step 4, namely 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile (300mg,0.84mmol), 4, 6-dimethoxypyrimidine-2-thiophenol (218mg,1.26mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.04mmol), bis (2-diphenylphosphino) phenyl ether (45mg,0.084mmol) and potassium tert-butoxide (236mg,2.1mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 140mg, 41.5%).
MS(ESI,pos.ion)m/z:400.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.98(d,J＝2.0Hz,1H),7.59(dd,J＝8.4,2.0Hz,1H),7.05(d,J＝8.4Hz,1H),5.77(s,1H),3.74(s,6H),3.56(d,J＝12.3Hz,2H),3.35～3.25(m,1H),2.81(t,J＝11.5Hz,2H),2.76(s,6H),2.09(d,J＝11.4Hz,2H),1.74(qd,J＝12.0,3.8Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):171.1,168.9,157.0,141.4,133.6,126.7,120.4,118.4,106.6,86.7,62.7,54.2,50.3,39.0,25.9；
HPLC:98.61％.
EXAMPLE 14 Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- ((4- (trifluoromethyl) pyrimidin-2-yl) thio) benzonitrile
Figure BDA0001149217270000241
The title compound was prepared as described in example 1, step 4, namely 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile (300mg,0.84mmol), 4- (trifluoromethyl) pyrimidin-2-thiophenol (228mg,1.26mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.04mmol), bis (2-diphenylphosphino) phenyl ether (45mg,0.084mmol) and potassium tert-butoxide (236mg,2.1mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 103mg, 29.93%).
MS(ESI,pos.ion)m/z:408.00[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.72(d,J＝4.9Hz,1H),7.88(d,J＝2.0Hz,1H),7.65(dd,J＝8.4,2.0Hz,1H),7.35(d,J＝4.9Hz,1H),7.10(d,J＝8.4Hz,1H),3.53(d,J＝12.3Hz,2H),3.19～3.15(m,1H),2.77(t,J＝11.5Hz,2H),2.70(s,6H),2.06(d,J＝11.6Hz,2H),1.50(qd,J＝12.0,3.7Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):172.4,160.1,157.4,156.0,140.7,134.7,125.4,121.2,120.0,118.1,113.1,107.3,62.6,50.1,39.2,26.2；
HPLC:98.64％.
EXAMPLE 15 Synthesis of 4- (4- (dimethylamino) piperidin-1-yl) -3- ((2, 4-dimethylphenyl) thio) benzonitrile
Figure BDA0001149217270000242
The title compound was prepared as described in example 1, step 4, namely 4- (4- (dimethylamino) piperidin-1-yl) -3-iodobenzonitrile (300mg,0.84mmol), 2, 4-dimethylthiophenol (175mg,1.27mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.043mmol), bis (2-diphenylphosphino) phenyl ether (45mg,0.08mmol) and potassium tert-butoxide (236mg,2.10mmol) in DMSO (10mL) overnight under nitrogen at 120 ℃. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 105mg, 34.01%).
MS(ESI,pos.ion)m/z:366.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.36～7.34(m,1H),7.34～7.32(m,1H),7.20(s,1H),7.08(d,J＝7.0Hz,1H),7.01(d,J＝8.2Hz,1H),6.67(d,J＝1.8Hz,1H),3.62(d,J＝12.2Hz,2H),3.45～3.37(m,1H),2.86(s,6H),2.81(t,J＝11.4Hz,2H),2.38(s,3H),2.28(s,3H),2.17(d,J＝11.5Hz,2H),2.01～1.91(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):151.6,142.5,140.8,136.5,132.4,129.5,129.1,128.5,125.2,120.1,118.9,108.0,63.2,49.8,39.4,26.1,21.2,20.5；
HPLC:94.26％.
EXAMPLE 16 Synthesis of N, N-dimethyl-1- (2- (pyrimidin-2-ylthio) -4- (trifluoromethyl) -phenyl) piperidin-4-amine
Figure BDA0001149217270000251
Step 1) Synthesis of N, N-dimethyl-1- (2-nitro-4- (trifluoromethyl) phenyl) piperidin-4-amine
The title compound was prepared as described in example 1, step 1, by reacting 1-fluoro-2-nitro-4- (trifluoromethyl) benzene (1.8g,8.58mmol), N-dimethylpiperidin-4-amine (1.0g,7.80mmol) and DIPEA (2.02g,15.60mmol) in dry DMF (15mL) under nitrogen at 90 ℃ for 12 h. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound (pale yellow solid, 1.64g, 66.2%).
MS(ESI,pos.ion)m/z:318.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.00(s,1H),7.58(dd,J＝8.8,1.7Hz,1H),7.13(d,J＝8.8Hz,1H),3.37(d,J＝12.7Hz,2H),2.92(dd,J＝17.9,6.4Hz,2H),2.32(ddd,J＝14.9,7.4,3.8Hz,1H),2.28(s,6H),1.88(d,J＝12.2Hz,2H),1.68～1.62(m,2H).
Step 2) Synthesis of 1- (2-amino-4- (trifluoromethyl) phenyl-N, N-dimethylpiperidin-4-amine
The title compound of this step was prepared as described in example 1, step 2, by catalytic hydrogenation of N, N-dimethyl-1- (2-nitro-4- (trifluoromethyl) phenyl) piperidin-4-amine (1.50g,4.73mmol) in methanol (15mL) over palladium on charcoal (150mg,0.47 mmol). The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow solid, 1.19g, 87.5%).
MS(ESI,pos.ion)m/z:288.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.04(s,1H),7.60(dd,J＝8.8,1.7Hz,1H),7.15(d,J＝8.8Hz,1H),3.35(d,J＝12.7Hz,2H),2.90(dd,J＝17.9,6.4Hz,2H),2.30(ddd,J＝14.9,7.4,3.8Hz,1H),2.27(s,6H),1.84(d,J＝12.2Hz,2H),1.70～1.64(m,2H).
Step 3) Synthesis of 1- (2-iodo-4- (trifluoromethyl) phenyl-N, N-dimethylpiperidin-4-amine
This title compound was prepared as described in example 1, step 3, with reference to 1- (2-amino-4- (trifluoromethyl) phenyl-N, N-dimethylpiperidin-4-amine (0.30g,1.04mmol) in a mixed solvent of acetonitrile (15mL) and water (6mL), by reaction with concentrated hydrochloric acid (3mL) and sodium nitrite (86mg,1.25mmol) at 0 ℃ for 1 hour followed by reaction with potassium iodide (276mg,1.66mmol) at 0 ℃ for 1 hour and room temperature for 4 hours after which the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound (yellow liquid, 0.18g, 43.5%).
MS(ESI,pos.ion)m/z:399.00[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.05(s,1H),7.55(d,J＝8.1Hz,1H),7.04(d,J＝8.3Hz,1H),3.42(d,J＝11.6Hz,2H),2.90(t,J＝11.6Hz,1H),2.74(t,J＝11.5Hz,2H),2.59(s,6H),2.15(d,J＝11.5Hz,2H),1.94～1.88(m,2H).
Step 4) Synthesis of N, N-dimethyl-1- (2- (pyrimidin-2-ylthio) -4- (trifluoromethyl) -phenyl) piperidin-4-amine To become
The title compound was prepared as described in example 1, step 4, namely 1- (2-iodo-4- (trifluoromethyl) phenyl) -N, N-dimethylpiperidin-4-amine (400mg,1.00mmol), pyrimidine-2-thiophenol (169mg,1.50mmol), tris (dibenzylideneacetone) dipalladium (45mg,0.05mmol), bis (2-diphenylphosphino) phenyl ether (54mg,0.10mmol) and potassium tert-butoxide (299mg,2.50mmol) in DMSO (10mL) at 120 ℃ under nitrogen protection overnight. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 150mg, 39.05%).
MS(ESI,pos.ion)m/z:383.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.52(s,2H),7.89(s,1H),7.62(d,J＝5.8Hz,1H),7.19～7.04(m,2H),3.50(d,J＝8.1Hz,2H),3.23(s,1H),2.84(s,2H),2.76(s,6H),2.02(d,J＝6.2Hz,2H),1.55(d,J＝8.4Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):171.4,157.6,156.2,133.8,127.7,126.4,126.2,123.8,121.0,117.7,63.2,50.1,39.5,29.7；
HPLC:97.05％.
EXAMPLE 17 Synthesis of 1- (2- ((4, 6-dimethylpyrimidin-2-yl) thio) -4- (trifluoromethyl) -phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000261
The title compound of this step was prepared by the method described in example 1, step 4, namely 1- (2-iodo-4- (trifluoromethyl) phenyl) -N, N-dimethylpiperidin-4-amine (400mg,1.00mmol), 4, 6-dimethylpyrimidine-2-thiophenol (211mg,1.50mmol), tris (dibenzylideneacetone) dipalladium (45mg,0.05mmol), bis (2-diphenylphosphino) phenylate (54mg,0.10mmol) and potassium tert-butoxide (299mg,2.50mmol) in DMSO (10mL) under nitrogen at 120 ℃ overnight. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 120mg, 29.10%).
MS(ESI,pos.ion)m/z:411.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.00(d,J＝1.6Hz,1H),7.56(dd,J＝8.4,1.7Hz,1H),7.11(d,J＝8.4Hz,1H),6.79(s,1H),3.47(d,J＝12.2Hz,2H),3.31～3.23(m,1H),2.78(d,J＝11.6Hz,2H),2.75(s,6H),2.36(s,6H),2.04(d,J＝10.2Hz,2H),1.71～1.65(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):169.7,167.6,155.4,133.1,127.2,126.6,126.1,123.9,120.5,116.9,63.0,50.4,39.1,26.0,23.6；
HPLC:98.21％.
EXAMPLE 18 Synthesis of 1- (2- ((4, 6-dimethoxypyrimidin-2-yl) thio) -4- (trifluoromethyl) -phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000271
The title compound of this step was prepared as described in example 1, step 4, namely 1- (2-iodo-4- (trifluoromethyl) phenyl) -N, N-dimethylpiperidin-4-amine (400mg,1.00mmol), 4, 6-dimethoxypyrimidine-2-thiophenol (259mg,1.50mmol), tris (dibenzylideneacetone) dipalladium (45mg,0.05mmol), bis (2-diphenylphosphino) phenyl ether (54mg,0.10mmol) and potassium tert-butoxide (299mg,2.50mmol) in DMSO (10mL) overnight at 120 ℃ under nitrogen protection. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 100mg, 22.50%).
MS(ESI,pos.ion)m/z:443.10[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.01(d,J＝1.5Hz,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.10(d,J＝8.3Hz,1H),5.76(s,1H),3.74(s,6H),3.49(d,J＝11.9Hz,2H),3.32(t,J＝11.9Hz,1H),2.81(s,2H),2.78(s,6H),2.08(d,J＝11.1Hz,2H),1.82～1.76(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):171.0,169.3,155.7,126.8,125.7,124.8,123.7,123.0,120.1,86.6,63.0,54.1,50.5,39.1,26.0；
HPLC:97.15％.
EXAMPLE 19 Synthesis of N, N-dimethyl-1- (4- (trifluoromethyl) -2((4- (trifluoromethyl) pyrimidin-2-yl) thio) phenyl) piperidin-4-amine
Figure BDA0001149217270000272
The title compound of this step was prepared as described in example 1, step 4, namely 1- (2-iodo-4- (trifluoromethyl) phenyl) -N, N-dimethylpiperidin-4-amine (400mg,1.00mmol), 4- (trifluoromethyl) pyrimidin-2-thiol (271mg,1.50mmol), tris (dibenzylideneacetone) dipalladium (45mg,0.05mmol), bis (2-diphenylphosphino) phenyl ether (54mg,0.10mmol) and potassium tert-butoxide (299mg,2.50mmol) in DMSO (10mL) overnight at 120 ℃ under nitrogen protection. The resulting crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 150mg, 45.24%).
MS(ESI,pos.ion)m/z:451.20[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.70(d,J＝4.9Hz,1H),7.86(d,J＝1.8Hz,1H),7.61(dd,J＝8.4,1.9Hz,1H),7.31(d,J＝4.9Hz,1H),7.14(d,J＝8.4Hz,1H),3.43(d,J＝9.2Hz,2H),2.77～2.74(m,1H),2.71(t,J＝11.1Hz,2H),2.47(s,6H),1.92(d,J＝10.7Hz,2H),1.42～1.35(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):173.0,159.8,157.0,155.9,133.6,127.8,125.8,125.2,123.8,120.8,116.8,112.7,62.2,50.8,45.7,27.1；
HPLC:99.45％.
EXAMPLE 20 Synthesis of 1- (2- ((2, 4-dimethylphenyl) thio) -4- (trifluoromethyl) phenyl) -N, N-dimethylpiperidin-4-amine
Figure BDA0001149217270000281
The title compound of this step was prepared as described in example 1, step 4, namely 1- (2-iodo-4- (trifluoromethyl) phenyl) -N, N-dimethyl-piperidin-4-amine (300mg,0.75mmol), 2, 4-dimethylthiophenol (156mg,1.13mmol), tris (dibenzylideneacetone) dipalladium (34mg,0.04mmol), bis (2-diphenylphosphino) phenyl ether (40mg,0.07mmol) and potassium tert-butoxide (224mg,2.0mmol) in DMSO (10mL) at 120 ℃ overnight under nitrogen. The obtained crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (yellow liquid, 220mg, 70.05%).
MS(ESI,pos.ion)m/z:409.30[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.34～7.29(m,2H),7.17(s,1H),7.05(d,J＝8.3Hz,2H),6.75(d,J＝1.8Hz,1H),3.59(d,J＝12.2Hz,2H),3.35(ddd,J＝12.2,9.0,3.6Hz,1H),2.82(s,6H),2.79(d,J＝11.6Hz,2H),2.37(s,3H),2.29(s,3H),2.17(d,J＝11.6Hz,2H),1.97～1.91(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm):151.0,142.1,140.1,135.9,135.5,132.0,128.2,126.8,126.1,123.9,123.2,122.7,119.9,62.9,50.2,39.0,26.1,21.2,20.4；
HPLC:99.00％.
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 [ 2 ] to a cell membrane at 22 ℃, [ 3 H]Imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1% BSA) were incubated with or without test compound for 60 min.
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 curve through experimental test of series concentration 50 . 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
Example No. 1 IC 50 (nM)
Example 2 15.6
Example 3 10.1
Example 7 14.4
Example 8 16.3
Example 12 8.1
Example 13 7.2
The experimental result shows that the compound has stronger affinity to human 5-HT transporters (SERT).
Example B pharmacokinetic evaluation of the Compounds of the invention after intravenous or intragastric dosing in rats
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 table of the tested animals of the present invention
Figure BDA0001149217270000291
Test method
The compounds of the present 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 group, the dose was 2.5mg/kg or 5mg/kg, followed by intravenous blood (0.3mL) at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours at the time points 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 ℃.
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 illustrations described in this specification, as well as features of different examples, embodiments, or illustrations, can be combined or combined by one skilled in the art without being mutually inconsistent.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, 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 (10)

1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),
Figure FDA0003632102710000011
wherein:
each X 1 And X 2 Independently is N;
q is-S (O) m -；
m is 0;
n is 0, 1,2 or 3;
each R 1 Independently H, D, F, Cl, Br, I, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group;
R 2 is H, D, F, Cl, Br, I, -CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkoxy group; and
R 3 is C 1 -C 6 An alkylamino group.
2. The compound of claim 1, wherein each R 1 Independently H, D, F, Cl, Br, I, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
3. The compound of claim 1, wherein R 2 Is H, D, F, Cl, Br, I, -CN, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group.
4. A compound according to claim 1 or 2, wherein each R is 1 Independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propyloxy or isopropyloxy.
5. A compound according to claim 1 or 3, wherein R 2 Is H, D, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl,Isopropyl, -CF 3 or-CH 2 CF 3 。
6. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0003632102710000012
Figure FDA0003632102710000021
7. a pharmaceutical composition comprising a compound of any one of claims 1-6; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
8. The pharmaceutical composition of claim 7, 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.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.
10. Use according to claim 9, for the prevention, treatment or alleviation of affective disorders.
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