Aryl propylamine derivative and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an aryl propylamine derivative and application thereof, a compound shown in a general formula I, a stereoisomer or pharmaceutically acceptable salt of the compound, a pharmaceutical composition containing the compound and application of the compound and the stereoisomer or pharmaceutically acceptable salt in the field of medicine, and further relates to a method for preparing the compound. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 202311770077.2 with an application date of December 21, 2023, Chinese Patent Application No. 202311770226.5 with an application date of December 21, 2023, Chinese Patent Application No. 202410773345.4 with an application date of June 17, 2024, and Chinese Patent Application No. 202410773552.X with an application date of June 17, 2024, and incorporates all of their contents herein by reference. The detailed description of the invention Advantageous effects Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and particularly relates to an arylpropylamine derivative, its stereoisomer or its pharmaceutically acceptable salt, a composition containing the compound, and their applications in the medical field. In addition, the preparation method of the compound is also involved. Background Art

[0003] Depression is the most common mental illness that endangers the physical and mental health of humans today. Currently, the number of depression patients worldwide has accounted for 3-5% of the world's population.

[0004] Drug treatment is the main means for treating depression. The main therapeutic drugs include: tricyclic antidepressants, such as imipramine, etc.; monoamine oxidase inhibitors, such as moclobemide, etc.; selective serotonin (5-HT) reuptake inhibitors (SSRIs), such as fluoxetine, etc.; selective norepinephrine (NE) reuptake inhibitors, such as reboxetine, etc.; 5-HT and NE dual reuptake inhibitors, such as duloxetine, etc.

[0005] Although many antidepressant drugs have been used clinically, due to the low response rate of some drugs, long onset time, and potential side effects of some drugs, there are still quite a number of patients who are ineffective in various treatments, and some even need to resort to electroconvulsive therapy. Therefore, the development of antidepressants remains a hot topic in new drug research.

[0006] US4018895 discloses antidepressants with the following structure including fluoxetine:

[0007] Among them, Ar is a naphthalene ring or a substituted benzene ring, and R l and R2 are respectively H or methyl.

[0008] CN1019113A discloses antidepressant drugs with the following structure including duloxetine:

[0009] Among them, Ar is a naphthalene ring or a substituted benzene ring, Ar l is a cycloalkyl group, a furyl group, a thienyl group or a thiazolyl group, and R l and R2 are respectively H or CH3.

[0010] CN101613347A discloses antidepressant compounds with the following structure including amoxapine:

[0011] Among them, X is O or S, and R lR1 and R2 each independently represent H or C1-C3 alkyl.

[0012] WO2016101898A1 discloses that a compound of 3-[(benzo[d][1,3]dioxol-4-yl)-oxy]-3-arylpropylamine is used as an antidepressant.

[0013] wherein, R1 and R2 are each independently hydrogen or C 1-5 alkyl; and R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted C 1-5 alkyl or C 1-3 alkoxy.

[0014] Although the above-mentioned drugs such as duloxetine and amoxapine have good antidepressant activity, their structures are unstable to acids and are easily decomposed in the stomach, which is not conducive to the disintegration and absorption of the drugs in the stomach. They are not suitable for preparing ordinary tablets and have high selectivity for preparations.

[0015] In addition, it is well known that neurotransmitters that regulate human emotions and emotional states include dopamine, 5-hydroxytryptamine and norepinephrine. These three substances are synthesized by different types of neurons and act on different downstream brain regions, thus forming a neural "three-channel" closely related to depression. Depression is a syndrome caused by changes in the levels of multiple neurochemical molecules. The treatment of depression should not only focus on one or two targets, but should "attack from three sides" and simultaneously increase the levels of dopamine, serotonin and norepinephrine in the brain. Dopamine (DA) plays an important role in the etiology of depression. Increasing the synaptic dopamine level in the mesolimbic cortex can improve the delayed effect of antidepressants (Dunlop BW and Nemeroff, 2007; Belujon and Grace, 2017). Pharmacological Characterization of Toludesvenlafaxine as a Triple Reuptake Inhibitor (Zhu H, et al. Front Pharmacol. 2021, 14(12):741794) shows that toludesvenlafaxine has triple reuptake inhibitory effects on 5-hydroxytryptamine, norepinephrine and dopamine. Compared with existing selective 5-HT reuptake inhibitors and 5-HT / NE dual reuptake inhibitors, it increases the intervention on dopamine, can achieve synergistic therapeutic effects, and comprehensively improve depression, anxiety, anhedonia, fatigue, retardation and cognitive symptoms, bringing new hope for the cure of depression.

[0016] Nomifensine is also a new type of antidepressant, applicable to the treatment of endogenous depression, manic-depressive psychosis, and anxious depression. It acts on organisms mainly by inhibiting dopamine transporters. Specifically, nomifensine can selectively triple inhibit the reuptake of NE, DA, and 5-HT by central neurons, thereby producing an antidepressant effect.

[0017] In summary, it is still of great significance to find an antidepressant with good antidepressant activity, a stable structure, and triple reuptake inhibitory effects on serotonin, norepinephrine, and dopamine. SUMMARY OF THE INVENTION

[0018] The object of the present invention is to provide a new type of arylpropylamine derivative. Such compounds have certain binding ability and reuptake inhibitory effects on SERT, NET, and DAT. In particular, they have higher selective affinity and inhibitory ability for dopamine transporters. It is expected that the provided compounds have good antidepressant activity and drug-forming properties.

[0019] On the one hand, the present invention provides a compound represented by general formula I, its stereoisomer, or its pharmaceutically acceptable salt:

[0020]

[0021] Wherein: R1 and R2 are each independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen;

[0022] R3 and R4 are each independently selected from hydroxyl, hydrogen, halogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen;

[0023] Or R3 and R4 together with the C atom to which they are attached form a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from O, N, and S. Preferably, R3 and R4 together with the C atom to which they are attached form a five-membered heterocycle containing 1 to 3 heteroatoms selected from O, N, and S. More preferably, R3 and R4 together with the C atom to which they are attached form 1,3-dioxolane;

[0024] R5 is selected from H and optionally substituted C1-C8 alkyl, preferably selected from H and optionally substituted C1-C5 alkyl, more preferably selected from H and C1-C3 alkyl, and the optional substituent is halogen;

[0025] When R3 and R4 together with the C atom to which they are attached form a heterocycle, R5 is H.

[0026] In a preferred embodiment of the present invention, the compound represented by the general formula I is a compound of formula II:

[0027]

[0028] Wherein: R1 and R2 are as defined above.

[0029] In a preferred embodiment of the present invention, the compound represented by the general formula I is a compound of formula III:

[0030]

[0031] Wherein: R1, R2, R3, and R4 are as defined above; preferably, R3 and R4 are each independently a hydroxyl group.

[0032] In one embodiment, the compound represented by the general formula I is selected from II-a, II-b, III-a, III-b, or a mixture thereof,

[0033]

[0034] In some embodiments of the present invention, the C1-C8 alkyl group is a C1-C5 alkyl group, preferably a C1-C3 alkyl group, more preferably selected from methyl, ethyl, and propyl, and even more preferably methyl.

[0035] In some embodiments, the halogen is selected from fluorine, chlorine, and bromine, preferably fluorine.

[0036] In some embodiments of the present invention, R1 is selected from hydrogen, halogen, optionally substituted C1-C5 alkyl, and optionally substituted C1-C5 alkoxy; the optional substituent is halogen.

[0037] In some embodiments, R2 is selected from hydrogen, halogen, optionally substituted C1-C5 alkyl, and optionally substituted C1-C5 alkoxy; the optional substituent is halogen.

[0038] In some embodiments, R1 is selected from hydrogen, fluorine, chlorine, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 alkoxy; the optional substituent is halogen.

[0039] In some embodiments, R2 is selected from hydrogen, fluorine, chlorine, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 alkoxy; the optional substituent is halogen.

[0040] In some embodiments, R1 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, and ethoxy, preferably selected from hydrogen, fluorine, chlorine, methyl, and methoxy; R2 is selected from hydrogen, fluorine, chlorine, methyl, and methoxy.

[0041] In some embodiments, R3 and R4 are each independently selected from hydroxy, hydrogen, halogen, optionally substituted C1-C5 alkyl, and optionally substituted C1-C5 alkoxy, and the optional substituent is halogen.

[0042] In some embodiments, R3 and R4 are each independently selected from hydroxy, hydrogen, fluorine, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 alkoxy; the optional substituent is halogen.

[0043] In some embodiments, R3 and R4 are each independently selected from hydroxy, hydrogen, and halogen.

[0044] In some particularly preferred embodiments, the compound represented by the general formula I, its stereoisomers, or its pharmaceutically acceptable salts are characterized by being selected from the following compounds:

[0045]

[0046]

[0047] In one embodiment, the pharmaceutically acceptable salts are selected from oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esylate, benzenesulfonate, and p-toluenesulfonate, preferably oxalate or hydrochloride.

[0048] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers or excipients.

[0049] The present invention further relates to the use of any of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs related to the treatment of mental diseases.

[0050] The present invention also relates to a method for preventing and / or treating mental diseases, which comprises administering to the mammal a therapeutically effective dose of any of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives, or their pharmaceutical compositions.

[0051] In a further preferred embodiment of the present invention, the mental disease is selected from depression.

[0052] Embodiments

[0053] Unless otherwise defined, 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. In case of conflict, the definitions provided in this application shall prevail. When trade names appear in this text, they are intended to refer to the corresponding goods or their active ingredients. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0054] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl preferably has an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 alkyl), still more preferably an alkyl group having 1 to 5 carbon atoms (i.e., C 1-5 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3(alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkyl group is substituted by a substituent, the substituent is not further substituted.

[0055] The term "alkoxy" means an alkyl group attached to the remainder of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. In one embodiment, the alkoxy group contains 1 - 8 carbon atoms; in one embodiment, the alkoxy group contains 1 - 5 carbon atoms; in another embodiment, the alkoxy group contains 1 - 3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in the present invention. Non-limiting examples include: methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), etc.

[0056] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom.

[0057] The terms "comprises", "comprising", "has", "having", "includes", "including", or "relates to" and other variant forms thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art should understand that the above terms such as "comprises" cover the meaning of "consisting of".

[0058] The phrase "one or more" or a similar expression "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0059] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within that range are specifically disclosed. In particular, each range of values disclosed herein should be understood to represent every numerical value and range subsumed within the broader range.

[0060] As used herein, the expression m - n refers to the range from m to n, as well as sub-ranges and individual point values composed of the respective point values therein. For example, the expression "C2 - C8" or "C" 2-8”covers the range of 2 to 8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression “C3-C 10 ” or “C 3-10 ” should also be understood in a similar manner, for example, it can cover any sub-ranges and point values included therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 、C7-C9、C7-C8、C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. Again, for example, the expression “C1-C6” or “C 1-6 ” covers the range of 1 to 6 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., and C1, C2, C3, C4, C5, C6, etc. Again, for example, the expression “ternary to decyl” should be understood to cover any sub-ranges and each point value therein, such as ternary to quinary, ternary to hexyl, ternary to heptyl, ternary to octyl, quaternary to quinary, quaternary to hexyl, quaternary to heptyl, quaternary to octyl, quinary to heptyl, quinary to octyl, hexyl to heptyl, hexyl to octyl, nonyl to decyl, etc., and three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should also be understood in a similar manner.

[0061] The different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” used in this article all express the same meaning, that is, it means that X can be any one or several of A, B, and C.

[0062] The term “stereoisomer” refers to a compound having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0063] Such as The stereoisomer of is

[0064] The term “mental illness” refers to a disease that occurs due to disorders in the functions of brain nerve activities, specifically manifested as disorders in brain functions, resulting in varying degrees of disorders in mental activities such as cognition, emotion, will, and behavior, such as schizophrenia, depression, anxiety disorder, phobia, etc.

[0065] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and this description includes both the occurrence and non-occurrence of the described event or circumstance. For example, "a cycloalkyl group optionally (being) substituted by an alkyl group" means that the alkyl group may or may not be present, and this description includes both the case where the cycloalkyl group is substituted by an alkyl group and the case where the cycloalkyl group is not substituted by an alkyl group.

[0066] The terms "substituted" and "substitution" refer to one or more (e.g., one, two, three, or four) hydrogens on the specified atom being replaced by a selection from the indicated groups, provided that the normal atomic valence of the specified atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only when such combinations form a stable compound. When it is described that a certain substituent is absent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, the condition is that the normal atomic valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0067] If a substituent is described as "optionally... substituted", the substituent can be unsubstituted or can be substituted. If an atom or group is described as optionally being substituted by one or more from a list of substituents, one or more hydrogens on that atom or group can be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is "unsubstituted" or "not substituted". Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0068] When the bond of a substituent is shown passing through a bond connecting two atoms in a ring, such a substituent can be bonded to any ring-forming atom in the ring that can be substituted.

[0069] When any variable (e.g., R), and variables with markings (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definitions are independent in each case for each occurrence. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group can optionally be substituted by at most four R substituents, and the options for each R substituent in each case are independent of each other.

[0070] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, are all within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereoisomer mixtures, are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0071] The compounds of the present invention may be in isolated or purified free or salt forms. The terms "purified", "purified form", or "isolated and purified form" for a compound refer to the physical state of the compound after separation from a synthetic method (e.g., from a reaction mixture), or from a natural source, or a combination thereof. Thus, the terms "purified", "purified form", or "isolated and purified form" refer to the physical state of a compound after being obtained from one or more purification processes described herein or known in the art (such as chromatography, recrystallization, LC-MS, and LC-MS / MS techniques, etc.), which has sufficient purity to be characterized by standard analytical techniques described herein or known in the art.

[0072] The compounds of the present invention may be in an isolated or purified form obtained after chemical synthesis and / or separation, or may be in the form of active metabolites generated or released in a mammalian (preferably human) body through chemical or physiological processes after administration of certain drugs, particularly the metabolites generated in the human body after administration of the 3-[(benzo[d][1,3]dioxol-4-yl)-oxy]-3-arylpropanamine compounds described in the aforementioned patent document WO2016101898A1.

[0073] The term "pharmaceutically acceptable" substances refers to substances that, within the scope of normal medical judgment, are suitable for contact with a patient's tissues without undue toxicity, irritation, allergic reaction, etc., have a reasonable benefit-risk ratio, and are effective for their intended uses.

[0074] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which salts are safe and effective when used in a mammalian body and have the appropriate biological activity.

[0075] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0076] The term "pharmaceutically acceptable carrier" refers to those substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0077] The terms "administer" or "administration" etc. refer to methods by which a compound or composition can be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0078] As used herein, the term "treatment" includes alleviating, reducing or improving a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the development of a disease or symptom, alleviating a disease or symptom, promoting the remission of a disease or symptom, or arresting the signs of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit means eradicating or improving the treated condition. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit means that a composition is used by a patient to prevent the risk of a certain disease, or is taken when the patient exhibits one or more physiological conditions of a disease, although the disease has not been diagnosed.

[0079] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease or condition. The term "neuropsychiatric disease" refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0080] For a drug, drug unit or active ingredient, the terms "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refer to a sufficient amount of the drug or agent that is acceptable in terms of side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art through routine tests.

[0081] The following detailed description of the invention aims to illustrate non - restrictive embodiments, enabling other technicians in the art to more fully understand the technical solution of the invention, its principles, and its practical applications, so that other technicians in the art can modify and implement the invention in many forms to best meet the requirements of specific uses.

[0082] Biological test evaluation

[0083] The compounds of the present invention exhibit good multi - target binding activity. They have triple reuptake inhibitory effects on serotonin, norepinephrine, and dopamine. In particular, they have higher selective affinity and inhibitory ability for the dopamine transporter. At the same time, they show good in - vivo pharmacodynamic strength and good drug - like properties in terms of half - life, exposure, bioavailability, etc., and are expected to have advantages in the development of drugs for treating mental diseases such as depression. Detailed Embodiments

[0084] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0085] ​

[0086] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0087] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography - mass spectrometry (LC - MS).

[0088] The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is carried out using a Bruker Advanced 400 nuclear magnetic resonance instrument. The solvent for the measurement is deuterated dimethyl sulfoxide (DMSO - d6), and the internal standard is tetramethylsilane (TMS).

[0089] The liquid chromatography - mass spectrometry (LC - MS) measurement is carried out using a Shimadzu LCMS2020 liquid chromatography - mass spectrometer from Japan.

[0090] The determination by HPLC was performed using an Agilent 1260 liquid chromatograph.

[0091] The TLC silica gel plate used was the Qingdao Marine silica gel plate. The specifications used for TLC were 0.2 mm - 0.25 mm, and the specifications used for the separation and purification of products by TLC were 0.2 mm - 0.25 mm.

[0092] The general synthetic process of the compounds in the examples of the present invention includes:

[0093]

[0094] Chloroacetophenone was reduced with sodium borohydride to obtain 3-chloro-1-phenyl-1-propanol, which was then reacted with benzod[d][1,3]dioxol-4-ol to obtain 3-(benzod[d][1,3]dihydroxy-4-yloxy)-3-phenylpropan-1-chloride, which was then reacted with potassium phthalimide to obtain 2-(3-(benzod[d][1,3]dihydroxy-4-yloxy)-3-phenylpropyl)isoindole-1,3-dione. Finally, it was salted with oxalic acid under the action of hydrazine hydrate to obtain the target compound shown by the general formula.

[0095]

[0096] 3-Fluorocatechol was protected with triethyl orthoformate to obtain 2-ethoxy-4-fluorobenzod[d][1,3]dioxol, which was then reacted with 3-(dimethylamino)-1-substituted phenylpropan-1-ol to obtain 3-(2-ethoxybenzod[d][1,3]dioxol-4-yloxy)-N,N-dimethyl-3-phenylpropyl-1-amine derivative, which was then reacted with phenyl chloroformate to obtain methyl phenyl(3-(2-ethoxybenzod[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)carbamate derivative. After hydrolysis, 3-(2-ethoxybenzod[d][1,3]dioxol-4-yloxy)-N-methyl-3-phenylpropan-1-amine derivative was obtained. Finally, the target compound was obtained under the action of ethyl acetate hydrogen chloride gas.

[0097] Example:

[0098] R-3-[(benzod[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine hydrochloride was prepared by referring to the method of Example 1 of CN118541358A.

[0099] Example 1. Preparation of 3-(benzod[d][1,3]dihydroxy-4-yloxy)-3-phenylpropylamine oxalate (Compound 1 oxalate)

[0100]

[0101] 1.1 Preparation of 3-chloro-1-phenylpropan-1-ol

[0102] Chloropropiophenone (8.4 g, 0.05 mol) and absolute ethanol (60 mL) were successively added to a 2 L four-necked flask, and stirred magnetically. Under an ice-salt bath, the temperature was controlled at -10 - 0 °C, and sodium borohydride (2.27 g, 0.06 mol) was added in batches. After addition, it was transferred to room temperature and reacted for 3 h. Then the reaction solution was concentrated to remove methanol, 60 mL of water was added, and it was extracted with ethyl acetate 3 times (3 × 40 mL). The organic phase was washed with saturated sodium chloride solution 2 times (2 × 30 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated to obtain 7.91 g of a colorless oily liquid.

[0103] 1.2 Preparation of 3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylprop-1-yl chloride

[0104] 3-chloro-1-phenylpropan-1-ol (6.8 g, 0.04 mol), triphenylphosphine (20.98 g, 0.08 mol), and tetrahydrofuran (300 mL) were successively added to a 500 L four-necked flask, and stirred mechanically. The temperature was controlled below 0 °C, and DIAD (16.17 g, 0.08 mol) was added. After addition, the temperature was still controlled below 0 °C, and a tetrahydrofuran solution of benzo[d][1,3]dioxol-4-ol (6.07 g, 0.04 mol) was added. After addition, the temperature was raised to room temperature and reacted for 5 h. After the reaction was completed, tetrahydrofuran was removed by concentration under reduced pressure, DCM (300 mL) was added, the organic phase was washed with saturated sodium chloride solution 2 times (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated. It was separated by silica gel column chromatography (PE / EA = 20:1) to obtain 9.57 g of a light yellow oily liquid.

[0105] 1.3 Preparation of 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)isoindoline-1,3-dione 3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylprop-1-yl chloride (8.7 g, 0.03 mol) and DMF (100 mL) were successively added to a 250 mL three-necked flask, and stirred magnetically. Then potassium phthalimide (5.56 g, 0.03 mol, a catalytic amount of sodium iodide was added), and the temperature was raised to 85 °C and reacted for 8 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (300 mL) was added, filtered by suction, the filtrate was washed with saturated sodium chloride solution 2 times (2 × 200 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated. It was separated by silica gel column chromatography (PE / EA = 10:1) to obtain 9.57 g of an oily liquid.

[0106] 1.4 Preparation of 3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropylamine oxalate

[0107] 2-(3-(Benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)isoindoline-1,3-dione (6.02 g, 0.015 mol), hydrazine hydrate (20 mL), and methanol (50 mL) were successively added to a 100 mL single-necked flask, and the mixture was stirred magnetically and heated to 55 °C for 4 h. After the reaction was completed, it was concentrated under reduced pressure until no distillate was obtained, filtered, 200 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate three times (3 × 100 mL). The organic phase was washed twice with saturated sodium chloride solution (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered by suction, concentrated, and separated by silica gel column chromatography (DCM / MeOH = 20:1) to obtain 2.44 g. 30 mL of ethyl acetate was added thereto, and the mixture was stirred magnetically to dissolve, and then a saturated ethyl acetate solution of oxalic acid (prepared by oneself) was slowly added to adjust the pH to 4 - 5, and the temperature was controlled at 10 - 20 °C for crystallization. After stirring for 1 h, it was filtered and dried to obtain 2.89 g of the final product 3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropylamine oxalate (Compound 1 oxalate). 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.39 (d, J = 8.3 Hz, 4H), 7.30 (d, J = 7.0 Hz, 1H), 6.65 (t, J = 8.2 Hz, 1H), 6.51 (t, J = 8.9 Hz, 2H), 5.99 (d, J = 9.3 Hz, 2H), 5.58 (t, J = 6.1 Hz, 1H), 2.92 (d, J = 7.4 Hz, 1H), 2.88 (d, J = 7.7 Hz, 1H), 2.25 (dq, J = 14.9, 7.7 Hz, 1H), 2.10 (dt, J = 12.8, 6.8 Hz, 1H); MS (ESI, m / z): 272.1 (M + H) + 。

[0108] Example 2 Preparation of 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methylphenyl)propylamine oxalate (Compound 2 oxalate)

[0109]

[0110] 2.1 According to the method of 1.1 in Example 1, 3-chloro-1-(4-methylphenyl)propan-1-one was used instead of chloropropiophenone to participate in the reaction to obtain 3.5 g of a light yellow oily liquid.

[0111] 2.2 According to the method of 1.2 in Example 1, 3-chloro-1-(4-methylphenyl)propan-1-ol was used instead of 3-chloro-1-phenylpropan-1-ol to participate in the reaction to obtain 2.9 g of a light yellow oily liquid.

[0112] 2.3 According to the method of 1.3 in Example 1, use 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methylphenyl)propyl)isoindole-1,3-dione to replace 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)isoindole-1,3-dione to participate in the reaction, and obtain 2.4 g of a light yellow oily liquid.

[0113] 2.4 According to the method of 1.4 in Example 1, use 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methylphenyl)propyl)isoindole-1,3-dione to participate in the reaction, and obtain 2.2 g of the product 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methylphenyl)propylamine oxalate (Compound 2 oxalate). 1 H NMR(400MHz,DMSO-d6)δ8.19(s,2H),7.27(d,J=7.8Hz,2H),7.16(d,J=7.7Hz,2H),6.63(m,1H),6.50(dd,J=15.8,8.1Hz,2H),5.98(d,J=11.9Hz,2H),5.49-5.44(m,1H),3.02-2.98(m,2H),2.58(s,3H),2.31-2.27(m,1H),2.14-2.10(m,1H);MS(ESI,m / z):286.1(M+H) + 。

[0114] Example 3. Preparation of 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methoxyphenyl)propylamine oxalate (Compound 3 oxalate)

[0115]

[0116] 3.1 According to the method of 1.1 in Example 1, use 3-chloro-1-(4-methoxyphenyl)propan-1-one to replace chloropropiophenone to participate in the reaction, and obtain 4.7 g of a light yellow oily liquid.

[0117] 3.2 According to the method of 1.2 in Example 1, use 3-chloro-1-(4-methoxyphenyl)propan-1-ol to replace 3-chloro-1-phenylpropan-1-ol to participate in the reaction, and obtain 4.5 g of a light yellow oily liquid.

[0118] 3.3 According to the method of 1.3 in Example 1, use 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methoxyphenyl)propyl)isoindole-1,3-dione to replace 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)isoindole-1,3-dione to participate in the reaction, and obtain 3.3 g of a light yellow oily liquid.

[0119] 3.4 According to the method of 1.4 in Example 1, use 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methoxyphenyl)propyl)isoindole-1,3-dione to participate in the reaction, and obtain 1.42 g of the product 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-methoxyphenyl)propylamine oxalate (Compound 3 oxalate). 1 H NMR(400MHz,DMSO-d6)δ8.20(s,2H),7.31(d,J=8.5Hz,2H),6.92(d,J=8.5Hz,2H),6.65(t,J=8.1Hz,1H),6.50(dd,J=15.9,8.1Hz 2H),5.98(d,J=10.9Hz,2H),5.45(dd,J=5.0Hz,1H),3.73(s,3H),3.00-2.95(m,2H),2.26-2.20(m,1H),2.11-2.06(m,1H); MS(ESI,m / z):311.1(M+H) + 。

[0120] Example 4. Preparation of 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-fluorophenyl)propylamine oxalate (Compound 4 oxalate)

[0121]

[0122] 4.1 According to the method of 1.1 in Example 1, use 3-chloro-1-(4-fluorophenyl)propan-1-one to replace chloropropiophenone to participate in the reaction, and obtain 7.2 g of a light yellow oily liquid.

[0123] 4.2 According to the method of 1.2 in Example 1, use 3-chloro-1-(4-fluorophenyl)propan-1-ol to replace 3-chloro-1-phenylpropan-1-ol to participate in the reaction, and obtain 5.9 g of a light yellow oily liquid.

[0124] 4.3 According to the method of 1.3 in Example 1, 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-fluorophenyl)propyl)isoindole-1,3-dione was used to replace 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-phenylpropyl)isoindole-1,3-dione to participate in the reaction, and 5.1 g of a light yellow oily liquid was obtained.

[0125] 4.4 According to the method of 1.4 in Example 1, 2-(3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-fluorophenyl)propyl)isoindole-1,3-dione was used to participate in the reaction, and 1.9 g of the product 3-(benzo[d][1,3]dioxol-4-yloxy)-3-(4-fluorophenyl)propylamine oxalate (Compound 4 oxalate) was obtained. 1 H NMR(400MHz,DMSO-d6)δ8.19(s,2H),7.43(dd,J=8.1 5.7Hz,2H),7.18(t,J=8.7Hz,2H),6.65(t,J=8.1Hz,1H),6.49(dd,J=19.9,8.1Hz,2H),5.95(d,J=11.2Hz,2H),5.51 -5.22(m,1H),3.06-2.98(m,2H),2.27-2.19(m,1H),2.10-2.02(m,1H); MS(ESI,m / z):290.1(M+H) + 。

[0126] Example 5 Preparation of 3-{[3-(methylamino)-1-phenylpropyl]oxy}phenyl-1,2-diol hydrochloride (Compound 5 hydrochloride)

[0127]

[0128] 5.1 Preparation of 2-ethoxy-4-fluorobenzo[d][1,3]dioxole

[0129] In a 500 mL round-bottom flask, 3-fluorocatechol (20 g, 156 mmol), 4A molecular sieve (10 g), triethyl orthoformate (34.7 g, 234 mmol), and toluene (200 mL) were successively added. Stir magnetically, protect with nitrogen, and heat to reflux for overnight reaction. Filter, wash with petroleum ether. Add aqueous sodium carbonate solution to the filtrate, separate the layers. Extract the aqueous phase with petroleum ether once again. Combine the organic phases, wash with saturated brine twice, and dry over anhydrous magnesium sulfate. Filter, concentrate under reduced pressure to dryness, perform silica gel column chromatography (in a petroleum ether system), collect the product, and concentrate under reduced pressure to dryness to obtain 11.3 g of a colorless oily product.

[0130] 5.2 Preparation of 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-phenylpropyl-1-amine

[0131] In a 250 mL reaction flask, 3-(dimethylamino)-1-phenylpropyl-1-ol (11 g, 61.5 mmol) and dimethyl sulfoxide (80 mL) were added. With magnetic stirring, potassium tert-butoxide (9 g, 80.4 mmol) was added in batches. The temperature was controlled at 40 °C and a solution of 2-ethoxy-4-fluorobenzo[d][1,3]dioxole (11.3 g, 61.4 mmol) / dimethyl sulfoxide (40 mL) was added dropwise. After the addition was complete, the reaction was carried out at 55 °C for 6 hours. After the reaction was completed, water (400 mL) and ethyl acetate (200 mL) were added. The layers were separated. The ethyl acetate phase was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain 6.5 g of a pale yellow oil.

[0132] 5.3 Preparation of methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-phenylpropyl)carbamate

[0133] In a 500 mL reaction flask, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-phenylpropyl-1-amine (6.5 g, 18.9 mmol), toluene (60 mL), and N,N-diisopropylethylamine (0.5 g, 3.9 mmol) were added. With magnetic stirring, the temperature was raised to 60 °C and a solution of phenyl chloroformate (3 g, 19.2 mmol) / toluene (5 mL) was added dropwise. After the addition was complete, the reaction was carried out at 80 °C for 5 hours. The reaction solution was cooled, saturated sodium bicarbonate solution (50 mL) was added, the layers were separated, the organic phase was washed 2 times with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 8.1 g of an oily product.

[0134] 5.4 Preparation of 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-phenylpropan-1-amine

[0135] In a 250 mL reaction flask, methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-phenylpropyl)carbamate (8 g, 17.8 mmol), dimethyl sulfoxide (100 mL), and sodium hydroxide (5.3 g, 132.5 mmol) / water (25 mL) solution were added. After addition, the reaction was carried out at 80 °C overnight. 200 mL of water and 100 mL of ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate three times. The organic phases were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain 2.0 g of a pale green oily product.

[0136] 5.5 Preparation of 3-{[3-(methylamino)-1-phenylpropyl]oxy}benzene-1,2-diol hydrochloride

[0137] In a 50 mL reaction flask, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-phenylpropan-1-amine (1.0 g, 3 mmol), ethyl acetate (10 mL), methanol (2 mL), and hydrochloric acid gas / ethyl acetate solution (1 mL) were added. Under nitrogen protection, the reaction was carried out for 3 hours. The solvent was removed by distillation under reduced pressure, and the residue was replaced with ethyl acetate twice. A solid precipitated, which was slurried with ethyl acetate, filtered, and dried in vacuo to obtain 0.34 g of 3-{[3-(methylamino)-1-phenylpropyl]oxy}benzene-1,2-diol hydrochloride (Compound 5 hydrochloride). 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.41(s,1H),7.42(d,J=8.0Hz,2H),7.39–7.31(m,2H),7.31–7.22(m,1H),6.42–6.32(m,2H),6.22(dt,J=6.7,2.4Hz,1H),5.41(dd,J=9.1,4.1Hz,1H),3.08(s,1H),2.55(s,3H),2.28(dq,J=15.3,8.1Hz,2H),2.14(q,J=7.3,6.8Hz,2H).MS(ESI,m / z):274.1(M+H) + 。

[0138] Example 6 Preparation of 3-{[3-(methylamino)-1-(4-methylphenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 6 hydrochloride)

[0139]

[0140] 6.1 According to the method in 5.2 of Example 5, 3-(dimethylamino)-1-(4-methylphenyl)propan-1-ol was used to replace 3-(dimethylamino)-1-phenylpropan-1-ol to participate in the reaction, and 6.4 g of a pale yellow oily substance was obtained.

[0141] 6.2 According to the method in 5.3 of Example 5, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-(p-tolyl)propan-1-amine was used to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-phenylpropan-1-amine to participate in the reaction, and 7.5 g of an oily product was obtained.

[0142] 6.3 According to the method in 5.4 of Example 5, methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-(4-methylphenyl)propyl)carbamate was used to replace methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-phenylpropyl)carbamate to participate in the reaction, and 1.6 g of a light green oily product was obtained.

[0143] 6.4 According to the method in 5.5 of Example 5, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-(4-methylphenyl)propan-1-amine was used to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-phenylpropan-1-amine to participate in the reaction, and 0.6 g of the product 3-{[3-(methylamino)-1-(4-methylphenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 6 hydrochloride) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.41 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.7 Hz, 2H), 6.68 - 6.56 (m, 1H), 6.50 (dd, J = 15.8, 8.1 Hz, 2H), 5.49 - 5.40 (m, 1H), 3.01 - 2.89 (m, 2H), 2.58 (s, 3H), 2.51 (s, 1H), 2.339 - 2.22 (m, 4H), 2.15 - 2.07 (m, 1H). MS (ESI, m / z): 288.1 (M + H) + 。

[0144] Example 7. Preparation of 3-{[3-(methylamino)-1-(4-methoxyphenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 7 hydrochloride)

[0145]

[0146] 7.1 According to the method in 5.2 of Example 5, 3-(dimethylamino)-1-(4-methoxyphenyl)propan-1-ol was used to replace 3-(dimethylamino)-1-phenylpropan-1-ol to participate in the reaction, and 7.6 g of a pale yellow oil was obtained.

[0147] 7.2 According to the method in 5.3 of Example 5, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-(4-methoxyphenyl)propan-1-amine was used to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-phenylpropan-1-amine to participate in the reaction, and 6.9 g of an oily product was obtained.

[0148] 7.3 According to the method in 5.4 of Example 5, methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-(4-methoxyphenyl)propyl)carbamate was used to replace methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-phenylpropyl)carbamate to participate in the reaction, and 1.8 g of a light green oily product was obtained.

[0149] 7.4 According to the method in 5.5 of Example 5, 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-(4-methoxyphenyl)propan-1-amine was used to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-phenylpropan-1-amine to participate in the reaction, and 0.7 g of 3-{[3-(methylamino)-1-(4-methoxyphenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 7 hydrochloride) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.38 (s, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.65 (t, J = 8.1 Hz, 1H), 6.50 (dd, J = 15.9, 8.1 Hz 2H), 5.45 (dd, J = 7.8, 5.0 Hz, 1H), 3.73 (s, 3H), 2.98 (m, 2H), 2.55 (s, 3H), 2.51 (s, 1H), 2.24 - 2.18 (m, 1H), 2.08 - 2.00 (m, 1H). MS (ESI, m / z): 304.1 (M + H) + .

[0150] Example 8 Preparation of 3-{[3-(methylamino)-1-(4-fluorophenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 8 hydrochloride)

[0151]

[0152] 8.1 According to the method in 5.2 of Example 5, use 3-(dimethylamino)-1-(4-fluorophenyl)propan-1-ol to replace 3-(dimethylamino)-1-phenylpropan-1-ol to participate in the reaction, and obtain 10.2 g of a pale yellow oily substance.

[0153] 8.2 According to the method in 5.3 of Example 5, use 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-(4-fluorophenyl)propan-1-amine to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N,N-dimethyl-3-phenylpropan-1-amine to participate in the reaction, and obtain 8.7 g of an oily product.

[0154] 8.3 According to the method in 5.4 of Example 5, use methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-(4-fluorophenyl)propyl)carbamate to replace methyl phenyl(3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-3-phenylpropyl)carbamate to participate in the reaction, and obtain 2.3 g of a light green oily product.

[0155] 8.4 According to the method in 5.5 of Example 5, use 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-(4-fluorophenyl)propan-1-amine to replace 3-(2-ethoxybenzo[d][1,3]dioxol-4-yl)oxy)-N-methyl-3-phenylpropan-1-amine to participate in the reaction, and obtain 0.9 g of the product 3-{[3-(methylamino)-1-(4-fluorophenyl)propyl]oxy}benzene-1,2-diol hydrochloride (Compound 8 hydrochloride). 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.39(s,1H),7.43(dd,J=8.1 5.7Hz,2H),7.18(t,J=8.7Hz,2H),6.65(t,J=8.1Hz,1H),6.49(dd,J=19.9,8.1Hz,2H),5.49-5.40(m,1H),3.01-2.92(m,2H),2.56(s,3H),2.51(s,1H),2.24 -2.18(m,1H),2.09 -2.00(m,1H);.MS(ESI,m / z):292.1(M+H) + 。

[0156] ​

[0157] The present invention will be further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0158] Test Example 1: In vitro Affinity Test

[0159] 1.1 Test Method

[0160] 1.1.1 Preparation of Homogenate

[0161] Weigh 2.19 g of NaCl and 93 mg of KCl, and add them to 250 mL of 50 mM Tris-HCl buffer to adjust the pH to 7.4. Make their concentrations 150 mM NaCl and 5 mM KCl respectively.

[0162] 1.1.2 Preparation of Receptor Membranes for SERT (Serotonin Transporter), NET (Norepinephrine Transporter), and DAT (Dopamine Transporter)

[0163] After the cells are taken out of the -80°C refrigerator and thawed naturally, centrifuge them at 2000 g for 15 min. Add the precipitate to the homogenate, mix well with a vortex mixer, centrifuge at 48000 g at 4°C for 25 min, discard the supernatant, take the precipitate, add the buffer (homogenate) again for washing, repeat 2 times. After centrifugation, discard the supernatant, weigh, and store the precipitate at -80°C for standby.

[0164] 1.1.3 Receptor Competition Binding Assay

[0165] 1) SERT Receptor Competition Binding Experiment

[0166] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding wells (TB), and add 50 μL of Paroxetine (final concentration 1.0×10

[0167] M) to the non-specific binding wells (NB), and add 50 μL of the test compound to each test compound well (CB). -5 M) to the non-specific binding wells (NB), and add 50 μL of the test compound to each test compound well (CB).

[0168] Step 2: Add 100 μL of buffer (homogenate) to each reaction well.

[0169] Step 3: First, prepare the membrane into a 5 mg / mL membrane suspension with the homogenate for standby.

[0170] Step 4: Add 50 μL of radioactive ligand 3 H-Paroxetine to each reaction well, with a final concentration of 1 nM.

[0171] Step 5: Add 50 μL of the membrane suspension to each reaction well.

[0172] Step 6: Incubate each reaction well at 25 °C for 90 min. After the reaction is completed, the bound ligand is rapidly filtered under reduced pressure. The GF / C plate is pre-soaked with 0.5% PEI for more than 1 h. After filtration, the filter membrane is dried in an oven at 60 °C

[0173] and then dried. After attaching the bottom film, 40 μL of scintillation fluid is added, the top film is sealed, and it is left to stand.

[0174] Step 7: Place the filter plate into a liquid scintillation counter for counting.

[0175] 2) NET receptor competitive binding assay

[0176] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding well (TB), and add 50 μL of Desipramine (final concentration 1.0×10

[0177] M) to the non-specific binding well (NB). Add 50 μL of the test compound to each test compound well (CB). -5 M) to the non-specific binding well (NB), and add 50 μL of the test compound to each test compound well (CB).

[0178] Step 2: Add 100 μL of buffer (homogenate) to each reaction well.

[0179] Step 3: First, prepare a suspension of the membrane at 2 mg / mL with the homogenate for later use.

[0180] Step 4: Add 50 μL of the radioactive ligand

[0181] H-Nisoxetine to each reaction well, with a final concentration of 1 nM. 3 H-Nisoxetine to each reaction well, with a final concentration of 1 nM.

[0182] Step 5: Add 50 μL of the membrane suspension to each reaction well.

[0183] Step 6: Incubate each reaction well at 25 °C for 90 min. After the reaction is completed, the bound ligand is rapidly filtered under reduced pressure. The GF / C plate is pre-soaked with 0.5% PEI for more than 1 h. After filtration, the filter membrane is dried in an oven at 60 °C

[0184] and then dried. After attaching the bottom film, 40 μL of scintillation fluid is added, the top film is sealed, and it is left to stand.

[0185] Step 7: Place the filter plate into a liquid scintillation counter for counting.

[0186] 3) DAT receptor competitive binding assay

[0187] Step 1: Add 30 μL of solvent (1% DMSO) to the total binding well (TB), and add 30 μL of Nomifensine (final concentration 1.0×10

[0188] to the non-specific binding well (NB). -5M), each well containing the test compound (CB)

[0189] Add 30 μL of the test compound.

[0190] Step 2: Add 100 μL of buffer (homogenate) to each reaction well.

[0191] Step 3: First, prepare a suspension of the membrane in the homogenate at a concentration of 5 mg / mL for later use.

[0192] Step 4: Add the radioactive ligand 3 60 μL of ³H-Nisoxetine to each reaction well, with a final concentration of 4 nM.

[0193] Step 5: Add 60 μL of the membrane suspension to each reaction well.

[0194] Step 6: Incubate each reaction well at 25 °C for 90 min. After the reaction is complete, the bound ligand is rapidly filtered under reduced pressure. The GF / C plate has been pre-soaked in 0.5% PEI for more than 1 h. After filtration, the filter membrane is dried in an oven at 60 °C

[0195] dried, a bottom film is attached, 40 μL of scintillation fluid is added, the top film is sealed, and left standing.

[0196] Step 7: Place the filter plate into a liquid scintillation counter for counting.

[0197] 1.1.4 Test Results

[0198] Table 1 In vitro receptor affinity test of compounds

[0199]

[0200] 1.1.5, Test Conclusions

[0201] The in vitro receptor affinity test shows that compound 1 oxalate of the present invention has considerable affinity for all three transporters, SERT, NET, and DAT, and is expected to have good antidepressant activity. In particular, the affinity of compound 1 oxalate at the DAT target is better than that of R-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N-methyl-3-phenylpropan-1-amine hydrochloride, indicating that its selective binding ability to the dopamine transporter is relatively stronger.

[0202] Test Example 2, Inhibition Test of SERT (Serotonin Transporter), NET (Norepinephrine Transporter), and DAT (Dopamine Transporter)

[0203] 2.1 Test Method

[0204] 2.1.1 Cell Seeding

[0205] The cultured cells were digested with trypsin. After adding complete medium to terminate the digestion, the cell suspension was transferred to a centrifuge tube and centrifuged at 750 rpm for 5 minutes. The supernatant was discarded, and the precipitate was resuspended with an appropriate amount of plating medium. 20 μL was taken for counting with a cell counter. An appropriate amount of the cell suspension was diluted to 1×106 cells / mL, and 20 μL of the cell suspension (cell density: 20,000 cells / well) was added to each well of the cell plate. The cell plate was placed in a 5% CO2 / 37 °C cell incubator and cultured for 16 - 20 h.

[0206] 2.1.2 Test detection

[0207] 2.1.2.1 Preparation of detection reagents

[0208] Preparation of experimental buffer: HBSS, 20 mM HEPES, 0.1% BSA. BSA is preferably added just before each experiment. The Transporter Dye Uptake Assay Kit was taken out from -20 °C and allowed to return to room temperature. 10 mL of HBSS was added to each bottle, vortexed and mixed well, and then left standing for 5 minutes to ensure complete dissolution. If not used up at one time, it was aliquoted at 500 μL / tube and stored at -80 °C, avoiding repeated freezing and thawing.

[0209] 2.1.2.2 Experimental procedures

[0210] The test compound was serially diluted with the experimental buffer in the compound plate, with the starting concentration of 50 μM and 10 concentration points with a 3.16-fold serial dilution. The cell plate was taken out from the incubator, the medium was manually flicked off, and the residual liquid was gently blotted with absorbent paper. Then, 25 μL of the compound buffer was immediately added, centrifuged at 1000 rpm for 1 minute, and pre-incubated at 37 °C for 30 minutes. The positive control well was 10 μL of 50 μM Nomifensine solution (final concentration 10 μM), and the negative control well was an equal volume of the experimental buffer. The prepared detection reagent was taken out and allowed to return to room temperature, 25 μL of the detection reagent was added, and centrifuged at 1000 rpm for 1 minute. The cell plate was placed at 37 °C and incubated for 30 minutes. Read the plate using Envision. Parameter settings: excitation light 450 nm (BW: 8 nm), emission light 535 nm (BW: 25 nm), dichroic mirror 403 (D505), bottom read mode.

[0211] 2.2 Test results

[0212] Table 2 Results of the compound protein inhibition experiment

[0213]

[0214] 2.3 Test conclusions

[0215] The hydrochloride salt of compound 5 of the present invention has a significant inhibitory effect on all three transporters, SERT, NET, and DAT, and is expected to have good antidepressant activity. In particular, the inhibitory effect of the hydrochloride salt of compound 5 on the DAT target is significantly better than that of R-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N-methyl-3-phenylpropanamine hydrochloride, indicating that its selective inhibitory effect on the dopamine transporter is relatively stronger.

[0216] Test Example 3: Tail Suspension Test in Mice

[0217] 2.1 Test Method

[0218] SPF-grade ICR mice were selected, and the animals were grouped according to body weight, with 8 animals in each group. The animals were allowed to acclimatize for at least 3 days before behavioral testing.

[0219] Behavioral testing began 1 h after intragastric administration. The mice were suspended and taped to a horizontal bar with tape at a position 1 cm from the tip of the tail, and video recorded for 6 min (mice that climbed their own tails during the test were considered eliminated). After the test, the video of the behavioral test was exported and analyzed using Tail Susp Scan TM 1.0 software to analyze the cumulative immobility time of the mice during the last 4 min of the 6-min tail suspension.

[0220] The test results were expressed as mean ± SD. The t-test was used for comparison between each group and the vehicle group, and P < 0.05 was considered statistically significant.

[0221] 2.2 Test Results

[0222] Single oral administration of duloxetine hydrochloride could reduce the immobility time in the tail suspension test of mice, P < 0.01, and its minimum effective dose was 64 mg / kg, ED 50 was 21.50 mg / kg. Single oral administration of the oxalate salt of compound 1 of the present invention could reduce the immobility time in the tail suspension test of mice, P < 0.01, P < 0.05, and its minimum effective dose was 10 mg / kg, ED 50 was 4.36 mg / kg. From the values of the minimum effective dose and the median effective dose, the oxalate salt of compound 1 of the present invention was less than duloxetine hydrochloride, indicating that it had better in vivo pharmacological activity.

[0223] Test Example 4: Forced Swimming Test in Mice

[0224] 4.1 Test Method

[0225] SPF-grade ICR mice were selected. The animals were grouped according to body weight, with 8 mice in each group. The animals were allowed to acclimatize for at least 3 days before the behavioral test. The behavioral test was conducted in the morning. One day before the behavioral test, the animals were marked, weighed, and medicated. The liquid medicine was stored at 4°C in the dark overnight.

[0226] During the behavioral test, the mice were placed in a transparent glass cylinder (water depth 15 cm, water temperature 23 - 25°C) for 6 minutes, and video recordings were made (the background of the mice was an LED light panel). At the end of the time, the mice were taken out of the water, and the water was poured out (usually changed every 4 batches of tests), and then the next batch of mice's behavioral test was carried out. After the experiment, the videos of the behavioral test were exported, and software was used to analyze the cumulative immobility time of the mice in the last 4 minutes during the 6-minute forced swimming.

[0227] The test results were expressed as mean ± SD. The t-test was used for comparison between each group and the vehicle group, and P < 0.05 was considered statistically significant.

[0228] 4.2. Test Results

[0229] After single oral administration of compound 5 hydrochloride of the present invention, the immobility time in the forced swimming test of mice could be reduced, P < 0.01, P < 0.05; its lowest effective dose was 10 mg / kg. After single oral administration of duloxetine hydrochloride at 15 mg / kg, the immobility time in the forced test of mice could be reduced, P < 0.01. It can be seen that compound 5 hydrochloride of the present invention also has better in vivo pharmacodynamic strength. The specific results are shown in the following table.

[0230] Table 3 Results of compounds reducing the forced swimming test in mice

[0231]

[0232]

[0233] Note: Compared with the vehicle group, *P < 0.05, **P < 0.01.

[0234] Test Example 5. Pharmacokinetic Study in Rats

[0235] 3.1. Test Method

[0236] Thirty-two healthy male SD rats were randomly divided into 8 groups with 4 rats in each group, and were divided into an intravenous injection group and a gavage administration group; the rats in the intravenous injection group were given a 1.0 mg / kg solution of R-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N-methyl-3-phenylpropanamine hydrochloride (the compound of the control example) or oxalate of compound 1 via tail vein injection, and blood was collected from the orbital cavity of the rats before administration and at 0.08, 0.25, 0.50, 1.0, 2.0, 4.0, 7.0, 10.0 h after administration, and the blood drug concentration was measured by LC-MS method; the rats in the gavage administration group were given low, medium and high dose solutions of R-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N-methyl-3-phenylpropanamine hydrochloride or oxalate of compound 1 via gavage, and blood was collected from the orbital cavity of the rats before administration and at 0, 0.25, 0.50, 1.0, 2.0, 4.0, 7.0, 10.0, 24.0 h after administration, and the blood drug concentration was measured by LC-MS method. The obtained data were processed and analyzed using WinNolin 8.0 to obtain the pharmacokinetic parameters and calculate the bioavailability.

[0237] 3.2. Test results

[0238]

[0239] 3.3. Test conclusions

[0240] The results of the pharmacokinetic experiment of rats showed that, compared with the pharmacokinetic parameters of R-3-[(benzo[d][1,3]dioxol-4-yl)oxy]-N-methyl-3-phenylpropanamine hydrochloride, the half-life, exposure and bioavailability of oxalate of compound 1 of the present invention were longer and greater.

[0241] Those skilled in the art understand that many modifications and variations can be made to the present invention without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to limit the scope of the present invention in any way.

Claims

1. A compound represented by general formula I, its stereoisomer or a pharmaceutically acceptable salt thereof: in: R1 and R2 are independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen; R3 and R4 are independently selected from hydroxy, hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen; Alternatively, R3, R4 and the C atom to which they are connected together form a 3-6-membered heterocyclic ring containing 1-3 heteroatoms selected from O, N, and S, preferably R3, R4 and the C atom to which they are connected together form a 5-membered heterocyclic ring containing 2 heteroatoms independently selected from O, N, and S, and more preferably R3, R4 and the C atom to which they are connected together form a 1,3-dioxolane ring; R5 is selected from H and optionally substituted C1-C8 alkyl, preferably selected from H and optionally substituted C1-C5 alkyl, further preferably selected from H and C1-C3 alkyl, wherein the optional substituent is halogen; When R3, R4 and the C atom to which they are connected together form a heterocyclic ring, R5 is H.

2. The compound of general formula I according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula I is further a compound of formula II or formula III: in: R1, R2 are as defined in claim 1; R3 and R4 are independently selected from hydroxy, hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen.

3. The compound of general formula I according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula I is formula II-a, II-b, or a mixture thereof: in: R1, R2 are as defined in claim 1 or 2.

4. The compound of general formula I according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula I is III-a, III-b or a mixture thereof: in: R1, R2 are as defined in claim 1 or 2; R3 and R4 are independently selected from hydroxy, hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy, and the optional substituent is halogen.

5. The compound of general formula I, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: It meets one or more of the following conditions: (1) R1 is selected from hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy, wherein the optional substituent is halogen; (2) R2 is selected from hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy, wherein the optional substituent is halogen; (3) R3 is selected from hydroxy, hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy, wherein the optional substituent is halogen; (4) R4 is selected from hydroxy, hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy, wherein the optional substituent is halogen; (5) When R3, R4 and the C atom to which they are connected together form a heterocyclic ring, R5 is H; otherwise, R5 is a C1-C5 alkyl group, preferably a methyl group.

6. The compound of formula I, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, C1-C3 alkyl and C1-C3 alkoxy; R2 is selected from hydrogen, fluorine, chlorine, C1-C3 alkyl and C1-C3 alkoxy; R3 is selected from hydroxy, hydrogen and halogen; R4 is selected from hydroxy, hydrogen and halogen.

7. The compound of formula I, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy and ethoxy, preferably selected from hydrogen, fluorine, chlorine, methyl and methoxy; R2 is selected from hydrogen, fluorine, chlorine, methyl and methoxy; R3 is hydroxy; R4 is hydroxy.

8. The compound of formula I, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: Selected from the following compounds:

9. The compound of general formula I, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: The pharmaceutically acceptable salt is selected from oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate, preferably oxalate or hydrochloride.

10. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt of claim 9 and one or more pharmaceutically acceptable carriers or excipients.

11. Use of the compound according to any one of claims 1 to 8, its stereoisomer, the pharmaceutically acceptable salt according to claim 9, or the pharmaceutical composition according to claim 10 in the preparation of drugs for treating mental illnesses.

12. The use according to claim 11, characterized in that The mental illness is depression.

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