CN116444484A - Salts of 1, 5-dihydro-2, 4-benzodiazepine-3-one derivatives and uses thereof - Google Patents

Salts of 1, 5-dihydro-2, 4-benzodiazepine-3-one derivatives and uses thereof Download PDF

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CN116444484A
CN116444484A CN202211299097.1A CN202211299097A CN116444484A CN 116444484 A CN116444484 A CN 116444484A CN 202211299097 A CN202211299097 A CN 202211299097A CN 116444484 A CN116444484 A CN 116444484A
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methyl
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窦飞
邱印利
王硕
杨庆路
徐祥清
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Nhwa Pharmaceutical Corp
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Abstract

The invention belongs to the field of medicines, and particularly relates to a salt of a compound shown in a general formula I, a preparation method, a composition containing the salt of the compound and application of the salt in the field of medicines.

Description

Salts of 1, 5-dihydro-2, 4-benzodiazepine-3-one derivatives and uses thereof
Technical Field
The invention belongs to the field of medicines, and in particular relates to 1, 5-dihydro-2, 4-benzodiazepineSalts of 3-keto derivatives, methods of preparation and compositions comprising salts of the compounds, and use in the medical field.
Technical Field
The Schizophrenia (Schizophrenia) has hidden incidence, low cure rate and higher incidence rate in life. About 0.3-0.7% of the world population is currently affected by schizophrenia throughout its lifetime, with an estimated over 2100 ten thousand schizophrenic patients worldwide in 2016. The existing anti-schizophrenia drugs mainly comprise typical anti-schizophrenia drugs and atypical anti-schizophrenia drugs, but the current anti-schizophrenia therapeutic drugs block dopamine receptors strongly, so that adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, increase of prolactin and the like are caused. In the medical field, although various types of active compounds acting on different targets are available for the treatment of sleep disorders, adverse reactions such as addiction, drug resistance and sequelae remain unsolved.
Traditionally, it is customary to block dopamine D by 2 Antipsychotics whose receptors exert pharmacological effects are known as first-generation antipsychotics, i.e. "typical" antipsychotics (e.g. haloperidol), which are breakthrough in the treatment of positive symptoms of schizophrenia but fail to treat negative symptoms andcognitive disorders. Typical antipsychotics generally have severe EPS side effects and are ineffective in one third of schizophrenic patients.
After the 60 s of the 20 th century, a series of new generation antipsychotics including Ziprasidone (Ziprasidone), risperidone (Risperidone) and the like, called second generation antipsychotics, i.e., new antipsychotics, have been developed. Although their respective pharmacological actions are not completely identical, they share the common pharmacological feature that the affinities for 5-hydroxytryptamine (5-HT) receptors (5-HT 1A, 2 c) and Norepinephrine (NA) receptors (. Alpha.1,. Alpha.2) are far greater than for D 2 High receptor, leading to D 2 /5-HT 2A The ratio of (2) is higher. Compared with the first-generation antipsychotics, the clinical effect of the traditional Chinese medicine composition has more advantages, is effective on positive symptoms and traditional antipsychotics, is effective on negative symptoms and cognition deficiency symptoms, has a wider action spectrum, and has adverse reactions such as QT interval prolongation, hyperprolactinemia, weight gain and the like. Thus, finding drugs that are effective against positive, negative symptoms and cognitive impairment of schizophrenia with small side effects is a hotspot of current research.
The 5-hydroxytryptamine system plays an important role in regulating the function of the prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons comprise several 5-HT with a particularly high density of 5-hydroxytryptamine receptor subtypes 1A And 5-HT 2A . PFC and NMDA receptor channels have recently been demonstrated to be 5-HT 1A The targets of R, these two receptors regulate cortical excitatory neurons, affecting cognitive function. Indeed, various preclinical data indicate 5-HT 1A R may be a new target for the development of antipsychotic drugs. Atypical antipsychotics (such as olanzapine, aripiprazole, etc.) against 5-HT 1A The high affinity of R and its low EPS side effects both indicate that the 5-hydroxytryptamine system plays an important role in regulating the function of the prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons comprise several 5-HT with a particularly high density of 5-hydroxytryptamine receptor subtypes 1A And 5-HT 2A . Recent studiesIndicating 5-HT 1A Agonists are associated with atypical antipsychotic therapy and improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic drug clozapine, 5-HT has been found 2A Play an important role in this context, involving various aspects of perception, mood regulation and motor control. Blocking 5-HT 2A The receptor can normalize dopamine release and act as an antipsychotic. In addition, 5-HT 2C The receptors are closely related to weight gain.
Pimozide is a p-5-HT 2A And 5-HT 2C Inverse agonists with high affinity, shown by in vitro experiments, for 5-HT 2A Affinity of the receptor [ inhibition constant (Ki) of 0.4nM]Compared with 5-HT 2C High (ki=16 nM), for 5-HT 2B None of the receptors, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors or calcium channel receptors have significant affinity (Ki>300 nM). The medicine is approved by the U.S. food and drug administration to be marketed in the 4 th year of 2016, and has the trade name of NuplazidTM, and is mainly used for treating parkinsonism symptoms such as illusion and illusion.
Therefore, there is a need to find a composition that is effective against both positive and negative symptoms, improves cognitive impairment and prevents extrapyramidal side effects, including tardive dyskinesia, parkinson's disease; and can reduce weight gain.
Disclosure of Invention
Patent application PCT/CN2021/089660 protects a series of 1, 5-dihydro-2, 4-benzodiazepines In order to ensure that the therapeutic effect of the active substances is maximally exerted in clinical research and that the product treatment is simplified and the product solubility is improved in the subsequent pharmaceutical development process, the salt of the active substances is subjected to comprehensive systematic research in order to obtain the most suitable salt form.
All that is referred to in patent application PCT/CN2021/089660 is incorporated herein by reference.
The present invention aims to provide 1, 5-dihydro-2, 4-benzodiazepinesSalts of 3-keto derivatives, phosphate or citrate or crystalline forms, compared to the free base form of the compound, are advantageous for increasing the solubility and hygroscopicity of the active substance, for enhancing the bioavailability and stability of the active substance, and for subsequent clinical development and production development.
The invention provides a salt of a compound shown in the following general formula I, preferably, the salt form of the compound shown in the general formula I is phosphate or citrate,
the invention also provides application of the phosphate or citrate of the compound shown in the general formula I in preparing medicaments for treating neuropsychiatric diseases.
The in vitro study results show that the compounds provided by the invention have substantially equivalent activity to pimecrin, but the compounds provided by the invention have lower 5-HT 2A 、5-HT 2C The Ki value of the receptor is obviously better than that of pimozide, which indicates that the compound provided by the invention is easier to combine with the receptor and has great clinical use value.
The invention is implemented by the following technical scheme:
in one aspect, the present invention provides a salt of a compound of formula I,
wherein:
n1 and n2 are integers from 1 to 3;
R 1 selected from straight-chain or branched C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl and C 2 -C 8 Alkynyl groups, said alkyl, alkenyl and alkynyl groups each independently and optionally being selected from halogen andC 1 -C 8 a substituent of a haloalkyl group;
R 2 selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 3 、R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 7 selected from straight-chain or branched C 1 -C 8 Alkyl, cycloalkylR 8 、R 9 Independently selected from linear or branched C 1 -C 8 Alkyl, said alkyl and cycloalkyl being optionally selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
z is selected from C, O, N;
q, W are each selected from C, N.
In a preferred embodiment of the present invention, the salt form of the compound of formula i is phosphate or citrate, as shown in formulas II and iii:
y is 0.5, 1, 1.5, 2, 2.5 or 3, preferably 0.5, 1, 1.5 or 2.
In a preferred embodiment of the invention, the phosphate or citrate salt of the compound of formula i is wherein:
Said straight or branched chain C 1 -C 8 Alkyl is selected from straight or branched chain C 1 -C 5 Alkyl and straight or branched C 1 -C 3 An alkyl group; and/or
The C is 2 -C 8 Alkenyl group is C 2 -C 5 Alkenyl groups; and/or
The C is 2 -C 8 Alkynyl is C 2 -C 5 Alkynyl; and/or
The C is 1 -C 8 Haloalkyl is C 1 -C 5 A haloalkyl group; and/or
The cycloalkyl group is C 3 -C 10 Cycloalkyl, preferably C 3 -C 6 Cycloalkyl groups.
In a preferred embodiment of the invention, the phosphate or citrate salt of the compound of formula i is wherein:
the halogen is selected from fluorine, chlorine, bromine and iodine; and/or
Said straight or branched chain C 1 -C 5 Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl; and/or
The C is 3 -C 6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl; and/or
Said straight or branched chain C 1 -C 3 The alkyl is selected from methyl, ethyl, propyl, isopropyl. In a preferred embodiment of the invention, the phosphate or citrate salt of the compound of formula i is wherein:
the halogen is fluorine and chlorine; and/or
Said straight or branched chain C 1 -C 5 Alkyl is selected from methyl, ethyl, propyl, isopropyl, isobutyl; and/or
The C is 3 -C 6 Cycloalkyl is selected from cyclopropyl, cyclobutyl; and/or
Said straight or branched chain C 1 -C 3 Alkyl is selected from methyl, ethyl, propyl, isopropyl;
The saidIs->
In a preferred embodiment of the present invention, the phosphate or citrate salt of the compound represented by formula i is characterized by comprising a phosphate or citrate salt selected from the group consisting of the compounds represented by the following formulae:
in one embodiment of the invention, the phosphate or citrate salt of the compound of formula I comprises a solvate form thereof.
In one embodiment of the invention, there is provided an a19006 citrate salt, as shown in formula IV:
in one embodiment of the invention, there is provided an a19006 phosphate salt, as shown in formula V:
in another aspect, the invention provides a crystalline form I of a19006 citrate of formula IV, characterised in that Cu-ka radiation is used to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ±0.2° which shows characteristic peaks at 10.03, 12.62, 13.69, 14.68, 16.44, 17.19, 19.10, 20.27, 21.77, wherein each characteristic peak 2 θ has an error range of ± 0.2.
In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of form I shows characteristic peaks expressed in terms of 2θ±0.2° at 17.67, 19.57, 21.30, 23.78, 24.03, 25.57, 26.22, wherein each characteristic peak has an error range of 2θ of ±0.2.
In a preferred embodiment of the invention, the X-ray powder diffraction pattern of form I shows characteristic peaks expressed in degrees 2θ±0.2° at 5.42, 10.03, 11.10, 12.62, 13.69, 14.68, 16.44, 17.19, 17.67, 18.39, 19.10, 19.57, 20.27, 21.30, 21.77, 22.50, 23.78, 24.03, 25.57, 26.22, 27.65, 28.62, 30.29, 30.56, 31.67, 32.76, 33.62, 34.04, 34.88, 35.49, 36.33, 39.02, 39.69, wherein the error range of each characteristic peak 2θ is ±0.2°.
In a more preferred embodiment of the invention, the DSC melting endotherm peak of form I is selected from 164.7-170.0deg.C, preferably 167.7deg.C.
Preparation method
The invention provides a preparation method of a salt of a compound shown in a general formula I, which comprises the following steps:
dissolving the free alkali of the compound shown in the general formula I in an organic solvent to form a solution, optionally dissolving acid in the organic solvent, dripping the organic solvent-acid solution into the free alkali solution of the compound shown in the general formula I, stirring, separating and drying to obtain the salt of the compound shown in the general formula I; the organic solvents include, but are not limited to, absolute ethanol, ethyl acetate, and the like; the acids include, but are not limited to, phosphoric acid, citric acid, and the like.
Detailed Description
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. If there is a conflict, the present application provides definitions. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. All patents, published patent applications, and publications cited herein are incorporated by reference.
General terms and definitions
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects. It should be understood that the term "comprising" may cover the closed meaning, i.e. "consisting of …".
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above or as specified in the examples, subclasses, and examples. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent, provided that the normal valency of the indicated atom in the present case is not exceeded and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When it is described that a substituent is absent, it is understood that the substituent may be one or more hydrogen atoms, provided that the structure is such that the compound is stable. An optionally substituted group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent. When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
In addition, unless explicitly stated otherwise, the description as used in this application is to be construed broadly as meaning that the terms "independently of each other" and "independently of each other" may refer to the fact that, in different groups, specific terms expressed between the same symbols do not affect each other, or may mean that, in the same groups, specific terms expressed between the same symbols do not affect each other.
When lower and upper limits of a range of values are disclosed, any number and any range encompassed within the range are specifically disclosed. In particular, each numerical range of values disclosed herein is to be understood as meaning every number and range that is encompassed within the broader range. When any variable (e.g., R), and the variable with a label (e.g., R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 Etc.) are independent in each case when they occur more than once in the composition or structure of the compound. For example, if a group is substituted with 0, 1, 2, 3 or 4R substituents, the group may optionally be up to Is substituted by four R substituents, and the options for each R substituent in each case are independent of each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the expression m-n as used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein as well as the individual point values. For example, the term "C 1 -C 5 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 An alkyl group. For example, the expression "C 2 -C 8 "OR" C 2-8 "ranges from 2 to 8 carbon atoms are intended to encompass any subrange therein as well as every point value, e.g., C 2 -C 5 、C 3 -C 4 、C 2 -C 6 、C 3 -C 6 、C 4 -C 6 、C 4 -C 7 、C 4 -C 8 、C 2 -C 4 Etc. and C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 Etc. Also for example, the expression "C 1 -C 5 "OR" C 1-5 "ranges from 1 to 5 carbon atoms are to be understood as also covering any subrange therein as well as every point value, e.g. C 2 -C 5 、C 3 -C 4 、C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 Etc. and C 1 、C 2 、C 3 、C 4 、C 5 Etc. Also for example, the expression "C 2 -C 5 "OR" C 2-5 "ranges from 2 to 5 carbon atoms are intended to encompass any subrange therein as well as every point value, e.g., C 2 -C 5 、C 3 -C 4 、C 2 -C 3 、C 2 -C 4 、C 3 -C 5 、C 4 -C 5 Etc. and C 2 、C 3 、C 4 、C 5 Etc. Also for example, the expression "C 1 -C 8 "OR" C 1-8 "ranges from 1 to 8 carbon atoms are intended to encompass any subrange therein, and each point value, e.g., C 2 -C 5 、C 3 -C 4 、C 2 -C 6 、C 3 -C 6 、C 4 -C 6 、C 4 -C 7 、C 4 -C 8 、C 2 -C 4 Etc. and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 Etc. For another example, the expression "ternary to octant" should be understood to encompass any subrange therein and every point value, such as ternary to penta, ternary to hexa, ternary to hepta, ternary to octant, quaternary to penta, quaternary to hexa, quaternary to hepta, quaternary to octant, penta to hepta, penta to octant, hexa to hepta, hexa to octant, etc., as well as tri, tetra, penta, hexa, hepta, octant, etc. Other similar expressions herein should be understood in a similar manner.
Ranges recited herein (e.g., numerical ranges) can encompass each and every subrange within the range as well as each subrange formed by each value. Thus, for example, the expression "n 2 An "integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, etc., such as 1, 2, 3.
The term "one or more" or similar expression "at least one" may denote, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.
The term "selected from …" means that one or more elements in the group listed below are independently selected and may include a combination of two or more elements.
When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, provided that the normal valency of all atoms in the group in the current case is not exceeded, and stable compounds are formed.
The term "hydrogen (H)" means a single hydrogen atom and such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
The term "halogen" or "halo" is understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine, bromine atoms, more preferably fluorine atoms, chlorine atoms.
The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder of the molecule by a single bond. "alkyl" may have 1 to 6 carbon atoms, i.e. "C 1 -C 6 Alkyl ", e.g. C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 1-6 Alkyl, C 3-6 An alkyl group. May also have 1 to 3 carbon atoms, i.e. "C 1 -C 3 Alkyl ", e.g. C 1-3 Alkyl, C 1-2 Alkyl, C 3 An alkyl group. Also for example, the term "C 1 -C 5 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl and C 5 An alkyl group. 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 (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 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms. Alkenyl groups can have 2 to 5 carbon atoms, i.e. "C 2-5 Alkenyl ", e.g. C 2-4 Alkenyl, C 3-4 Alkenyl groups. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, and the like.
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spiro ring structure. Cycloalkyl groups can have 3 to 6 carbon atoms, i.e. "C 3 -C 6 Cycloalkyl ", e.g. C 6 Cycloalkyl, C 5 Cycloalkyl, C 4 Cycloalkyl, C 3 Cycloalkyl groups. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term also covers the case where the C atom may be substituted by oxo (=o).
The term "alkynyl" refers toA linear or branched unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon atoms and hydrogen atoms. Alkynyl groups can have 2 to 5 carbon atoms, i.e. "C 2-5 Alkynyl ", e.g. C 2-3 Alkynyl, C 2-4 Alkynyl groups. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
The term "pharmaceutically acceptable carrier" refers to those substances which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. "pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, disintegrants, stabilizers, solvents or emulsifiers.
The term "free base" refers to amine compounds in non-salt form, and the present invention refers to compounds of formula I which are not salified.
The salt refers to pharmaceutically acceptable acid and base salt, and concretely relates to hydrochloride, phosphate, citrate, tartrate, maleate, fumarate, acetate, succinate, malate, mandelate, oxalate, dihydrogen phosphate, hydrogen phosphate, bisulfate, sulfate, formate, chloroacetate, glycolate, trifluoroacetate, propionate, acrylate, butyrate, isobutyrate, valerate, pivalate, caproate, benzoate, phenylacetate, oxalate, malonate, succinate, maleate, fumarate, glutarate, adipate, phthalate, isophthalate, terephthalate and the like.
By "y" is meant the stoichiometry of the base and the pharmaceutically acceptable acid, y can be 0.5, 1, 1.5, 2, 2.5 or 3, preferably 0.5, 1, 1.5 or 2.
By "crystalline form" is meant an ordered arrangement of molecules having the same chemical structure in a certain manner. Form I of the a19006 citrate is specified in this application.
The invention relates to an X-ray powderThe diffraction pattern "or" XRPD "refers to a pattern of diffraction according to bragg equation 2dsin theta = nλ (where λ is the wavelength of X-rays,the number of diffraction orders n is any positive integer, typically taking the first order diffraction peak, n=1), and the bragg equation is satisfied when the X-rays are incident on an atomic plane of the crystal or a portion of the crystal sample with a glancing angle θ (the complementary angle of the incident angle, also known as the bragg angle), which has a d-lattice plane spacing, so that the set of X-ray powder diffraction patterns is measured.
The term "2θ" or "2θ angle" as used herein refers to the diffraction angle, θ is the bragg angle, the units are degrees or degrees, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, more preferably ±0.2.
The term "interplanar spacing" or "interplanar spacing (d value)" as used herein refers to the fact that the space lattice selects 3 non-parallel unit vectors a, b, c that connect two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepipedal unit lines to obtain a set of rectilinear grids, called space lattices or lattices. The lattice and the lattice respectively reflect the periodicity of the crystal structure by using geometric points and lines, and the surface pitches (i.e. the distance between two adjacent parallel crystal surfaces) of different crystal surfaces are different; the unit is that Or angstroms.
The "differential scanning calorimetric analysis" or "DSC" described in the present invention determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the isoforms of the same compound, the thermal transition temperature and melting point errors may be within about 5 ℃, typically within about 3 ℃ in successive assays. When a compound is described as having a given DSC peak or melting point, it is referred to that DSC peak or melting point ± 5 ℃. "substantially" also takes such temperature variations into account. DSC provides an auxiliary method to distinguish between different crystal forms. Different crystal morphologies can be identified based on their different transition temperature characteristics. It should be noted that the DSC peak or melting point of the mixture may vary over a larger range. Furthermore, since decomposition is accompanied during melting of the substance, the melting temperature is related to the rate of temperature rise.
The term "psychotic disorder" is a neurological disorder, including schizophrenia, schizoaffective disorder, psychosis, parkinson's disease, dementia-related behavioral disorders and psychosis, delusional disorder, acute transient psychotic disorder, depressive disorder, bipolar disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia disorder, venue fear disorder, post-traumatic stress disorder, and the like.
The term "schizophrenia" is a group of chronic diseases of unknown etiology, which are often clinically manifested as syndrome of diverse symptoms, involving multiple disorders of sensory perception, thinking, emotion and behavior, and uncoordinated mental activities. The patient generally has clear consciousness, and intelligence is basically normal, but part of the patient can have impairment of cognitive function during the course of the disease.
The term "psychosis" refers to a disorder of brain function under the influence of various biological, psychological and social environmental factors, which results in the occurrence of different degree of disorders of mental activities such as cognition, emotion, mind and behavior as clinical manifestations.
The following detailed description is intended to illustrate non-limiting embodiments so that others skilled in the art may more fully understand the invention's solution, its principles and its practical application, to thereby modify and practice the invention in many forms best suited to the requirements of a particular use.
Salts of compounds of formula i:
in the formula I, n1 and n2 are integers from 1 to 3;
R 1 selected from straight-chain or branched C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl and C 2 -C 8 Alkynyl, said alkyl, alkenyl and alkynyl optionally being selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
R 2 selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 3 、R 4 、R 5 、R 6 each independently selected from the group consisting of hydrogen, halogen, and haloalkyl;
R 7 selected from straight-chain or branched C 1-8 Alkyl, cycloalkylR 8 、R 9 Independently selected from straight or branched chain C 1 -C 8 Alkyl, said alkyl and cycloalkyl being optionally selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
z is selected from C, O, N;
q, W are each selected from C, N.
In a preferred embodiment of the present invention, the salt form of the compound of formula i is preferably a phosphate or citrate salt, as shown in formulas II, iii:
y is 0.5, 1, 1.5, 2, 2.5 or 3, preferably 0.5, 1, 1.5 or 2.
In one embodiment, the phosphate or citrate salt of the compound of formula I, wherein n1 and n2 are integers selected from 1-3. For example, n1 and n2 are each independently selected from 1, 2 and 3, for example 1, 2 or 3. In a preferred embodiment, n1 is selected from 2 and 3. In a more preferred embodiment, n1 is 1. In another preferred embodiment, n2 is 1. In a more preferred embodiment, n1 is 2. In another more preferred embodiment, n2 is 2. In a more preferred embodiment, n1 is 3. In another more preferred embodiment, n2 is 3. In a particularly preferred embodiment, n1 is 2 and n2 is 1.
In one embodiment, R 1 Selected from straight-chain or branched C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl and C 2 -C 8 Alkynyl groups, said alkyl, alkenyl and alkynyl groups each independently and optionally being selected from halogen and C 1 -C 8 The substituent of the haloalkyl group. In a preferred embodiment, R 1 Is straight-chain or branched C 1 -C 8 An alkyl group, wherein the alkyl group is optionally selected from halogen and C 1 -C 8 The substituent of the haloalkyl group. In a more preferred embodiment, R 1 Is straight-chain or branched C 1 -C 8 An alkyl group. In a particularly preferred embodiment, R 1 Is straight-chain or branched C 1 -C 5 An alkyl group. In another particularly preferred embodiment, R 1 Is straight-chain or branched C 1 -C 3 An alkyl group. In a specific embodiment, R 1 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl. In a more specific embodiment, R 1 Selected from methyl, ethyl and propyl. Such as methyl, ethyl or propyl. In a particular embodiment, R 1 Is methyl. In another particular embodiment, R 1 Is ethyl. In a further particular embodiment, R 1 Is propyl.
In one embodiment, R 2 Selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group. In a preferred embodiment, R 2 Selected from hydrogen and halogen. In a more preferred embodiment, R 2 Is hydrogen. In another more preferred embodiment, R 2 Is halogen. In a specific embodiment, R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine. In a more specific embodiment, R 2 Selected from hydrogen, fluorine, chlorine, bromine. In a more specific embodimentIn the scheme, R 2 Is fluorine. In another more specific embodiment, R 2 Is chlorine. In yet a more specific embodiment, R 2 Is bromine.
In one embodiment, R 3 、R 4 、R 5 、R 6 Independently selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group.
In a preferred embodiment, R 3 Selected from hydrogen and halogen. In a more preferred embodiment, R 3 Is hydrogen. In another more preferred embodiment, R 3 Is halogen. In a particularly preferred embodiment, R 3 Selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R 3 Selected from fluorine, chlorine and bromine. In a specific embodiment, R 3 Selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R 3 Selected from hydrogen, fluorine and chlorine. In a particular embodiment, R 3 Is fluorine. In another particular embodiment, R 3 Is chlorine.
In a preferred embodiment, R 4 Selected from hydrogen and halogen. In a more preferred embodiment, R 4 Is hydrogen. In another more preferred embodiment, R 4 Is halogen. In a particularly preferred embodiment, R 4 Selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R 4 Selected from fluorine, chlorine and bromine. In a specific embodiment, R 4 Selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R 4 Selected from hydrogen, fluorine and chlorine. In a particular embodiment, R 4 Is fluorine. In another particular embodiment, R 4 Is chlorine.
In a preferred embodiment, R 5 Selected from hydrogen and halogen. In a more preferred embodiment, R 5 Is hydrogen. In another more preferred embodiment, R 5 Is halogen. In a particularly preferred embodiment, R 5 Selected from fluorine, chlorine, bromine and iodine. In one placeIn a more preferred embodiment, R 5 Selected from fluorine, chlorine and bromine. In a specific embodiment, R 5 Selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R 5 Selected from hydrogen, fluorine and chlorine. In a particular embodiment, R 5 Is fluorine. In another particular embodiment, R 5 Is chlorine.
In a preferred embodiment, R 6 Selected from hydrogen and halogen. In a more preferred embodiment, R 6 Is hydrogen. In another more preferred embodiment, R 6 Is halogen. In a particularly preferred embodiment, R 6 Selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R 6 Selected from fluorine, chlorine and bromine. In a specific embodiment, R 6 Selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R 6 Selected from hydrogen, fluorine and chlorine. In a particular embodiment, R 6 Is fluorine. In another particular embodiment, R 6 Is chlorine.
In one embodiment, R 7 Selected from straight-chain or branched C 1 -C 8 Alkyl, cycloalkylR 8 、R 9 Independently selected from straight or branched chain C 1 -C 8 Alkyl, said alkyl and cycloalkyl being optionally selected from halogen and C 1 -C 8 The substituent of the haloalkyl group.
In a preferred embodiment, R 7 Is straight-chain or branched C 1 -C 8 An alkyl group. In a more preferred embodiment, R 7 Is straight-chain or branched C 1 -C 5 An alkyl group. In a particularly preferred embodiment, R 7 Is straight-chain or branched C 1 -C 3 An alkyl group. In a specific embodiment, R 7 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl. In a more specific embodiment, R 7 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl. In a particular embodiment, R 7 Is isopropyl.
In a preferred embodiment, R 7 Is cycloalkyl. In a more preferred embodiment, R 7 Is C 3 -C 10 Cycloalkyl groups. In a particularly preferred embodiment, R 7 Is C 3 -C 6 Cycloalkyl groups. In a specific embodiment, R 7 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a more specific embodiment, R 7 Selected from cyclopropyl, cyclobutyl and cyclopentyl. Such as cyclopropyl, cyclobutyl, or cyclopentyl.
In a preferred embodiment, R 7 Is thatWherein R is 8 And R is 9 Independently selected from linear or branched C 1 -C 8 An alkyl group. In a preferred embodiment, R 7 Is->Wherein R is 8 And R is 9 Independently selected from linear or branched C 1 -C 3 An alkyl group. In a specific embodiment, R 7 Is->Wherein R is 8 And R is 9 Each independently selected from methyl, ethyl, propyl, butyl and pentyl. In a more specific embodiment, R 7 Is->Wherein R is 8 And R is 9 Each independently selected from methyl, ethyl and propyl. Such as methyl, ethyl, n-propyl, and isopropyl. In a particular embodiment, R 8 And R is 9 Is methyl.
In one embodiment, Z is selected from C, O, N. In a preferred embodiment, Z is C. In another preferred embodiment, Z is O. In yet another preferred embodiment, Z is N.
In one embodiment, Q, W is selected from C, N, respectively. In a preferred embodiment, Q is N. In a preferred embodiment, Q is C. In a preferred embodiment, W is C. In a preferred embodiment, W is N.
In one embodiment, straight or branched C 1 -C 8 Alkyl is selected from straight or branched chain C 1 -C 5 Alkyl and straight or branched C 1 -C 3 An alkyl group. In a particular embodiment, straight or branched C 1 -C 8 Alkyl, straight or branched C 1 -C 5 Alkyl and straight or branched C 1 -C 3 Alkyl groups are each independently selected from methyl, ethyl, propyl, butyl, pentyl and isopentyl. In a more specific embodiment, straight or branched C 1 -C 8 Alkyl, straight or branched C 1 -C 5 Alkyl and straight or branched C 1 -C 3 The alkyl groups are each independently selected from methyl, ethyl, propyl and butyl.
In one embodiment, the propyl group includes, but is not limited to, n-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Or isopropyl (i-Pr, -CH (CH) 3 ) 2 ). The butyl includes, but is not limited to, 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 ) Or tert-butyl (t-Bu, -C (CH) 3 ) 3 ). The pentyl group includes, but is not limited to, n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) Or 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 )。
In one embodiment, C 2 -C 8 Alkenyl group is C 2 -C 5 Alkenyl groups. In a specific embodiment, C 2 -C 8 Alkenyl and C 2 -C 5 Alkenyl groups are each independently selected from ethenyl, propenyl, butenyl and pentenyl. In a more preferred embodiment, C 2 -C 8 Alkenyl and C 2 -C 5 Alkenyl groups are each independently selected from ethenyl, propenyl, and butenyl.
In one embodiment, the propenyl group includes, but is not limited to, -CH 2 -CH＝CH 2 ，-CH＝CH-CH 3 . The butenyl groups include, but are not limited to, -CH 2 -CH 2 -CH＝CH 2 ，-CH 2 -CH＝CH-CH 3 ，-CH＝CH-CH 2 -CH 3 ，-CH＝C(CH 3 ) 2 ，-C(CH 3 )＝CHCH 3 ，-CH(CH 3 )CH＝CH 2 . The pentenyl groups include, but are not limited to, -ch=chch 2 CH 2 CH 3 ，-CH 2 CH＝CHCH 2 CH 3 ，-CH 2 CH 2 CH＝CHCH 3 ，-CH 2 CH 2 CH 2 CH＝CH 2 ，-C(CH 3 )＝CHCH 2 CH 3 ，-CH(CH 3 )CH＝CHCH 3 ，-CH(CH 3 )CH 2 CH＝CH 2 。
In one embodiment, C 2 -C 8 Alkynyl is C 2 -C 5 Alkynyl groups. In a specific embodiment, C 2 -C 8 Alkynyl and C 2 -C 5 Alkynyl groups are each independently selected from ethynyl, propynyl, butynyl and pentynyl. In a more specific embodiment, C 2 -C 8 Alkynyl and C 2 -C 5 Alkynyl groups are each independently selected from ethynyl, propynyl and butynyl.
In one embodiment, thePropynyl includes, but is not limited to, -H 2 C-C≡CH、-C≡C-CH 3 . The butynyl group includes, but is not limited to, -H 2 C-CH 2 -C≡CH、-H 2 C-C≡C-CH 3 、H 3 C-CH 2 -C≡C-. The pentynyl groups include, but are not limited to H 3 C-H 2 C-CH 2 -C≡C-、-H 2 C-H 2 C-C≡C-CH 3 、H 3 C-H 2 C-C≡C-CH 2 -、(H 3 C) 2 C-C≡C-。
In one embodiment, C 1 -C 8 Haloalkyl is C 1 -C 5 A haloalkyl group. In a specific embodiment, at C 1 -C 8 Haloalkyl and C 1 -C 5 In haloalkyl, C 1 -C 8 Alkyl or C 1 -C 5 Alkyl is substituted with 1, 2, 3 or 4 halogens. In a preferred embodiment, C 1 -C 8 Alkyl or C 1 -C 5 Alkyl is- (CH) 2 ) a CX 3 Wherein a is selected from 1, 2, 3, 4, 5, 6 and 7 and X represents halogen. In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine, iodine. In a preferred embodiment, a is selected from 1, 2, 3 and 4. In a preferred embodiment, the halogen is fluorine.
In one embodiment, the C 1 -C 8 Haloalkyl or C 1 -C 5 Haloalkyl includes, but is not limited to, -CF 3 ，-CCl 3 ，-CBr 3 ，-CI 3 ，-CH 2 CF 3 ，-CH 2 CCl 3 ，-CH 2 CBr 3 ，-CH 2 CI 3 ，-(CH 2 ) 2 CF 3 ，-(CH 2 ) 2 CCl 3 ，-(CH 2 ) 2 CBr 3 ，-(CH 2 ) 2 CI 3 Etc.
In one embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine. In a preferred embodiment, the halogen is selected from fluorine, chlorine and bromine. Such as fluorine, chlorine, bromine or iodine. In a specific embodiment, the halogen is fluorine.
In one embodiment, the phosphate or citrate salt of the compound of formula i, wherein n1, n2 are integers from 1 to 3; r is R 1 Is methyl; r2 is selected from fluorine and hydrogen; r is R 3 、R 4 、R 5 、R 6 Respectively selected from hydrogen, fluorine and chlorine; r is R 7 Selected from isopropyl, cyclopropyl, isobutyl, methyl,Z is selected from C, O, N; q, W are each selected from C, N.
The present invention provides a crystalline form I of a19006 citrate of formula IV, characterized in that Cu-ka radiation is used to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angles 2Θ ± 0.2 ° which shows characteristic peaks at 10.03, 12.62, 13.69, 14.68, 16.44, 17.19, 19.10, 20.27, 21.77, wherein each characteristic peak has an error range of 2Θ ± 0.2.
In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of form I shows characteristic peaks expressed in terms of 2θ±0.2° at 17.67, 19.57, 21.30, 23.78, 24.03, 25.57, 26.22, wherein each characteristic peak has an error range of 2θ of ±0.2.
In a preferred embodiment of the invention, the X-ray powder diffraction pattern of form I shows characteristic peaks expressed in degrees 2θ±0.2° at 5.42, 10.03, 11.10, 12.62, 13.69, 14.68, 16.44, 17.19, 17.67, 18.39, 19.10, 19.57, 20.27, 21.30, 21.77, 22.50, 23.78, 24.03, 25.57, 26.22, 27.65, 28.62, 30.29, 30.56, 31.67, 32.76, 33.62, 34.04, 34.88, 35.49, 36.33, 39.02, 39.69, wherein the error range of each characteristic peak 2θ is ±0.2°.
In a more preferred embodiment of the invention, the DSC melting endotherm peak of form I is selected from 164.7-170.0deg.C, preferably 167.7deg.C.
The beneficial technical effects of the invention
Compared with the prior art, the technical scheme of the invention has the following advantages:
the in vitro study results show that the compounds provided by the invention have substantially equivalent activity to pimecrin, but the compounds provided by the invention have lower 5-HT 2A 、5-HT 2C The Ki value of the receptor is obviously better than that of pimozide, which indicates that the compound provided by the invention is easier to combine with the receptor and has great clinical use value.
Experimental results show that the compounds provided by the invention act on 5-HT 2A 、5-HT 2C Receptors for 5-HT 2A Is superior or similar to pimecroline in its antipsychotic activity, comparable to pimecroline, less sedative and motor deterioration side effects than pimecroline, and less cardiotoxic than pimecroline.
Compared with the compound in the form of free alkali, the phosphate or citrate is beneficial to improving the solubility and the moisture absorption performance of the active substance, enhancing the bioavailability and the stability of the active substance, and the crystal form I of the A19006 citrate is stable at normal temperature, is beneficial to subsequent clinical development and production development, and has good clinical application prospect.
Description of the drawings:
FIG. 1 is an X-ray powder diffraction pattern of crystalline form I of citrate of compound A19006 of formula IV
FIG. 2 is a DSC chart of crystalline form I of citrate of compound A19006 of formula IV
FIG. 3 is a graph of voltage stimulation protocol for hERG potassium current in cells
Examples
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, the proportions, percentages, etc., referred to herein are by weight.
Synthetic examples
Example 1 preparation of Compounds of formula I
Prepared by the method described in the examples of patent application PCT/CN 2021/089660.
Examples 1-1, 2- (1-methylpiperidin-4-yl) -4- { [4- (2-methylpropyloxy) phenyl]Methyl } -1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19020):
the synthetic route is as follows:
preparation of 1-1.1 2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] benzyl alcohol:
1, 2-Benzenedimethanol (22.0 g,159.2 mmol), t-butyldimethylchlorosilane (24.0 g,159.2 mmol), triethylamine (16.1 g,159.2 mmol), DCM (200.00 mL) were added to a 500mL three-necked round bottom flask under nitrogen and stirred overnight at room temperature. Then quenched with water, extracted with 3X 100mL of DCM, then washed with 200mL of saturated brine, dried over anhydrous sodium sulfate in DCM phase, filtered with suction and concentrated to give 30g (yield 74.64%) of a colorless oil.
1-1.2 preparation of 2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] benzaldehyde:
2- [ [ (tert-Butyldimethylsilyl) oxy ] methyl ] benzyl alcohol (30.00 g,118.8 mmol), dess Martin (50.4 g,118.8 mmol), DCM (300 mL) were added to a 1L three port round bottom flask and reacted at room temperature under nitrogen for 4h, then quenched with water, extracted with 3X 100mL DCM, then washed with 200mL saturated brine, dried over anhydrous sodium sulfate in DCM phase, filtered with suction, concentrated, and chromatographed on ethyl acetate/petroleum ether (1/35) to give 17g (yield 58.62%) of a colorless oil.
1-1.3 preparation of [ (2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] phenyl) methyl ] ([ 4- (2-methylpropyloxy) phenyl ] methyl) amine:
2- [ [ (tert-butyldimethylsilyl) oxy]Methyl group]Benzaldehyde (1.00 g,3.9 mmol), 1- (4-isobutyl)Oxyphenyl) methylamine (0.66 g,3.9 mmol), mgSO 4 (0.1 g,0.83 mmol), etOH (10 mL) was added to a 50mL three-necked round-bottomed flask, purged with nitrogen and held, reacted at room temperature for 3h, then NaBH was added 4 (0.76 g,19.9 mmol) was stirred at room temperature for 1h. 30mL of water was added, followed by extraction with 3X 20mL of ethyl acetate, followed by washing with 30mL of saturated brine, drying over anhydrous sodium sulfate of ethyl acetate phase and concentration by suction filtration, to give 1.6g (yield 96.85%) of a colorless oil.
1-1.4 preparation of benzyl- [ N-2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] benzyl ] -N- [4- (2-methylpropyloxy) benzyl ] carbamate:
[ (2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] phenyl) methyl ] ([ 4- (2-methylpropyloxy) phenyl ] methyl) amine (1.6 g, 0.04 mol), tetrahydrofuran (5 mL) and water (5 mL), benzyl chloroformate (0.79 g,0.005 mol), potassium carbonate (1.08 g,0.008 mol) were added to a 50mL round-bottomed flask, stirred at 50℃for 2 hours, then water was added for 30mL, extracted with 3X 20mL ethyl acetate, followed by washing with 50mL saturated brine, and the ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated by suction filtration to give 2.27g of an oil.
1-1.5 preparation of benzyl- [ N-2- (hydroxymethyl) benzyl ] -N- [4- (2-methylpropyloxy) benzyl ] carbamate:
benzyl- [ N-2- [ [ (tert-butyldimethylsilyl) oxy ] methyl ] benzyl ] -N- [4- (2-methylpropyloxy) benzyl ] carbamate (2.27 g,4.14 mmol), dioxane (Dioxane) (20.00 mL), HCl (5.2 mL) were placed in a 50mL three-necked round bottom flask, purged with inert nitrogen and maintained. Stirring for 1h at room temperature. The reaction mixture was then concentrated and chromatographed on a 1/5 ethyl acetate/petroleum ether silica gel column to give 0.87g (yield 48.6%) of a colorless oil.
Preparation of 1-1.6 benzyl- [ N-2- (formylbenzyl) ] -N- [4- (2-methylpropyloxy) benzyl ] carbamate:
benzyl- [ N-2- (hydroxymethyl) benzyl ] -N- [4- (2-methylpropyloxy) benzyl ] carbamate (0.87 g,2.0 mmol), manganese dioxide (2.62 g,30.1 mmol), DCM (20 mL) was placed in a 50mL round bottom flask, warmed to 80℃and stirred overnight, then the solid was filtered off and the filtrate concentrated directly to give 0.75g (yield 86.61%) of an oil.
Preparation of 1-1.7 tert-butyl 4- [ [2- [ [ [ (benzyloxy) carbonyl ] (4-isobutoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate:
benzyl- [ N-2- (formylbenzyl)]-N- [4- (2-methylpropyloxy) benzyl group]Carbamate (0.75 g,1.74 mmol), 4-amino-1-t-butoxycarbonyl piperidine (0.42 g,2.08 mmol), magnesium sulfate (0.10 g,0.001 mmol), ethanol (10 mL) were added to a 50mL three-necked round bottom flask, purged with nitrogen and maintained, stirred at room temperature for 3h, and NaBH was added 4 (0.33 g,8.69 mmol) was stirred at room temperature for 1h, then 30mL of water was added, extracted with 3X 20mL of ethyl acetate, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate in ethyl acetate phase and concentrated by suction filtration to give 1.1g of oil.
Preparation of 1-1.8 t-butyl 4- [ [2- [ [ (4-isobutoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate:
Tert-butyl 4- [ [2- [ [ [ (benzyloxy) carbonyl ] (4-isobutoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate (1.1 g), palladium on carbon (0.1 g), methanol (5 mL), tetrahydrofuran (5 mL) were placed in a 50mL three-necked round bottom flask, hydrogen was introduced, stirring was performed at room temperature for 3h, then the solid was filtered off, and the filtrate was concentrated directly to give 0.65g of an oil.
1-1.9 2- (tert-Butoxycarbonylpiperidine) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
tert-butyl 4- [ [2- [ [ (4-isobutoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate (0.65 g,1.34 mmol) and tetrahydrofuran (10 mL) were added to a 50mL round-bottomed flask, purged with inert nitrogen and held, BTC (0.16 g,0.54 mmol) was added at-40℃and reacted for 1h with heat preservation, then water 30mL was added, extracted with 3X 20mL ethyl acetate, washed with 50mL saturated brine, and the ethyl acetate phase dried over anhydrous sodium sulfate and concentrated by suction to give 0.78g of oil.
1-1.10 2- (piperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
2- (tert-Butoxycarbonylpiperidine) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine3-Ketone (0.78 g,1.53 mmol), DCM (10 mL), HCl/dioxane 4M (0.22 g,1.6 mmol) was added to a 50mL round bottom flask and stirred at room temperature for 1h before the reaction was concentrated directly to give 0.66g of oil.
1-1.11 2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
2- (piperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine3-Ketone (0.66 g,1.6 mmol), formaldehyde (0.1 g,3.2 mmol), triethylamine (0.66 g,6.4 mmol), magnesium sulfate (0.02 g,0.16 mmol), methanol (10 mL) were added to a 50mL round bottom flask, stirred at room temperature for 3h, then NaBH was added 4 (0.31 g,8.1 mmol) was stirred at room temperature for 1h, then 30mL of water was added, extracted with 3X 20mL of ethyl acetate, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate of ethyl acetate phase and concentrated by suction filtration, and finally purified by Intel Flash-1 chromatography to give 11.6mg (yield 1.7%) of a pale yellow oil. 1 H NMR(400MHz,Methanol-d 4 )δ7.40-7.19(m,5H),7.03(d,J＝7.3Hz,1H),6.91–6.82(m,2H),4.51(s,2H),4.46(s,2H),4.41(s,2H),4.34(tt,J＝12.2,3.9Hz,1H),3.74(d,J＝6.5Hz,2H),3.64-3.56(m,2H),3.21-3.04(m,2H),2.91(s,3H),2.32-2.17(m,2H),2.07(dq,J＝13.3,6.6Hz,1H),1.97(t,J＝15.8Hz,2H),1.04(d,J＝6.7Hz,6H),LCMS(ES,m/z):422[M+H] + .
Examples 1-2: 7-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19001):
the synthetic route is as follows:
preparation of 1-2.1 2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-benzoic acid methyl ester:
methyl 2-cyano-5-fluorobenzoate (1.8 g,10.05 mmol), raney-Ni (0.5 g), boc 2 O(2.63g,12.06mmol)、NaHCO 3 (1.69 g,20.1 mmol) and THF (20 mL) were added to a 50mL three-necked round bottom flask, hydrogen was introduced, the mixture was stirred at 50℃for 48 hours, the reaction solution was filtered, and the filtrate was directly concentrated to obtain 2g (70.26%) of a solid.
Preparation of 1-2.2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-benzoic acid:
2- [ (tert-Butoxycarbonyl) aminomethyl group]-5-fluoro-benzoic acid methyl ester (2.0 g,7.06 mmol), sodium hydroxide (1.41 g,35.3 mmol), THF/H 2 O (10/10 mL) was placed in a 50mL three-necked round bottom flask, stirred overnight at room temperature, then adjusted to pH 5 with 3N HCl, extracted with 3X 20mL EA, washed with 30mL saturated brine, dried over anhydrous sodium sulfate and concentrated by suction to give 1.2g (yield 63.13%) of a solid.
Preparation of 1-2.3[ 4-fluoro-2- [ (4-isobutoxybenzyl) carbamoyl ] benzyl ] carbamic acid tert-butyl ester:
2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-benzoic acid (1.2 g,4.4 mmol), 4-isobutoxybenzylamine (0.88 g,4.9 mmol), HATU (2.2 g,5.8 mmol), DIEA (1.15 g,8.9 mmol), DMF (20 mL) were placed in a 50mL three-necked round bottom flask, stirred overnight at room temperature, then 30mL of water was added, extracted with 3X 20mL of EA, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate and concentrated by suction, ethyl acetate/petroleum ether (1/3) silica gel column chromatography to give 1g (yield 52.12%) of solid.
Preparation of 1-2.4 2- (aminomethyl) -5-fluoro-N- (4-isobutoxybenzyl) benzamide:
prepared according to the method of examples 1-1.10 to give 1g of oil.
Preparation of 1-2.5-fluoro-N- (4-isobutoxybenzyl) -2- [ [ (1-methylpiperidin-4-yl) amino ] methyl ] benzamide:
2- (aminomethyl) -5-fluoro-N- (4-isobutoxybenzyl) benzamide (1 g,3.02 mmol), 1-methylpiperidin-4-one (0.41 g,3.6 mmol), naBH 3 CN (0.38 g,6.05 mmol), etOH (10 mL) and HOAc (1 mL) were placed in a 50mL round bottom flask and stirred overnight at room temperature, then 30mL saturated NaHCO was added 3 The solution was extracted with 3X 20mL of EA, then washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, concentrated by suction filtration, and chromatographed on a dichloromethane/methanol (10/1) silica gel column to give 0.75g (yield 57.96%) of a solid.
Preparation of 1-2.6N- [ 4-fluoro-2- [ (4-isobutoxybenzyl) amino ] methyl ] benzyl } -1-methylpiperidin-4-amine:
5-fluoro-N- (4-isobutoxybenzyl) -2- [ [ (1-methylpiperidin-4-yl) amino]Methyl group]Benzamide (0.3 g,0.702 mmol), BH 3 THF (10.00 mL) was placed in a 50mL round bottom flask, stirred at reflux overnight, then quenched with 2N HCl, EA (30 mL) was added, the aqueous phase was extracted with EA (2X 20 mL), then the aqueous phase was adjusted to pH 10 with 15% NaOH solution, extracted with DCM, the solvent removed, and purified by reverse phase chromatography to give 0.1g (yield 34.46%) of a white solid.
1-2.7-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ] ]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 2.8mg (yield 2.63%) of a white solid. H-NMR (400 MHz, methanol-d) 4 ):δ7.34(dd,J＝8.4,5.4Hz,1H),7.25-7.17(m,2H),7.00(td,J＝8.6,2.7Hz,1H),6.91-6.82(m,2H),6.77(dd,J＝9.1,2.7Hz,1H),4.47(d,J＝15.2Hz,4H),4.39(s,2H),4.43–4.27(m,1H),3.74(d,J＝6.4Hz,2H),3.64-3.56(m,2H),3.21–3.10(m,2H),2.90(s,3H),2.32(dd,J＝13.4,4.0Hz,1H),2.25(dd,J＝13.1,4.1Hz,1H),2.06(dp,J＝13.3,6.7Hz,1H),1.95(d,J＝13.9Hz,2H),1.04(d,J＝6.7Hz,6H)；LCMS(ES,m/z):440[M+H] + .
Examples 1-3: 7-chloro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A190017):
the synthetic route is as follows:
preparation of 1-3.1 2- [ (tert-Butoxycarbonyl) aminomethyl ] -4-chloro-benzoic acid methyl ester:
prepared according to the method of example 1-2.1 to give 1.58g (103.10%) of a white solid.
Preparation of 1-3.2- [ (tert-Butoxycarbonyl) aminomethyl ] -4-chloro-benzoic acid:
prepared according to the method of example 1-2.2 to give 1.12g (74.37%) of a white solid.
Preparation of 1-3.3- [ (tert-Butoxycarbonyl) aminomethyl ] -4-chloro-4- (piperidine-1-carboxylic acid benzyl ester) benzamide:
prepared according to the method of examples 1-2.3 to give 2g (101.63%) of a yellow oil.
Preparation of 1-3.4 2- (aminomethyl) -4-chloro-4- (piperidine-1-carboxylic acid benzyl ester) benzamide:
prepared according to the method of examples 1-1.10 to give 2g (124.91%) of a white solid.
Preparation of 1-3.5 2- (2-methylpropyloxy) -benzylamine-4-chloro-4- (piperidine-1-carboxylic acid benzyl ester) benzamide:
prepared according to the method of examples 1-2.5 to give 1g (35.62%) of a yellow oil.
1-3.6 preparation of 2- (2-methylpropyloxy) -benzylamine-4-chloro-4- (piperidine-1-carboxylic acid benzyl ester) benzylamine:
prepared according to the method of examples 1-2.6 to give 0.22g (22.56%) of a yellow oil.
1-3.7-chloro-2- (piperidine-1-carboxylic acid benzyl ester) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.21g (yield 91.15%) of a yellow oil.
1-3.8-7-chloro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
7-chloro-2- (piperidine-1-carboxylic acid benzyl ester) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine3-Ketone (0.21 g,0.365 mmol), pd/C (77.58 mg,0.729 mmol), HCHO (43.78 mg,1.46 mmol), meOH (3 mL) were placed in a 50mL round bottom flask, stirred at room temperature for 10h, suction filtered, the filtrate concentrated and purified by preparative liquid chromatography to give 2.4mg (1.44% yield) of a white solid. 1 H NMR(400MHz,DMSO-d 4 )δ9.62(s,1H),7.33(dd,J＝8.0,2.2Hz,1H),7.28-7.18(m,6H),6.90-6.83(m,3H),4.37-4.30(m,8H),4.17(d,J＝12.6Hz,2H),3.72(d,J＝6.5Hz,3H),3.05(d,J＝10.8Hz,2H),2.76(d,J＝4.7Hz,4H),2.38(s,4H),2.18-2.08(m,3H),2.00(dt,J＝13.4,6.7Hz,1H),1.75(d,J＝13.3Hz,3H),1.24(s,1H),0.98(d,J＝6.7Hz,9H)；LCMS(ES,m/z):456[M+H] + .
Examples 1 to 4: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (A19005): />
The synthetic route is as follows:
preparation of 1-4.1-fluoro-2- [ [ (1-methylpiperidin-4-yl) carbamoyl ] benzyl ] carbamic acid tert-butyl ester:
Prepared according to the method of examples 1-2.3 to give 8g (84.21%) of an oil.
Preparation of 1-4.2- (aminomethyl) -5-fluoro-N- (1-methylpiperidin-4-yl) benzamide:
prepared according to the method of examples 1-1.10 to give 2g of oil.
Preparation of 1-4.3-fluoro-2- [ [ (4-isobutoxybenzyl) amino ] methyl ] -N- (1-methylpiperidin-4-yl) benzamide:
prepared according to the method of examples 1-2.5 to give 0.65g (20.17%) of a yellow oil.
Preparation of 1-4.4N- [ 5-fluoro-2- [ [ (4-isobutoxybenzyl) amino ] methyl ] benzyl ] -1-methylpiperidin-4-amine:
prepared according to the method of examples 1-2.6 to give 0.25g (12.31%) of a yellow oil.
1-4.5-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to yield 35mg (13.17% yield) of a white solid. H-NMR (400 MHz, methanol-d) 4 )δ7.24-7.17(m,2H),7.11(dd,J＝9.0,2.6Hz,1H),7.03(dd,J＝8.4,5.5Hz,1H),6.95(td,J＝8.6,2.6Hz,1H),6.90-6.83(m,2H),4.52 -4.36(m,7H),4.31(tt,J＝12.3,3.9Hz,1H),3.73(d,J＝6.5Hz,2H),3.60(d,J＝12.4Hz,2H),3.40(s,0H),3.15(t,J＝12.7Hz,2H),2.91(s,3H),2.25(qd,J＝13.3,4.0Hz,2H),2.06(dt,J＝13.3,6.6Hz,1H),1.96(d,J＝13.8Hz,2H),1.04(d,J＝6.7Hz,6H)；LCMS(ES,m/z):440[M+H] + .
Examples 1 to 5: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropylamino) phenyl ]]Methyl group]-1,5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (A19007): />
The synthetic route is as follows:
preparation of 1-5.1 2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-benzoic acid methyl ester:
prepared according to the method of example 1-2.1 to give 4.7g of oil.
Preparation of 1-5.2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-benzoic acid:
prepared according to the method of example 1-2.2 to give 4.0g (89.54%) of an oil.
Preparation of 1-5.3- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-N- (4- (piperidine-1-carboxylic acid benzyl ester)) benzamide was prepared according to the method of examples 1-2.3 to give 4.6g of oil.
Preparation of 1-5.4 2- (aminomethyl) -5-fluoro-N- (4- (piperidine-1-carboxylic acid benzyl ester)) benzamide:
prepared according to the method of examples 1-1.10 to give 5.6g of oil.
Preparation of benzyl 1-5.5- [2- [ (4-bromobenzamide) methyl ] -5-fluorobenzamide ] piperidine-1-carboxylate:
prepared according to the method of examples 1-2.3 to give 3.2g (38.75%) of a white solid.
Preparation of benzyl 1-5.6 4- [ 5-fluoro-2- [ [4- (isobutylamino) benzamide ] methyl ] benzamide ] piperidine-1-carboxylate:
4- [2- [ (4-bromobenzamide) methyl group]-5-fluorobenzamide]Benzyl piperidine-1-carboxylate (1 g,1.76 mmol), isobutyl amine (0.193 g,2.64 mmol), sodium tert-butoxide (0.34 g,3.52 mmol), ruphos (82.1 mg,0.176 mmol), pd 2 (dba) 3 (0.161 mg,0.176 mmol), toluene (13 mL) were placed in a 50mL round bottom flaskIn the above, the mixture was stirred at 80℃for 1h, filtered with suction, and the filtrate was concentrated and chromatographed on silica gel (PE/EA=3:1) to give 0.797g (yield 80.8%) of a yellow solid.
Preparation of benzyl 1-5.7 benzyl 4- [ [ 5-fluoro-2- [ [ (4- (isobutylamino) benzyl ] amino ] methyl ] benzyl (amino) piperidine-1-carboxylate:
prepared according to the method of 2.6 in example 2 to give 260mg of an off-white solid (34.33%).
1-5.8-fluoro-2- (piperidine-1-carboxylic acid benzyl ester) -4- [ [4- (2-methylpropylamino) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone: />
Prepared according to the method of examples 1-1.9 to give 0.26g of oil.
1-5.9-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropylamino) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 4.1mg (yield 2.61%) of a white solid. 1 H NMR(400MHz,Methanol-d 4 )δ8.48(s,1H,FA),7.10-6.98(m,4H),6.93(td,J＝8.6,2.7Hz,1H),6.58(d,2H),4.42(s,4H),4.36(s,2H),4.30-4.18(m,1H),3.46-3.39(m,2H),2.96-2.83(m,4H),2.77(s,3H),2.25-2.05(m,2H),1.96-1.84(m,3H),1.36-1.30(m,1H),0.99(d,J＝6.6Hz,6H)；LCMS(ES,m/z):439[M+H] + .
The compounds A19006, A19008, A19009, A19011, A19012 and A19015 have the following synthetic formulas:
examples 1 to 6: 7-fluoro-2- [ (4-cyclopropoxyphenyl) methyl]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (a 19006):
preparation of 1-6.1 2- [ (tert-Butoxycarbonyl) aminomethyl ] -5-fluoro-N- (4- (piperidine-1-carboxylic acid benzyl ester)) benzamide:
prepared according to the method of examples 1-2.3 to give 2.3g (63.77%) of a yellow solid.
Preparation of benzyl 1-6.2- [2- (aminomethyl) -5-fluorobenzamido ] piperidine-1-carboxylate hydrochloride:
Prepared according to the method of examples 1-1.10 to give 1.9g of oil.
Preparation of benzyl 1-6.3- [2- [ [ (4-cyclopropoxybenzyl) amino ] methyl ] -5-fluorobenzamido ] piperidine-1-carboxylate:
prepared according to the method of examples 1-1.7 to give 1.3g of oil.
Preparation of benzyl 1-6.4- [2- [ [ (4-cyclopropoxybenzyl) amino ] methyl ] -5-fluorobenzylamino ] piperidine-1-carboxylate:
prepared according to the method of examples 1-2.6 to give 0.23g (18.17%) of a yellow oil.
1-6.5 4- [4- (4-cyclopropoxybenzyl) -8-fluoro-3-oxo-1, 3,4, 5-tetrahydro-2H-benzo [ e ]][1,3]Dinitrogen-2-yl]Preparation of piperidine-1-carboxylic acid benzyl ester:
prepared according to the method of examples 1-1.9 to give 0.2g of oil.
1-6.6-fluoro-2- [ (4-cyclopropoxyphenyl) methyl]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 37.9mg (yield 24.32%) of a brown solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.30-7.19(m,3H),7.11(dd,J＝8.4,5.7Hz,1H),7.05-6.94(m,3H),4.36(d,J＝7.1Hz,4H),4.29(s,2H),3.96(tt,J＝11.4,4.0Hz,1H),3.80(tt,J＝6.0,3.0Hz,1H),2.86-2.78(m,2H),2.16(s,3H),1.95-1.85(m,2H),1.89-1.75(m,2H),1.45(dd,J＝11.0,3.9Hz,2H),0.81-0.67(m,2H),0.67-0.59(m,2H)；LCMS(ES,m/z):424[M+H] + .
Examples 1 to 7: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19008):
preparation of benzyl 1-7.1- [ 5-fluoro-2- [ (4-isobutylbenzyl) amino ] methyl ] benzamide ] piperidine-1-carboxylate:
prepared according to the method of examples 1-1.7 to give 2.3g (yield 61.76%) of a yellow oil.
Preparation of benzyl 1-7.2 4- [ [ 5-fluoro-2- [ (4-isobutylbenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate:
prepared according to the method of examples 1-2.6 to give 0.69g of a yellow oil.
1-7.3-fluoro-2- (4- (piperidine-1-carboxylic acid benzyl ester)) -4- [ [4- (2-methylpropyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.7g of a yellow oil.
1-7.4-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [4- (2-methylpropyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 21mg (yield 3.85%) of a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),7.23-6.96(m,7H),4.43(d,J＝7.8Hz,4H),4.34(s,3H),3.86(s,1H),3.45-3.37(m,2H),3.17(s,1H),3.11-2.95(m,2H),2.71(d,J＝4.8Hz,3H),2.44-2.27(m,4H),1.80(dp,J＝13.5,6.8Hz,1H),1.72-1.59(m,2H),0.85(d,J＝6.6Hz,6H)；LCMS(ES,m/z):424[M+H] + .
Examples 1 to 8: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ (4-methoxyphenyl) methyl]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (a 19009): />
Preparation of benzyl 1-8.1- [ 5-fluoro-2- [ [ (4-methoxybenzyl) amino ] methyl ] benzamide ] piperidine-1-carboxylate:
prepared according to the method of examples 1-1.7 to give 0.48g of a yellow oil.
Preparation of benzyl 1-8.2- [ 5-fluoro-2- [ [ (4-methoxybenzyl) amino ] methyl ] benzyl ] aminopiperidine-1-carboxylate:
prepared according to the method of examples 1-2.6 to give 0.13g of a yellow oil.
1-8.3-fluoro-2- (4- (piperidine-1-carboxylic acid benzyl ester)) -4- [ (4-methoxyphenyl) methyl ]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.09g of a yellow oil.
1-8.4-fluoro-2- (1-methylpiperidin-4-yl) -4- [ (4-methoxyphenyl) methyl]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 9mg (yield 13.2%) of a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.25(dd,J＝11.0,7.5Hz,3H),7.10(dd,J＝8.5,5.7Hz,1H),7.01(td,J＝8.7,2.7Hz,1H),6.87(d,J＝8.4Hz,2H),4.36(d,J＝7.2Hz,4H),4.28(s,2H),4.03 -3.92(m,1H),3.73(s,3H),2.85(d,J＝9.8Hz,2H),2.20(s,3H),1.96(s,2H),1.91-1.77(m,2H),1.46(d,J＝11.2Hz,2H)；LCMS(ES,m/z):398[M+H] + .
Examples 1 to 9: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [ (2-fluoro-4-isopropoxy) phenyl]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19011):
preparation of benzyl 1-9.1- [ 5-fluoro-2- [ (2-fluoro-4-isopropoxybenzyl) amino ] methyl ] benzamide ] piperidine-1-carboxylate:
prepared according to the method of examples 1-1.7 to give 0.88g of a yellow oil.
Preparation of benzyl 1-9.2- [ 5-fluoro-2- [ (2-fluoro-4-isopropoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate:
prepared according to the method of examples 1-2.6 to give 0.117g of a yellow oil.
1-9.3-fluoro-2- (4- (piperidine-1-carboxylic acid benzyl ester)) -4- [ [ (2-fluoro-4-isopropoxy) phenyl [ (methyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.09g of a yellow oil.
1-9.4-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [ (2-fluoro-4-isopropoxy) phenyl ]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 5.3mg (yield 7.5%) of an orange solid. 1 H NMR(400MHz,DMSO-d 6 )δ9.54(s,1H),7.22-7.00(m,4H),6.76(dd,J＝12.4,2.5Hz,1H),6.69(dd,J＝8.5,2.5Hz,1H),4.60(p,J＝6.0Hz,1H),4.42(s,2H),4.36(d,J＝16.6Hz,4H),2.76(d,J＝4.7Hz,3H),2.14-2.04(m,1H),1.74(d,J＝14.9Hz,2H),1.25(d,J＝5.9Hz,7H)；LCMS(ES,m/z):444[M+H] + .
Examples 1 to 10: 8-fluoro-2- (1-methylpiperidin-4-yl) -4- { [ (3-fluoro-4-isopropoxy) phenyl]Methyl } -1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19012):
preparation of benzyl 1-10.1- [ 5-fluoro-2- [ (3-fluoro-4-isopropoxybenzyl) amino ] methyl ] benzamide ] piperidine-1-carboxylate:
prepared according to the method of examples 1-1.7 to give 1.0g of a yellow oil.
Preparation of benzyl 1-10.2- [ 5-fluoro-2- [ (3-fluoro-4-isopropoxybenzyl) amino ] methyl ] benzyl ] amino ] piperidine-1-carboxylate:
prepared according to the method of examples 1-2.6 to give 0.118g of a yellow oil.
1-10.3-fluoro-2- (4- (piperidine-1-carboxylic acid benzyl ester)) -4- [ [ (3-fluoro-4-isopropoxy) phenyl [ (l-methyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.11g of a yellow oil.
1-10.4-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [ (3-fluoro-4-isopropoxy) phenyl]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 4.3mg (yield 4.9%) of a yellow oil. 1 H NMR(400MHz,DMSO-d 6 )δ9.16(s,1H),7.18(dd,J＝8.3,5.6Hz,1H),7.15-7.01(m,5H),4.58(p,J＝6.0Hz,1H),4.40-4.32(m,6H),4.16(s,1H),2.78(d,J＝4.4Hz,3H),2.44(s,12H),2.05(q,J＝12.9,12.3Hz,2H),1.78(d,J＝13.5Hz,2H),1.27(d,J＝6.0Hz,6H),1.24(s,1H)；LCMS(ES,m/z):444[M+H] + .
Examples 1 to 11: 7-fluoro-2- [ (6-isopropoxypyridin-3-yl) methyl ]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (A19013):
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the synthetic route is as follows:
preparation of 1-11.1 2- [ (6-isopropoxypyridin-3-yl) ] -methyl-amino-methyl-5-fluoro-4- (piperidine-1-carboxylic acid benzyl ester) benzamide:
prepared according to the method of examples 1-1.7 to give 2.4g of a yellow oil.
1-11.2 preparation of 2- [4- (4-isopropoxypyridin-3-yl) ] -methyl-amino-methyl-5-fluoro-4- (piperidine-1-carboxylic acid benzyl ester) benzylamine:
prepared according to the method of examples 1-2.6 to give 0.38g of a yellow oil.
1-11.3-fluoro-2- (4- (piperidine-1-carboxylic acid benzyl ester)) -4- [ [ (6-isopropoxy) pyridin-3-yl]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.37g of a yellow oil.
1-11.4-8-fluoro-2- (1-methylpiperidin-4-yl) -4- [ [ (6-isopropoxy) pyridin-3-yl]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 50.6mg (yield 17.3%) of a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ 1 H NMR(400MHz,DMSO-d 6 )δ8.09(s,1H),7.62(d,J＝8.6Hz,1H),7.27(d,J＝9.3Hz,1H),7.15(t,J＝7.1Hz,1H),7.02(t,J＝8.3Hz,1H),6.67(d,J＝8.6Hz,1H),5.21(dt,J＝13.0,6.6Hz,1H),4.39-4.31(m,6H),3.98(d,J＝12.3Hz,1H),2.82(d,J＝10.3Hz,2H),2.17(s,3H),1.88(dt,J＝28.7,12.2Hz,4H),1.48-1.40(m,2H),1.27(d,J＝6.1Hz,6H)；LCMS(ES,m/z):427[M+H] + .
Examples 1 to 12: 8-fluoro-2- (1-methylpyrrolidin-3-yl) -4- [ [ (4-isobutoxy) phenyl group]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-ketone (a 19015):
preparation of 1-12.1 2- [ (4-isobutoxyphenyl-3-yl) ] -methyl-amino-methyl-5-fluoro-4- (pyrrole-1-carboxylic acid benzyl ester) benzamide:
Prepared according to the method of examples 1-1.7 to give 3.3g of a yellow oil.
1-12.2 preparation of 2- [4- (4-isobutoxyphenyl-3-yl) ] -methyl-amino-methyl-5-fluoro-4- (piperidine-1-carboxylic acid benzyl ester) benzylamine:
prepared according to the method of examples 1-2.6 to give 0.32g of a colorless oil.
1-12.3-fluoro-2- (3- (pyrrole-1-carboxylic acid benzyl ester)) -4- [ [ (4-isobutoxy) phenyl group]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.31g of a yellow oil.
1-12.4-fluoro-2- (1-methylpyrrolidin-3-yl) -4- [ [ (4-isobutoxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-3.8 to give 47.3mg (yield 18.6%) of a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ 1 H NMR(400MHz,DMSO-d 6 )δ8.53(s,1H),7.23-7.17(m,2H),7.09(dd,J＝9.0,2.6Hz,1H),7.02(dd,J＝8.3,5.5Hz,1H),6.94(td,J＝8.6,2.6Hz,1H),6.89-6.82(m,2H),4.67-4.28(m,7H),3.73(d,J＝6.4Hz,2H),3.70-3.55(m,2H),3.28(dd,J＝11.9,8.8Hz,1H),3.04(td,J＝10.5,8.2Hz,1H),2.87(s,3H),2.55-2.43(m,1H),2.15(ddt,J＝13.6,8.8,4.6Hz,1H),2.05(dq,J＝13.3,6.7Hz,1H),1.04(d,J＝6.7Hz,6H)；LCMS(ES,m/z):426[M+H] + .
The synthetic formulas of the compounds A19014-0 and A19014-0A are shown as follows:
examples 1 to 13: (3R, 4S) -8-fluoro-2- (1-methyl-3-fluoropiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19014-0):
preparation of 1-13.1-amino-3-fluoropiperidine-1-carboxylic acid benzyl ester:
benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (2 g,7.9 mmol), acetamide (2.35 g,39.8 mmol), naBH 3 CN (1 g,15.9 mmol) and methanol (10 mL) were placed in a 25mL three-necked round-bottomed flask, purged with nitrogen, the reaction was allowed to proceed overnight at room temperature, and after completion of the reaction, the mixture was extracted with EtOAc (3X 30 mL), washed with brine (2X 20 mL), and dried over Na 2 SO4 was dried, filtered, and the filtrate was concentrated under reduced pressure, and chromatographed on a silica gel column of ethyl acetate/petroleum ether (1:1) system to give 0.7g (yield 34.86%) of a colorless oil.
Preparation of benzyl 1-13.2- [2- [ [ (tert-butoxycarbonyl) amino ] methyl ] -5-fluorobenzamido ] -3-fluoropiperidine-1-carboxylate:
prepared according to the method of examples 1-2.3 to give 1.3g of oil.
Preparation of 1-13.3 benzyl 4- [2- (aminomethyl) -5-fluorobenzamide ] -3-fluoropiperidine-1-carboxylate:
prepared according to the method of examples 1-1.10 to give 1g of a pale yellow oil.
Preparation of benzyl 1-13.4-fluoro-4- [ 5-fluoro-2- [ [ [4- (2-methylpropyloxy) phenyl ] methyl ] methylamino } benzamide-piperidine-1-carboxylate:
prepared according to the method of examples 1-2.5 to give 0.6g (42.8%) of a yellow oil.
Preparation of 1-13.5-fluoro-4- [ 5-fluoro-2- [ [4- (2-methylpropyloxy) benzyl ] methylamino ] benzylamino-piperidine-1-carboxylic acid benzyl ester:
prepared according to the method of examples 1-2.6 to give 0.23g (18.32%) of a yellow oil.
1-13.6-fluoro-2- (3-fluoropiperidine-1-carboxylic acid benzyl ester) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared according to the method of examples 1-1.9 to give 0.13g (yield 88.7%) of a colorless oil.
1-13.7 (3R, 4S) -8-fluoro-2- (1-methyl-3-fluoropiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
prepared by the experimental method of reference examples 1-3.8 and then obtained 18.1mg (17.03% yield) of a yellow solid by Flash-Prep-HPLC. 1 H NMR(400MHz,Methanol-d 4 )δ7.23-7.18(m,2H),7.13(dd,J＝9.0,2.6Hz,1H),7.00(dd,J＝8.4,5.5Hz,1H),6.93(td,J＝8.6,2.6Hz,1H),6.88-6.84(m,2H),4.85-4.77(m,1H),4.71(d,J＝5.1Hz,1H),4.59-4.40(m,5H),4.35-4.21(m,2H),3.74(d,J＝6.5Hz,2H),3.26(dt,J＝10.5,5.3Hz,0H),2.98 2.84(m,1H),2.38(s,3H),2.221.90(m,4H),1.87 1.71(m,1H),1.04(d,J＝6.7Hz,6H)；LCMS(ES,m/z):458[M+H] + .
Examples 1 to 14: (3S, 4S) -8-fluoro-2- (1-methyl-3-fluoropiperidin-4-yl) -4- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19014-0A):
84mg (yield 74.25%) of a colorless oil was obtained by referring to the experimental method in examples 1-13. 1 H NMR(400MHz,Methanol-d 4 )δ7.22(d,J＝8.5Hz,2H),7.07(dd,J＝9.1,2.7Hz,1H),7.01(dd,J＝8.4,5.5Hz,1H),6.93(td,J＝8.6,2.7Hz,1H),6.89–6.84(m,2H),4.80-4.19(m,8H),3.74(d,J＝6.5Hz,2H),3.24-3.11(m,1H),3.03(d,J＝11.5Hz,1H),2.49-2.17(m,6H),2.06(dt,J＝13.3,6.6Hz,1H),1.60(d,J＝12.4Hz,1H),1.09-0.99(m,6H)；LCMS(ES,m/z):458[M+H] + .
Examples 1 to 15:7, 8-difluoro-2- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -1,2,4, 5-tetrahydro-3H-benzo [ e][1,3]DinitrogenPreparation of 3-Ketone (A20001):
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51.9mg of a white solid was obtained by the experimental method in reference example 1-1. 1 H NMR(400MHz,Methanol-d 4 )δ7.34(dd,J＝10.0,8.4Hz,1H),7.20(d,J＝8.4Hz,2H),6.92(dd,J＝10.0,8.4Hz,1H),6.90–6.82(m,2H),4.47(d,J＝14.0Hz,4H),4.36(s,2H),4.40–4.28(m,1H),3.73(d,J＝6.5Hz,2H),3.60(d,J＝12.2Hz,2H),3.21–3.11(m,2H),2.90(s,3H),2.35(dd,J＝13.5,3.8Hz,1H),2.29(dd,J＝13.1,3.8Hz,1H),2.05(hept,J＝6.7Hz,1H),1.94(d,J＝13.6Hz,2H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):458[M+H] + 。
Examples 1 to 16: 7-fluoro-2- [ [4- (2-hydroxy-2-methylpropyl) phenyl ]]Methyl group]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepine-3-onesPreparation (a 19010):
the synthetic route is as follows:
1-16.1 benzyl 4- [4- [ (4-bromophenyl) methyl ]]-8-fluoro-3-oxo-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Preparation of piperidine-1-carboxylic acid ester:
prepared according to the methods described in examples 1-4 to give 1g of a pale yellow oil.
1-16.2 benzyl 4- [4- ([ 4- [ (E) -2-ethoxyvinyl) ethyl ]]Phenyl group]Methyl) -8-fluoro-3-oxo-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Preparation of piperidine-1-carboxylic acid ester:
benzyl 4- [4- [ (4-bromophenyl) methyl ] was separately introduced into a 100ml three-necked flask]-8-fluoro-3-oxo-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Piperidine-1-carboxylic acid ester (1.00 g,1.765 mmol), (E) -1-ethoxyvinyl-2-boronic acid pinacol ester (0.70 g,3.531 mmol), dioxane (10.00 mL), water (2.00 mg) and K 3 PO 4 (1.12 g,5.296 mmol) and the resulting solution was stirred at 25℃for 10 minutes, pd (dppf) Cl was added thereto 2 (0.14 g,0.177 mmol) was heated to 100deg.C and reacted for 2 hours. After completion of the reaction, the system was quenched with water, extracted with ethyl acetate (3×20 mL), the organic phase was washed with 1N hydrochloric acid solution (2×20 mL), then with saturated brine (2×20 mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under pressure, and the mixture was purified by column chromatography (EA: pe=1:30) to give benzyl 4- [4- ([ 4- [ (E) -2-ethoxyvinyl) as a compound]Phenyl group]Methyl) -8-fluoro-3-oxo-1, 5-dihydro-2, 4-benzenediazepine>-2-yl]Piperidine-1-carboxylic acid ester 400mg, yield 40.63% as brown oil. />
1-16.3 4- (8-fluoro-3-oxo-4- [ [4- (2-oxoethyl) phenyl)]Methyl group ]-1, 5-dihydro-2, 4-benzodiazepine-2-yl) preparation of benzyl piperidine-1-carboxylate:
to 50mL three-necked flasks were added benzyl 4- [4- ([ 4- [ (E) -2-ethoxyvinyl) respectively]Phenyl group]Methyl) -8-fluoro-3-oxo-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Piperidine-1-carboxylic acid ester (200.00 mg, 0.259 mmol), tetrahydrofuran (2.00 mL) and HCl (6M) (2.00 mL) were stirred at 25℃for 2 hours. After the completion of the reaction, the reaction was quenched with water, extracted with methyl t-butyl ether (3X 10 mL), the organic phase was washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the compound 4- [ 8-fluoro-3-oxo-4- [ [4- (2-oxoethyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzenediazepine +.>-2-yl]Benzyl piperidine-1-carboxylate 200mg, yield 105.30%, yellow oil.
1-16.4 benzyl-4- [ 8-fluoro-4- [ [4- (2-hydroxypropyl) phenyl ]]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine-2-yl]Preparation of piperidine-1-carboxylic acid ester:
to a 50mL three-necked flask was added 4- (8-fluoro-3-oxo-4- [ [4- (2-oxoethyl) phenyl ] respectively]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-benzyl 2-yl) piperidine-1-carboxylate (200.00 mg,0.378 mmol) and tetrahydrofuran (3.00 mL), cooled to 0deg.C and stirred for 5 min, to which methyl magnesium bromide (180.12 mg,1.511 mmol) was added and warmed to 60deg.C for 2 h. After the reaction is completed, NH is used 4 Cl solution quenching reactionExtraction with ethyl acetate (3X 20 mL), washing the organic phase with 20mL of saturated brine, drying over anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to give the compound benzyl-4- [ 8-fluoro-4- [ [4- (2-hydroxypropyl) phenyl)]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine ∈>-2-yl]Piperidine-1-carboxylic acid ester 200mg, yield 97.06%, yellow oil.
1-16.5 benzyl-4- [ 8-fluoro-3-oxo-4- [ [4- (2-oxopropyl) phenyl ]]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Preparation of piperidine-1-carboxylic acid ester:
to a 50mL three-necked flask was added benzyl-4- [ 8-fluoro-4- [ [4- (2-hydroxypropyl) phenyl ] respectively]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine-2-yl]Piperidine-1-carboxylate (200.00 mg,0.367 mmol) and dichloromethane (20.00 mL), nitrogen protection, cooling to 0deg.C, stirring for 5 min, adding DMP (310.92 mg,0.733 mmol), and stirring at 25deg.C for 3 hr. After the reaction is finished, naHCO is added 3 The reaction was quenched, extracted with dichloromethane (3X 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the compound benzyl 4- [ 8-fluoro-3-oxo-4- [ [4- (2-oxypropyl) phenyl]Methyl group]-1, 5-dihydro-2, 4-benzenediazepine +.>-2-yl]Piperidine-1-carboxylic acid ester 180mg, yield 90.33%, yellow oil.
1-16.6 benzyl-4- [ 8-fluoro-4- [ [4- (2-hydroxy-2-methylpropyl) phenyl ]]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine-2-yl]Preparation of piperidine-1-carboxylic acid ester:
to a 50mL three-necked flask was added benzyl-4- [ 8-fluoro-3-oxo-4- [ [4- (2-oxypropyl) phenyl ] respectively]Methyl group]-1, 5-dihydro-2, 4-benzodiazepine-2-yl]Piperidine-1-carboxylate (150.00 mg,0.276 mmol), tetrahydrofuran (5.00 mL,0.069 mmol) and MeMgBr (2.00 mL,0.017 mmol), under nitrogen, was reacted at 60℃for 3 hours. After the reaction is completed, NH is used 4 The reaction was quenched with Cl solution, extracted with ethyl acetate (3X 10 mL), the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the compound benzyl-4- (8-fluoro-4- [ [4- (2-hydroxy-2-methylpropyl) phenyl)]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine ∈>-2-yl) piperidine-1-carboxylate 140mg, yield 90.66%, yellow oil.
1-16.7-fluoro-2- [ [4- (2-hydroxy-2-methylpropyl) phenyl ]]Methyl group]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepine-preparation of 3-ketone:
to a 100mL three-necked flask was added benzyl-4- [ 8-fluoro-4- [ [4- (2-hydroxy-2-methylpropyl) phenyl ] respectively]Methyl group]-3-oxo-1, 5-dihydro-2, 4-benzenediazepine-2-yl]Piperidine-1-carboxylic acid ester (150.00 mg,0.268 mmol), methanol (10.00 mL,246.989 mmol), formaldehyde (2.00 mL,0.067 mmol) and Pd (OH) 2 Per C (20.00 mg,0.142 mmol), hydrogen gas was introduced into the reaction system, stirred at 25℃for 5 hours, quenched with water, extracted with ethyl acetate (3X 10 mL), the organic phase was washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and purified by column chromatography (DCM: meOH=30:1) to give the compound 7-fluoro-2- [ [4- (2-hydroxy-2-methylpropyl) phenyl]Methyl group]-4- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzenediazepine>45mg of 3-keto, yield 38.19%, yellow oil. 1 H NMR(400MHz,Methanol-d 4 )δ8.48(s,1H,FA),7.10–6.98(m,4H),6.93(td,J＝8.6,2.7Hz,1H),6.58(d,2H),4.42(s,4H),4.36(s,2H),4.30–4.18(m,1H),3.46–3.39(m,2H),2.96–2.83(m,4H),2.77(s,3H),2.25–2.05(m,2H),1.96–1.84(m,3H),1.36–1.30(m,1H),0.99(d,J＝6.6Hz,6H).LCMS(ES,m/z):400[M+H] + 。
Examples 1 to 17:4- [ (4-Cyclopropoxyphenyl) methyl group]-7-fluoro-2- (1-methylpiperidin-4-yl) -1, 5-dihydro-2, 4-benzodiazepinePreparation of 3-Ketone (A19022):
9.5mg of a white solid was obtained by the experimental method in reference example 1-2. 1 H-NMR(400MHz,Chloroform-d):δ7.25(d,J＝8.5Hz,2H),7.15(t,J＝7.0Hz,1H),7.04–6.97(m,2H),6.90(td,J＝8.4,2.6Hz,1H),6.65(dd,J＝9.1,2.6Hz,1H),4.45(s,2H),4.40(s,2H),4.25(s,3H),3.74(p,J＝4.5Hz,1H),3.03(s,2H),2.42–2.38(m,3H),2.22(s,2H),1.99(s,2H),1.73(d,J＝12.5Hz,2H),0.78(d,J＝4.5Hz,4H).LCMS(ES,m/z):424[M+1] + 。
EXAMPLE 2 preparation of salts of the Compounds of formula I
Dissolving the free alkali of the compound shown in the general formula I in an organic solvent to form a solution, optionally dissolving acid in the organic solvent, dripping the organic solvent-acid solution into the free alkali solution of the compound shown in the general formula I, stirring, separating and drying to obtain the salt of the compound shown in the general formula I; the organic solvents include, but are not limited to, absolute ethanol, ethyl acetate, and the like; the acids include, but are not limited to, phosphoric acid, citric acid, and the like.
The following is exemplified only by a19006, and it will be understood by those skilled in the art that the other example compounds described above can also be prepared, characterized, and identified with reference to example 2.
Preparation of the phosphate salt of A19006, example 2-1
The preparation method comprises the following steps: about 5.2g of A19006 base sample is weighed into a 250mL single-neck flask, 100mL of ethyl acetate is added,stirring until the mixture is fully dissolved; 1.4g of phosphoric acid (85%) is weighed and dissolved in 20mL of ethyl acetate, and the ethyl acetate-phosphoric acid solution is slowly added dropwise under stirring; after 1h, the dripping is finished, stirring is continued for 1h at room temperature, and the reaction is stopped; the mixture was filtered under reduced pressure, the filter cake was washed with ethyl acetate (2X 20 ml), and dried in vacuo at 45℃for 3 hours to give A19006 phosphate, 6.0g, yield: 93.7 percent, 1 H NMR(400MHz,DMSO-d 6 )δ7.33(dd,J＝9.3,2.7Hz,1H),7.23(d,J＝8.3Hz,2H),7.10(dd,J＝8.4,5.7Hz,1H),7.04–6.94(m,3H),4.44(s,2H),4.38(s,2H),4.30(s,2H),4.19–4.28(m,1H),3.79(tt,J＝6.1,3.0Hz,1H),3.23(d,J＝11.5Hz,2H),2.85–2.64(m,2H),2.56(s,3H),2.26(qd,J＝13.1,4.1Hz,2H),1.58(dd,J＝13.1,3.8Hz,2H),0.80–0.72(m,2H),0.63(q,J＝3.4,2.9Hz,2H)。
examples 2-2, preparation of A19006 citrate
The preparation method comprises the following steps: weighing about 10g of A19006 base sample into a 500mL single-neck flask, adding 200mL of absolute ethyl alcohol, and stirring until the absolute ethyl alcohol is fully dissolved; weighing 5.0g of anhydrous citric acid, dissolving in 40mL of absolute ethyl alcohol, slowly dropwise adding the absolute ethyl alcohol-citric acid solution under the condition of stirring, and precipitating a large amount of white solids suddenly along with the process of dropwise adding; after 1h, transferring the flask to an ice water bath for cooling, and continuously stirring to precipitate a solid; filtering under reduced pressure, washing the filter cake with absolute ethanol (2×40 ml), and vacuum drying at 45deg.C for 3 hr to obtain A19006 citrate. Yield: 12.3g; yield: 84.6 percent, 1 H NMR(400MHz,DMSO-d 6 )δ7.24(d,J＝8.4Hz,2H),7.11–7.21(m,2H),7.00–7.07(m,1H),6.98(d,J＝8.3Hz,2H),4.38(s,4H),4.32(s,2H),4.18(tt,J＝12.2,4.0Hz,1H),3.80(tt,J＝6.0,2.9Hz,1H),3.31(d,J＝11.8Hz,2H),2.93–2.78(m,2H),2.66(d,J＝2.8Hz,3H),2.09(qd,J＝13.0,4.0Hz,2H),1.66(dd,J＝13.7,3.8Hz,2H),0.81–0.73(m,2H),0.63(q,J＝3.4,3.0Hz,2H)。
The obtained A19006 citrate is detected, the X-ray powder diffraction is shown in figure 1, the DSC spectrum is shown in figure 2, the starting point of the endothermic peak is 164.7 ℃, the ending point is 170.0 ℃ and the peak is 167.7 ℃ in the DSC heating process. This form was defined as form I, and the characteristic peak positions are shown in table 1 below:
TABLE 1X-ray powder diffraction
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Test case
Test example 1 salt type moisture permeability test
Reference is made to the guiding principle of the drug hygroscopicity test of the fourth portion 9103 of the pharmacopoeia of China in 2020.
The experimental method comprises the following steps:
(1) The dry glass weighing bottle with plug (outer diameter 50mm, height 15 mm) is placed in a proper constant temperature dryer (ammonium chloride or ammonium sulfate saturated solution is placed at the lower part) at 25+/-1 ℃ or a climatic chamber (set temperature is 25+/-1 ℃ and relative humidity is 80% +/-2%) at the temperature of 25+/-1 ℃ before the test, and the weight (m 1) is precisely weighed.
(2) And (3) a proper amount of a test sample is taken and paved in the weighing bottle, the thickness of the test sample is generally about 1mm, and the weight (m 2) is precisely weighed.
(3) The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
(4) The lid of the weighing flask was closed, and the weight (m 3 )。
Experimental results: the specific experimental results are shown in Table 2.
Table 2A19006 salt type results of moisture permeability measurement
Conclusion: as can be seen from the above table, the a19006 phosphate has low hygroscopicity.
Test example 2 solubility test
Reference is made to the fourth part of the pharmacopoeia of China in 2020.
The experimental method comprises the following steps: weighing the test substance ground into fine powder or measuring liquid test substance, shaking strongly at 25+ -2deg.C for 30 seconds every 5 minutes, and observing dissolution within 30 minutes, such as completely dissolving solute particles or liquid drops without visual observation.
Experimental results: the specific experimental results are shown in Table 3.
Table 3a19006 salt solubility
Conclusion: as can be seen from the above table, the A19006 citrate was dissolved in the pH1 solution and slightly dissolved in the pH7 solution.
Test example 3 stability test
The experimental method comprises the following steps:
(1) High humidity experiment
Samples of form I of the citrate salt of a19006 were placed in clean petri dishes, left for 30 days at 92.5% relative humidity, 25 ℃ or 75% ± 1% relative humidity, room temperature, and sampled on days 0, 30. XRPD, DSC, HPLC analysis was performed.
(2) Illumination experiment
Samples of form I of A19006 citrate were placed in clean petri dishes, tiled, placed in an illumination box (5000 lx.+ -. 500lx, UV intensity 90. Mu.W/cm 2) for 30 days, and sampled on day 0, day 30. XRPD, DSC, HPLC analysis was performed.
Experimental results: the specific experimental results are shown in Table 4.
Table 4 a19006 citrate form I stability HPLC assay results
Remarks: main peak content (%) area normalization method
Conclusion: from the above table, it can be seen that the a19006 citrate form I has good stability under high humidity and light.
One skilled in the art would also expect that the stability, hygroscopicity, etc. of the citrate of other compounds would also be preferred.
Test example 4 in vitro receptor binding assay
Experimental method
4.1. Preparation of solutions required for experiments
A: (for the preparation of 5-HT 2C Receptor membrane): 50mM Tris-HCl buffer: 96.8g Tris was dissolved in double distilled water to a total volume of 4000ml, pH 7.5 was adjusted with HCl, diluted to 16000mL, pH=7.4
B: (for the preparation of 5-HT 2A Receptor membrane): weighing 11.7mg EDTA,380.84mg MgCl 2 The total volume of 50mM Tris-HCl buffer was 400mL and pH=7.4 was adjusted. The final concentration is EDTA 0.1mM and MgCl 2 10mM。
C: (for preparing a Dopamine receptor film): weighing 2.978g HEPES,1.17g NaCl,0.119g MgCl 2 36.5mg EDTA was added to a total volume of 250ml of purified water to adjust pH=7.4. To final concentrations of 50mM HEPES,50mM NaCl,5mM MgCl respectively 2 ,0.5mM EDTA,pH 7.4。
4.2. Preparation of acceptor membranes
1)CHO-5-HT 2A Preparation of acceptor membranes
CHO-5-HT 2A The cells were removed from the freezer at-80℃and naturally thawed and centrifuged at 2000g for 15 minutes at 4 ℃. Taking the precipitate, and discarding the supernatant. Adding solution B into the sediment. The cells were mixed for 20-30 seconds and then centrifuged at 50000g for 25min at 4 ℃. Carefully discarding the supernatant, adding the solution B again, mixing well, centrifuging at 4 ℃ for 25min and 50000 g. The precipitate was stored at-80 ℃.
2)5-HT 2C Preparation of the film
Taking out rat cortex at-80deg.C, naturally thawing, adding solution A, homogenizing for 4 times at 4 th gear for 3-4s, centrifuging at-80deg.C for 25min, discarding supernatant, adding solution A, mixing with vortex mixer, centrifuging at-80deg.C for 25min, repeating the centrifugation twice, discarding supernatant, and storing at-80deg.C.
3)CHO-D 2 Preparation of acceptor membranes
Cell CHO-D 2 Naturally thawing after taking out by a refrigerator at-80 ℃, centrifuging 2000g for 15min, adding the precipitate into homogenate C, uniformly mixing by a vortex mixer, centrifuging at 50000g and 4 ℃ for 25min, discarding the supernatant, taking the precipitate, adding the buffer solution C again for washing, resuspending and centrifuging, discarding the supernatant after centrifuging, and storing the precipitate at-80 ℃ for later use.
4.3 receptor competitive binding assay
1)5-HT 2A Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 10mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, non-specific binding tube (NB) was filled with methyl 100. Mu.L (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Ketanserin 10. Mu.L, final concentration 2.98nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/C plate under reduced pressure to soak the combined ligand with 0.5% PEI for more than 1h, drying the filter membrane at 60 ℃ after filtering, adding 40 mu L of scintillation liquid after attaching a bottom membrane, sealing the upper membrane, and standing.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
2)5-HT 2C Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 210mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, nonspecific binding tube (NB) was filled with Ketansert (final concentration 1.0X10) -5 M) 100. Mu.L of each test compound tube (CB) was charged with 100. Mu.L of test compound.
Fourth step: the radioligand is added into each reaction tube 3 H-Mesulergine 10. Mu.L, final concentration 3nM.
Fifth step: after the reaction tube was incubated at 37℃for 25min, the bound ligands were rapidly filtered under reduced pressure, whatman paper GF/C was saturated with 0.5% PEI solution 1h ahead, washed well with ice-cold Tris buffer, the filter was removed and placed in a 4mL scintillation cup, 1mL toluene scintillation solution was added and mixed well.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
3)CHO-D 2 Receptor competitive binding assay
The first step: the prepared membrane is prepared into 8mg/mL membrane suspension by homogenate C for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L C solution and non-specific binding tube (NB) was filled with 100. Mu.L Haloposteridol (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound-binding tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Spiponone 10. Mu.L, final concentration 1.176nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/B plate by decompression, soaking the combined ligand in 0.5% PEI for more than 1h, filtering, drying the filter membrane at 60 ℃, attaching a bottom membrane, adding 40 mu L of scintillation liquid, sealing the upper membrane, and standing.
Sixth step: and (5) putting the filter plate into a liquid flash counter for counting.
4.4 experimental results
Pimozide 5-HT 2A 、5-HT 2C The receptor Ki values were 0.036, 2.94nM, 5-HT of the compound NH-K-A19016-OA, respectively 2A 、5-HT 2C The Ki values of the receptors are respectively 0.002 nM and 26.10nM, which are superior to pimozide; 5-HT of the Compound NH-K-A19001 2A 、5-HT 2C Receptor Ki values of 0.028, 2.40nM, respectively, superior to pimozide; compounds NH-K-A19005 and 5-HT 2A 、5-HT 2C The Ki values for the receptors were 0.43 and 3.39nM, respectively, at the same level 862 as pimozide. See table 5 below for details.
TABLE 5 in vitro receptor binding
Test example 5: in vitro hERG assay
5.1 preparation of Compounds
a. Stock solutions of test compounds were serially diluted with DMSO to dilutions of 0.3mM,1mM and 3 mM.
b. The stock solution of the compound to be tested is diluted with extracellular solution to obtain working solutions of the compound to be tested with the concentration of 0.3 mu M,1 mu M, 3 mu M,10 mu M and 30 mu M, and all working solutions of the compound to be tested are subjected to ultrasonic treatment for 20min.
c. 10mg of cisapride (system positive compound) was formulated in 10.113mM stock solution with 2002.42. Mu.L of dimethyl sulfoxide (DMSO).
d. Cisapride stock was diluted sequentially to 1. Mu.M, 10. Mu.M, 100. Mu.M, and 1mM with dimethyl sulfoxide (DMSO).
e. 10. Mu.L of each concentration was added to 10mL of extracellular fluid, ensuring a DMSO concentration of 0.1%.
f. The final working solution concentration of cisapride was 1nM,10nM,100nM and 1000nM.
g. All working fluid concentrations were tested and no precipitation was visible with the naked eye.
5.2 cell line information
In the experiment, HEK-293 cell line with stable expression of hERG potassium channel is adopted for experimental detection.
HEK-293 cell line stably expressing hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37℃and carbon dioxide concentration of 5%.
Cell passage: the old medium was removed and washed once with PBS, then 0.5mL TrypLE was added TM Express solution, incubated at 37℃for 1 min. When the cells were detached from the bottom of the dish, 3mL of the cells were added and the cells were preheated to 37℃Whole culture medium. The cell suspension was gently swirled with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and the cells were collected by centrifugation at 300G for 5 minutes. Cells were seeded in 6 cm cell culture dishes, each cell culture dish at an inoculum size of 1 x 10 5 Individual cells (final volume: 5 mL) were used for expansion or maintenance culture.
For patch clamp detection, 5 x 10 3 Individual cells were plated onto coverslips and incubated in 24-well plates (final volume: 500. Mu.L) for 18 hours before experimental detection.
To maintain the cell's electrophysiological activity, the cell density must not exceed 80%.
5.3 patch clamp detection
Under an inverted microscope, a glass electrode micromanipulator (micromanipulator) is manipulated to bring the recording electrode into contact with the cells, and then negative pressure is applied to promote the cells to form gΩ seals. After forming G omega sealing, quick capacitance compensation is carried out, then negative pressure is continuously given, cell membranes are sucked and broken, and a whole cell recording mode is formed. In whole cell recording mode, slow capacitance compensation is performed and the values of the film capacitance and series resistance are recorded.
The voltage stimulation protocol for cellular hERG potassium current is as follows: the cell membrane clamping voltage is-80 mV, then is polarized from-80 mV to +30mV for 2.5 seconds, then is rapidly maintained at-50 mV for 4 seconds, and the tail current of the hERG channel is excited. Data were collected repeatedly every 10 seconds. Leakage current was measured at-50 mV. See fig. 3.
The coverslip on which the cells were grown was placed in a recording cell of an inverted microscope, and negative control and test compound were flowed through the recording cell in order from low concentration to high concentration by gravity perfusion to rapidly act on the cells. In the recording, continuous circulation of the external liquid was performed by a vacuum pump. The current detected in each cell negative control was used as the control group of the cells themselves. Each drug concentration was allowed to act for 5 minutes or until the current stabilized. All experiments were performed at room temperature.
5.4 data analysis
First, the current after each drug concentration is applied is normalizedThen calculate the corresponding inhibition rateBasic statistics are calculated for each concentration, including Mean (Mean), standard Deviation (SD), standard Error (SE), and number of replicates (n). Dose-dependent curves were fitted using the following equation and the semi-Inhibitory Concentration (IC) of the test compound was calculated 50 )：
Wherein C represents the concentration of the test compound, IC 50 Represents the half-inhibitory concentration and h represents the Hill coefficient. Curve fitting and IC 50 Is done using GraphPad Prism 5.0 software.
5.5 experimental results
The pimecrin hERG test IC50 is 208nM, the NH-K-A19001, NH-K-A19005 and NH-K-A19006 hERG test IC50 are 206, 3173 and 1194nM respectively, and the cardiac toxicity of the three compounds is smaller than that of the pimecrin, which indicates that the compounds have lower cardiac toxicity compared with the pimecrin. The results are shown in the following table.
TABLE 6
Compounds of formula (I) hERG(nM)
NH-K-A19001 260
NH-K-A19005 3173
NH-K-A19006 1194
Pimozhen lin 208
Test example 6: animal experiment
6.1, test method
6.1.1.1 experiments on the influence of MPTP+MK-801 Parkinson's disease mouse model (anti-PDP drug efficacy model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP, and were continuously administered for 5 days, and after the MPTP injection at 5 morning, pimozhen or NS was intraperitoneally injected at 1.5h intervals, MK-801 was intraperitoneally injected at 0.5h intervals (or NS) at 0.3mg/kg intervals, and then video was recorded in an autonomous incubator (black polyethylene incubator with the specification of 29cm×29cm×30 cm) for 20min, and video analysis was performed after the video recording was completed to evaluate the activity of the mice.
6.1.2 influence on MPTP+APO-induced climbing behavior in Male mice (DA motor deterioration model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP, were continuously administered for 5 days, were intraperitoneally injected with pimozide, clozapine, quetiapine or NS 1.5h after MPTP injection at 5 morning, were subcutaneously injected with 1mg/kg APO (administration volume 0.1ml/10g body weight) at 0.5h intervals, were placed in climbing cages (climbing cages made of stainless steel wire mesh with a diameter of about 0.1cm, bottom made of translucent polyethylene plates, cage cover made of stainless steel cage cover) immediately after APO injection (climbing cage made of a cylindrical cage made of the same company, diameter of 13cm, height of 15 cm), and were observed for behavior for 10-11, 20-21, 30-31 minutes after APO injection and scored.
The scoring criteria were: the score of the four feet on the floor is 0; the scores of the two forefeet on the net cage are 1; the four feet scored 2 on the netpen.
6.1.3 sedation side effect investigation experiments (anti-sedation model)
Qualified SPF grade C57BL/6j mice are randomly divided into 13 groups, and 8 mice in each group: blank, pimozide, NH-K-A1900, NH-K-A19005, NH-K-A19006. Solutions with different concentrations are prepared according to different dosages of each group for intraperitoneal injection administration, and the final administration volume is 10ml/kg.
All groups were tested for voluntary activity 45min after administration of pimozerin and the like, video recorded for 0-20min movement, and Top Scan3.00 software analyzed for 20min movement path. The inhibition rate of each group was calculated relative to the blank group after administration, and the sedation of the compound was comprehensively evaluated in combination with the statistical conclusion.
6.1.4 test results
Experiments show that the PDP drug effect, sedation and exercise deterioration ED of pimozide 50 0.37mg/kg, 6.79mg/kg respectively,>30mg/kg, the sedative/PDP efficacy ratio was 18.35, the exercise deterioration/PDP efficacy ratio was>81.08; NH-K-A19001 PDP drug efficacy and sedated ED 50 The ratio of sedative/PDP efficacy was 11.33, which was 0.33mg/kg and 3.74mg/kg, respectively. The drug effect of the NH-K-A19005 PDP is 1.85mg/kg. NH-K-A19006PDP efficacy and sedated ED 50 0.31mg/kg and 11.9mg/kg, respectively. The drug effects of NH-K-A19001 and NH-K-A19006 were found to be equivalent to those of pimozide. The drug effect dosage of the NH-K-A19005 PDP is slightly higher than that of pimozide. In addition, the compounds of the present invention (e.g., NH-K-A19001, NH-K-A19005 and NH-K-A190016) do not have DA mechanism of action, and no deterioration of movement is observed.
TABLE 7
Test example 7: in vivo and in vitro experimental method and data
7.1. Mouse head-shaking test
7.1.1 test methods
Mice were randomly divided into model control groups, blank control groups, and each dosing group after weight stratification. 1h after the animal is subjected to gastric lavage administration of the solvent or the drug, the animal is placed in a beaker (with the diameter of 13cm and the height of 19 cm) paved with fresh padding, the molding drug DOI ((+ -.) -1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride, (+ -.) -2, 5-dimethoxy-4-iodoamphetamine hydrochloride) is injected intraperitoneally according to the dosage of 1mg/kg, and the number of times of head throwing of the mice within 0-20 minutes after the intraperitoneal injection of the DOI is recorded. The head-flick behavior is defined as rapid rotational twitching or wet dog-like shaking of the mouse head, which is distinguished from normal grooming or exploratory behavior.
7.1.2 test data
The test result shows that pimozide inhibits DOI to induce ED of mice to swing head 50 ED in which DOI was inhibited from inducing head-shaking behavior of mice at 0.39mg/kg, NH-K-A19001, NH-K-A19005, NH-K-A19006 and NH-K-A19012 50 0.06, 0.15, 0.012 and 0.30mg/kg, respectively, suggesting that the compound of the present invention has better effect of resisting mental diseases and better efficacy. The detailed results are shown in the following table.
Table 8 ED of pimecrin and like compounds inhibiting DOI-induced mice head-flick behavior 50
Note that: ED (ED) and method for producing the same 50 Is half of the effective amount.
MK-801 induced high mobility assay in mice
7.2.1 test methods
The mice are randomly divided into a model control group, a blank control group and each administration group after being layered according to the body weight, after the test (or the control) is given, the mice are put into an independent movable box (a black polyethylene box with the specification of 29cm multiplied by 30 cm) for adaptation, MK-801 with the volume of 0.3mg/kg is injected into the abdominal cavity 1h after the stomach irrigation administration, then the mice are put into the independent movable box for video recording, the video recording time is 60min, the video recording is finished, the video analysis is carried out, and the activity condition of the mice is evaluated.
7.2.2 test results
The test result shows that pimozide inhibits MK-801 to induce high activity of mice 50 3.288mg/kg, NH-K-A19005 and NH- ED (ED) for inhibiting MK-801 to induce high activity behavior of mice by K-A19006 and NH-K-A19012 50 1.01 mg/kg, 0.2648 mg/kg and 3.728mg/kg respectively, which indicates that the compound of the invention has better effect of resisting mental diseases and better drug effect. The detailed results are shown in the following table.
Table 9 ED in which compounds such as pimozide inhibit MK-801 induced hyperactive behavior in mice 50
Compounds of formula (I) ED 50 (mg/kg)
Pimozhen lin 3.288
NH-K-A19005 1.01
NH-K-A19006 0.2648
NH-K-A19012 3.728
Note that: ED (ED) and method for producing the same 50 Half of the effective amount.
DOI ((+ -.) -1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride, (+ -.) -2, 5-dimethoxy-4-iodophenylpropanamine hydrochloride) induced rat PPI injury Effect test
7.3.1 test methods
And (3) intervention test:
animals were placed in a shock reflex test box for testing 30min after gavage (or vehicle administration) and 30min after cervical subcutaneous injection of 0.5mg/kg DOI, i.e., 60min after gavage administration.
The test method is carried out by reference to literature and preliminary experiments, and the specific process is as follows: first an adaptation time of 5min (62 dB background sound), 5 separate shock reflex stimuli were given after the adaptation period (block 1, and as a result no analysis was included to reduce the initial response of the animals to a plateau level), followed by 4 different types of experiments (block 2) and appeared in a pseudo-random manner, respectively: 1) Shock-alone reflex stimulus (120 dB, 20ms duration); 2) Single pre-pulse-stimulus (75 dB for 20 ms) 13dB above background sound; 3) A combined test of pre-pulse stimulation and shock reflex stimulation (prepulse+pulse, each lasting 20ms, 100ms apart); 4) Non-stimulated test (no stick) given background sound only, each test (real) was presented 5 times with an average interval of 20s (10-30 s) between each test.
The response amplitude of the individual shock reflex stimulus or the pre-pulse combined shock reflex stimulus is expressed as AVG (instrument specific unit) value, which indirectly reflects the magnitude of the daunting response of the rat body.
Evaluation index: PPI% = (1-response amplitude of pre-pulse combined shock reflex stimulation/response amplitude of shock reflex stimulation alone) ×100. The larger the number, the deeper the inhibition.
Drug administration test:
the animals in each group changed the 0.5mg/kg DOI used to Normal Saline (NS), and other procedures including administration and testing were the same as those of the intervention test.
7.3.2 experimental results
PPI is indicative of the inhibition of shock reflex by weak stimuli occurring before (30-500 ms) strong shock reflex stimuli. Studies have shown that the nucleolus and pharmacological mechanisms that regulate PPI in humans and rodents are very similar and thus it is a trans-species behavioral indicator. Clinical studies have also found that there is a lesion in PPI in schizophrenic patients, and that some antipsychotics have an improving effect on this. Based on the characteristics, the model is widely applied to research on pathogenesis of the schizophrenia and pharmacological actions of antipsychotics, is also used as a tool for screening the antipsychotics, and can be particularly used for predicting curative effects on negative symptoms and cognitive defects of the schizophrenia.
In this experiment, DOI administration of 0.5mg/kg significantly destroyed PPI (P < 0.05), NH-K-A190060.3mg/kg, NH-K-A19005 3mg/kg, pimozide 3mg/kg significantly reversed DOI-induced PPI damage in rats (P < 0.05), as detailed in the following table. In the table, "MEAN" represents the average value, "SD" represents the standard deviation, and "P" represents the P value. The values in the table represent reversal lesions, where a larger value indicates more symptom relief than the model group.
This study showed that 0.3mg/kg of NH-K-A19006, 19005 3mg/kg of NH-K-A could significantly reverse DOI-induced PPI injury in rats, and no significant effect was seen in normal rats at this dose, suggesting that NH-K-A19005, NH-K-A19006 were effective against psychotic disorders, and on schizophrenia negative symptoms and cognitive deficits.
TABLE 10 influence of NH-K-A19006 on DOI-induced PPI injury in rats at 0.5mg/kg
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Note that: model group vs blank group; each dosing group was a vs model group.
TABLE 11 effect of pimecrin, NH-K-A19005 on DOI-induced PPI injury in rats at 0.5mg/kg
Note that: model group vs blank group; each dosing group was a vs model group.
TABLE 12 PPI Effect of NH-K-A19006 on Normal rats
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Note that: vs. blank for each dosing group.
TABLE 13 effect of pimecrin, NH-K-A19005 on PPI in normal rats
And (3) injection: vs. blank for each dosing group.
Test example 8DOI induced mouse head-flick behavior impact test
The experimental method comprises the following steps:
ICR mice were randomly split into following weight stratification: blank, model, a19006 citrate, phosphate: group 0.003, 0.01, 0.03, 0.1mg/kg, pimozide L-tartrate: groups of 0.1, 0.3, 1 and 3mg/kg, 16 groups (male and female halves). The test (or control) was administered by gavage for 1h, the animals were placed in a beaker (13 cm in diameter and 19cm in height) with fresh padding, the molding compound DOI (10 mL/kg body weight) was injected intraperitoneally at a dose of 1mg/kg, and the number of times of head flick in 0-20 minutes after the DOI was injected intraperitoneally in the mice was recorded. The head-flick behavior is defined as rapid rotational twitching or wet dog-like shaking of the mouse head, which is distinguished from normal grooming or exploratory behavior.
Experimental results: the specific experimental results are shown in Table 14. Under the experimental condition, A19006 citrate and phosphate inhibit mouse head-throwing action ED 50 0.018 mg/kg, 0.012mg/kg, pimozide L-tartrate, respectively, inhibits the head-flick behavior ED of mice 50 0.73mg/kg, suggesting that both A19006 citrate and phosphate have better activity and are superior to pimecrin L-tartrate.
Table 14A19006 citrate and phosphate inhibits ED of DOI induced mouse head flick behavior 50
It will be apparent to those skilled in the art that many modifications and variations of the present invention can be made without departing from its spirit and scope. The specific embodiments described herein are offered by way of example only and are not meant to be limiting in any way. The true scope and spirit of the invention is indicated by the following claims, which are exemplary only.

Claims (13)

1. A salt of a compound of formula I
Wherein: n1 and n2 are integers from 1 to 3;
R 1 selected from straight-chain or branched C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl and C 2 -C 8 Alkynyl groups, said alkyl, alkenyl and alkynyl groups each independently and optionally being selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
R 2 selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 3 、R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 7 selected from straight-chain or branched C 1 -C 8 Alkyl, cycloalkylR 8 、R 9 Independently selected from linear or branched C 1 -C 8 Alkyl, said alkyl and cycloalkyl being optionally selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
z is selected from C, O, N;
q, W are each selected from C, N.
2. A salt of a compound of formula i according to claim 1, wherein: the salt form is phosphate or citrate, and is shown in the formulas II and III:
Wherein: y is 0.5, 1, 1.5, 2, 2.5 or 3, preferably 0.5, 1, 1.5 or 2;
n1 and n2 are integers from 1 to 3;
R 1 selected from straight-chain or branched C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl and C 2 -C 8 Alkynyl groups, said alkyl, alkenyl and alkynyl groups each independently and optionally being selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
R 2 selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 3 、R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen and C 1 -C 8 A haloalkyl group;
R 7 selected from straight-chain or branched C 1 -C 8 Alkyl, cycloalkylR 8 、R 9 Independently selected from linear or branched C 1 -C 8 Alkyl, said alkyl and cycloalkyl being optionally selected from halogen and C 1 -C 8 A substituent of a haloalkyl group;
z is selected from C, O, N;
q, W are each selected from C, N.
3. A salt of a compound of formula i according to claim 1 or 2, characterized in that:
said straight or branched chain C 1 -C 8 Alkyl is selected from straight or branched chain C 1 -C 5 Alkyl and straight or branched C 1 -C 3 An alkyl group; and/or
The C is 2 -C 8 Alkenyl group is C 2 -C 5 Alkenyl groups; and/or
The C is 2 -C 8 Alkynyl is C 2 -C 5 Alkynyl; and/or
The C is 1 -C 8 Haloalkyl is C 1 -C 5 A haloalkyl group; and/or
The cycloalkyl group is C 3 -C 10 Cycloalkyl, preferably C 3 -C 6 Cycloalkyl groups.
4. A salt of a compound of formula i according to claim 3, wherein:
the halogen is selected from fluorine, chlorine, bromine and iodine; and/or
Said straight or branched chain C 1 -C 5 Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl; and/or
The C is 3 -C 6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl; and/or
Said straight or branched chain C 1 -C 3 The alkyl is selected from methyl, ethyl, propyl, isopropyl.
5. A salt of a compound of formula i according to claim 4, wherein:
the halogen is fluorine and chlorine; and/or
Said straight or branched chain C 1 -C 5 Alkyl is selected from methyl, ethyl, propyl, isopropyl, isobutyl; and/or
The C is 3 -C 6 Cycloalkyl is selected from cyclopropyl, cyclobutyl; and/or
Said straight or branched chain C 1 -C 3 Alkyl is selected from methyl, ethyl, propyl, isopropyl;
the saidIs->
6. A salt of a compound of formula i according to claim 5, comprising a phosphate or citrate salt selected from the group consisting of:
7. a19006 citrate or phosphate is characterized in that the structure is shown in formulas IV and V,
8. a crystalline form I of a19006 citrate of formula IV as claimed in claim 7 characterised in that Cu-ka radiation is used to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angles 2Θ ± 0.2 ° which shows characteristic peaks at 10.03, 12.62, 13.69, 14.68, 16.44, 17.19, 19.10, 20.27, 21.77, wherein each characteristic peak has an error range of 2Θ ± 0.2.
9. Form I of claim 8, wherein the X-ray powder diffraction pattern of form I exhibits characteristic peaks expressed in degrees 2Θ ± 0.2 ° at 17.67, 19.57, 21.30, 23.78, 24.03, 25.57, 26.22, wherein each characteristic peak has an error range of ± 0.2; preferably, the X-ray powder diffraction pattern of form I is substantially as shown in figure 1.
10. Form I of any one of claims 8 or 9, wherein the DSC of form I has a melting endotherm with a peak selected from 164.7-170.0 ℃, preferably 167.7 ℃.
11. A pharmaceutical composition comprising a salt according to any one of claims 1 to 7 or a crystalline form I of a19006 citrate salt according to any one of claims 8 to 10 and a pharmaceutically acceptable carrier.
12. Use of a salt according to any one of claims 1 to 7, form I of a19006 citrate according to any one of claims 8 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for the treatment of psychotic disorders.
13. The use according to claim 12, wherein the psychotic disorder is schizophrenia, psychosis, schizoaffective disorder, parkinson's disease, dementia-related behavioral disorders and psychosis (BPSD), delusional disorder, acute transient psychotic disorder, depressive disorder, bipolar disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia disorder, venue fear disorder, post-traumatic stress disorder, preferably parkinson's disease, dementia-related behavioral disorders and psychosis (BPSD), schizophrenia.
CN202211299097.1A 2021-10-25 2022-10-24 Salts of 1, 5-dihydro-2, 4-benzodiazepine-3-one derivatives and uses thereof Pending CN116444484A (en)

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