CN117924288A - Hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivative, and preparation method and application thereof - Google Patents

Hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivative, and preparation method and application thereof Download PDF

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CN117924288A
CN117924288A CN202311388058.3A CN202311388058A CN117924288A CN 117924288 A CN117924288 A CN 117924288A CN 202311388058 A CN202311388058 A CN 202311388058A CN 117924288 A CN117924288 A CN 117924288A
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acid salt
disorders
hydrochloride
compound
degrees
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周炳城
胡志京
吴永奇
王瑾
孔芒芒
冯子晋
梁小小
万泽红
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Shanghai Shujing Biotechnology Co ltd
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Abstract

The invention relates to hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivatives, and a preparation method and application thereof. In particular, the invention relates to hydrochloride, crystal forms and preparation methods and application of a compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-dehydroquinoxalin-2 (3H) -ketone, and pharmaceutical compositions containing the hydrochloride and crystal forms of the compound in a therapeutically effective amount and application of the hydrochloride and the crystal forms in preparation of medicaments for preventing and/or treating neuropsychiatric diseases.

Description

Hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivative, and preparation method and application thereof
The present application claims priority from chinese patent application 2022113212351, whose filing date is 2022, 10, 26. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to hydrochloride and crystal form of a heterocycle substituted condensed gamma-carboline derivative, and a preparation method and application thereof.
Background
Schizophrenia is a disease characterized by cognitive and deep emotional divisions, which is manifested by the most basic human behaviors that are affected, such as speech, thought, perception, and self-perception. The symptoms of the disease are inclusive of a wide range, most commonly mental disorders such as the creation of hallucinations, delusions, and illusions.
About 1% of all people worldwide suffer from schizophrenia, while only 5% of all treated patients eventually get fully recovered. In addition, complications such as anxiety disorders, depression, or substance abuse are often caused by schizophrenia.
Antipsychotics that exert pharmacological effects by blocking dopamine D2 receptors have traditionally been termed first-generation antipsychotics, i.e. "typical" antipsychotics (such as haloperidol), which are breakthrough in the treatment of positive symptoms of schizophrenia but fail to treat negative symptoms and cognitive 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, which are called second generation antipsychotics, i.e., novel antipsychotics, have been developed, which have common pharmacological characteristics, i.e., affinity for 5-hydroxytryptamine (5-HT 1A, 2 c) receptors (α1, α2) and Norepinephrine (NA) receptors (α1, α2) is far higher than D2 receptors, resulting in a higher D2/5-HT2A ratio, although their respective pharmacological actions are not completely identical. 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 contain several 5-HT1A and 5-HT2A subtypes which have particularly high densities of 5-hydroxytryptamine receptors. PFC and NMDA receptor channels have recently been shown to be targets for 5-HT1AR, both of which modulate cortical excitatory neurons, affecting cognitive function. Indeed, various preclinical data suggest that 5-HT1AR may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole, etc.) for 5-HT1AR and its low EPS side effects both suggest that the 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior, and working memory. Pyramidal neurons of PFC and GABA interneurons contain several 5-HT1A and 5-HT2A receptor subtypes with particularly high densities. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic therapy and improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT2A has been found to play an important role in this regard, involving various aspects of perception, mood regulation and motor control. Blocking the 5-HT2A receptor normalizes dopamine release and acts as an antipsychotic. In addition, 5-HT2C receptors are closely related to weight gain.
The D3 receptor distribution in the brain is mainly and selectively distributed in the limbic system, there are two main DA nerve pathways in the brain, one is the regulating motor function of the striatal pathway, the other is that the ventral fasciae of the midbrain is closely related to learning, cognition and emotional activities, the dysfunction of the DA pathway can lead to schizophrenia, the DA pathway is also the main pathway of the rewarding effect (REWARD EFECTS) in the brain, D3R is distributed in both DA nerve pathways, and complex interactions exist between the D3R and other DA receptor subtypes, and the antagonism of the selective D3 receptor can reduce the negative and cognitive symptoms of schizophrenia and can prevent extrapyramidal side effects including tardive dyskinesia and parkinson disease. Therefore, finding an anti-schizophrenia drug with little multi-receptor binding side effect is of great importance for clinical treatment.
An antagonist acting on the 5-HT 2A and D 2 receptors is disclosed in International patent application PCT/CN2021/122546, which has the chemical name (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one, has good antagonistic activity on both the 5-HT 2A receptor and the D 2(D2L、D2s receptor, has a high D 2/5-HT2A ratio, i.e. good selectivity, has good pharmacokinetic properties, has good in vivo efficacy, and can effectively treat and improve schizophrenia.
Different salts and solid forms of the pharmaceutically active ingredient may have different properties. Different salts and solid forms may vary significantly in appearance, solubility, melting point, pharmacokinetics, etc., and may also have different effects on the bioavailability and efficacy of the drug. Thus, problems with the salt form and/or solid form of the drug should be fully considered in drug development.
The inventors have found that, when studying the compound, the free base of the compound exists as an oil, which has poor solubility in water and low bioavailability, and is not a preferred form of clinical administration, and therefore, it is necessary to further conduct comprehensive screening and study on the acid salt of the compound and its crystalline form.
Disclosure of Invention
All that is referred to in International patent application PCT/CN2021/122546 is incorporated herein by reference.
The invention aims to solve the technical problem of providing hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivatives, and a preparation method and application thereof.
The invention aims to provide an acid salt of a compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one.
In a preferred embodiment of the invention, the acid salt is the hydrochloride salt.
In a preferred embodiment of the invention, the acid salt is in the crystalline form.
In a further preferred embodiment of the invention, the acid salt of the compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one is in hydrochloride form I, the X-ray powder diffraction pattern of which comprises diffraction peaks at 10.33.+ -. 0.2 °, 12.95.+ -. 0.2 °, 23.43.+ -. 0.2 °;
Preferably, the diffraction peaks at2θ of 10.33±0.2°, 12.95±0.2°, 15.89±0.2°, 23.43±0.2°, 27.10 ±0.2° are included;
More preferably, it comprises a diffraction peak at 10.33±0.2°、11.57±0.2°、11.98±0.2°、12.95±0.2°、15.38±0.2°、15.89±0.2°、20.82±0.2°、23.43±0.2°、24.23±0.2°、27.10±0.2°. 2. Theta.;
Further preferably, the diffraction peak at 6.91±0.2°、8.38±0.2°、10.33±0.2°、11.57±0.2°、11.98±0.2°、12.95±0.2°、15.38±0.2°、15.89±0.2°、16.76±0.2°、17.96±0.2°、20.82±0.2°、23.43±0.2°、24.23±0.2°、25.48±0.2°、26.03±0.2°、27.10±0.2°、27.76±0.2°、28.15±0.2°、28.88±0.2°、29.26±0.2°、30.47±0.2°、31.34±0.2°、32.07±0.2°、32.89±0.2°、33.82±0.2°、35.91±0.2°、37.02±0.2°、43.11±0.2° is included;
Still more preferably, cu-K alpha radiation is used, and X-ray diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d values are shown in Table 1.
XRPD x-ray diffraction data for hydrochloride form i of the compound of table 1
Sequence number 2θ(±0.2°) D value Relative intensity Sequence number 2θ(±0.2°) D value Relative intensity
1 6.91 12.778 1.6％ 15 26.03 3.421 10.6％
2 8.38 10.547 12.7％ 16 27.10 3.288 40.4％
3 10.33 8.558 100.0％ 17 27.76 3.211 7.0％
4 11.57 7.640 35.1％ 18 28.15 3.167 2.3％
5 11.98 7.381 16.1％ 19 28.88 3.089 7.0％
6 12.95 6.833 47.4％ 20 29.26 3.049 4.1％
7 15.38 5.756 20.6％ 21 30.47 2.931 0.9％
8 15.89 5.572 42.5％ 22 31.34 2.852 5.9％
9 16.76 5.285 11.3％ 23 32.07 2.789 5.8％
10 17.96 4.936 3.9％ 24 32.89 2.721 0.6％
11 20.82 4.264 28.0％ 25 33.82 2.648 3.3％
12 23.43 3.793 45.5％ 26 35.91 2.499 1.6％
13 24.23 3.670 22.1％ 27 37.02 2.426 0.8％
14 25.48 3.492 6.2％ 28 43.11 2.097 2.9％
Still more preferably, the X-ray powder diffraction pattern of hydrochloride form I of the compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one is substantially as shown in FIG. 1; the DSC spectrum is basically shown in figure 2; the TGA profile is substantially as shown in figure 3.
In a further preferred embodiment of the present invention, the acid salt is an anhydride.
In another aspect, the invention also relates to a process for the preparation of the acid salt of the compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one, comprising the steps of:
(1) Weighing a proper amount of compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -ketone free base, and dissolving the compound with a solvent 1;
(2) Weighing a proper amount of hydrochloric acid, and optionally dissolving with a solvent 2; the amount of hydrochloric acid is preferably 0.5 to 1.0 equivalent;
(3) Mixing the above two materials, stirring for crystallization, vacuum filtering, and vacuum drying to obtain target product;
Wherein:
The solvent 1 and the solvent 2 are respectively and independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, N-propanol, isopropanol, N-butanol, isobutanol, tertiary butanol, glacial acetic acid, acetone, butanone, 3-pentanone, N-hexane, cyclohexane, N-heptane, isopropyl ether, methyl tertiary butyl ether, petroleum ether, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1, 2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, 1, 2-dioxane, benzene or toluene; the solvent 1 and the solvent 2 are required to be mutually soluble when used.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of an acid salt of any one of the compounds shown, or a combination thereof, together with one or more pharmaceutically acceptable carriers or excipients.
The invention further relates to the use of an acid salt of any of the compounds shown, or a pharmaceutical composition thereof, for the manufacture of a medicament for the involvement or modulation of 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters and/or dopamine receptors; preferably in the manufacture of a medicament involving or modulating a 5-HT2A receptor, a 5-hydroxytryptamine transporter, a dopamine D1 receptor and/or a dopamine D2 receptor, more preferably in the manufacture of a medicament involving or modulating a 5-HT2A receptor and/or a dopamine D2 receptor.
The invention further relates to the use of an acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of neuropsychiatric disorders.
In a further preferred embodiment of the invention, the neuropsychiatric disease is selected from one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in dementia patients, parkinson's disease, alzheimer's disease, migraine, hyperactivity disorder, obsessive-compulsive disorders, social phobia, neurodegenerative disorders, bipolar disorders, post-traumatic stress syndrome, addictive disorders, withdrawal syndromes or attention deficit disorders, preferably any one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in dementia patients, neurodegenerative disorders or bipolar disorders; such as major depression, and such as attention deficit hyperactivity disorder.
Detailed description of the invention
The different expressions of X being A, B or C, X being A, B and C, X being A, B or C, X being A, B and C, etc. all express the same meaning, that is, X can be any one or more than one of A, B, C.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally (cycloalkyl) substituted by alkyl" means that alkyl may be, but is not necessarily, present, and the description includes both cases where cycloalkyl is substituted by alkyl and cases where cycloalkyl is not substituted by alkyl.
"Pharmaceutical composition" means a mixture comprising one or more compounds of the present invention or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
As used herein, "polymorph" or "polymorph" refers to a crystalline form that has the same chemical composition, but different spatial arrangements of molecules, atoms, and or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate and the like. The relative stability between the two solid phases is reversed according to their temperature-stability relationship. The phenomenon in which such compounds exist in different lattice structures is called drug polymorphism.
The equivalent crystal structure of the crystal structure disclosed or claimed herein may exhibit similar but not identical analytical properties within reasonable tolerances depending on the experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Applicant expects that this specification and examples are to be regarded as illustrative rather than limiting the scope thereof.
"X-ray powder diffraction pattern or XRPD" refers to a pattern of x-rays according to the bragg formula 2dsin theta = nλ (where λ is the wavelength of x-rays,The number of diffraction orders n is any positive integer, a first-order diffraction peak is generally taken, n=1), wherein "2θ or 2θ angle" refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree. The bragg equation is satisfied when x-rays are incident at a glancing angle theta (the complementary angle of incidence, also known as the bragg angle) to an atomic plane of a crystal or a portion of a crystal sample having a d-lattice plane spacing, whereby the set of x-ray powder diffraction patterns is measured.
It is well known to those of ordinary skill in the art that XRPD may experience certain displacements and intensity deviations due to the detection methods, conditions, and instrumentation. The same sample of the same crystal form will typically have the same main XRPD characteristic peaks, but there may be some operational error, when the same crystal form sample obtained by the corresponding method is detected by the same instrument and detection method by a person of ordinary skill in the art, the characteristic peak error will typically be within + -0.2 deg., whereas the error of a few characteristic peaks may occasionally occur outside this range by a different person using a different instrument, as the error is within + -0.5 deg. or + -0.3 deg. both of the XRPD characteristic peaks considered to belong to the same crystal form. Thus, as a specific example of a crystalline form of the present invention, its XRPD is shown in pattern X, but it will be understood by those of ordinary skill that when the deviation in the peak shift 2θ of the key feature is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, all can be considered to be the same crystalline form and are to be construed as being within the scope of the present invention.
The absolute intensities and relative intensities of the peaks shown in the foregoing tables and diagrams may vary depending on various factors such as the effect of the selective orientation of the crystalline solid on the x-ray beam, the influence of coarse particles, the purity of the substance to be analyzed, or the crystallinity of the sample. In addition, the peak position may be shifted according to the variation of the sample height. Further, if the measurement is performed using different wavelengths, different displacement values are obtained according to the bragg format (nλ= dsin θ), and different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.
"Interplanar spacing or interplanar spacing (d value)" refers to the fact that the spatial lattice selects 3 non-parallel unit vectors a, b, c joining two adjacent lattice points that divide the lattice into juxtaposed parallelepiped units, known as 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 thatOr angstroms.
"Relative intensity (I%)" refers to the ratio of the intensity of the first intensity peak to the intensity of the first intensity peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) at 100%.
"Differential scanning calorimetric analysis or DSC" 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 describing a compound as having a given DSC peak or melting point, it is meant that the DSC peak or melting point ± 5 ℃, such temperature variations are also substantially taken 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.
"Thermogravimetric analysis (TGA)" is a common method of determining the thermal stability of a compound. In the present invention, TGA can also be used to determine the hydration state of a compound, and the rate of temperature rise during the test will have some effect on the profile. The error in TGA may be within about ±0.5 mass%.
"Amorphous", "amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are arranged in three dimensions without periodicity, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous/form is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material.
"Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the basic raw materials used in each step (1 equivalent) in terms of equivalent relation of chemical reaction.
By "substantially as shown" is meant that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.
In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Or for one of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the average value. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.
"Room temperature" means a temperature from 10℃to 40 ℃. In some embodiments, "room temperature" refers to a temperature from 15 ℃ to 30 ℃; in other embodiments, "room temperature" refers to a temperature from 18 ℃ to 25 ℃.
Advantageous effects
The compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-de ] quinoxaline-2 (3H) -ketone hydrochloride crystal form I not only has good performance in terms of solubility performance parameters, but also has obvious advantages in pharmacokinetic research, can be rapidly absorbed after administration, has good metabolic property, has good exposure AUC and maximum blood concentration C max, has good oral absorption characteristics, and has important significance in the aspects of improving the drug effect, reducing the dosage of the drug, saving the cost and the like.
Drawings
FIG. 1 is an XRPD pattern for (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one hydrochloride form I.
FIG. 2 is a DSC illustration of (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one hydrochloride form I.
FIG. 3 is a TGA graphic representation of (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-de ] quinoxalin-2 (3H) -one hydrochloride salt form I.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
The compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-de ] quinoxaline-2 (3H) -ketone is hereinafter referred to as compound A, and the structural formula is shown in the specification
The free base is prepared by the method of example 1-A of International patent application PCT/CN 2021/122546.
Salt form study of Compound A
Experimental instrument:
1. Preparation of acid salts of Compound A
1.1 Preparation of Compound A hydrochloride Crystal form I
Compound A free base (402 mg,0.88 mmol) was added to a 25mL round bottom flask, ethyl acetate (4.0 mL) was purged with nitrogen and the solution was stirred at room temperature. Then 1M HCl-ethyl acetate solution (0.75 mL,0.75 mmol) was added, the reaction stirred for 1 hour, suction filtered, and the filter cake dried in vacuo for 3 hours to give an off-white solid identified as Compound A hydrochloride form I (263 mg).
A detected analysis, having an XRPD pattern as shown in figure 1, a DSC pattern as shown in figure 2 and a TGA pattern as shown in figure 3.
2. Solubility experiment
2.1 Experimental purposes:
the solubility of the compound A free base and the compound A hydrochloride crystal form I in water is inspected, and a basis is provided for salt patentability evaluation.
2.2 Experimental protocol:
weighing excessive free alkali of the compound A and hydrochloride crystal form I, placing the excessive free alkali of the compound A and the hydrochloride crystal form I into different 10mL centrifuge tubes, adding 1mL of deionized water, sealing a sealing film, shaking the mixture at a constant temperature of a shaking table at 37 ℃ and at 150rpm for 24 hours, diluting and sampling the mixture after passing through a 0.45 mu m organic filter head, and analyzing the mixture by HPLC.
2.3 Experimental results: the solubility results are shown in table 3.1 below.
Sample name Solubility (mg/mL)
Free base 0.08
Hydrochloride crystal form I 52.46
2.4 Experimental conclusion:
From the above data, it can be seen that the solubility of compound a hydrochloride form I in aqueous medium is significantly improved relative to compound a free base.
3. Pharmacokinetic experiments
3.1 Test purpose:
female SD rats were given oral gavage, the plasma concentration of compound a hydrochloride form I in the rats was determined, PK parameters were calculated, and pharmacokinetic evaluation was performed.
3.2 Test materials:
(1) Test sample: the invention relates to a compound A hydrochloride crystal form I, which is self-made.
(2) Test animals: SD rats, SPF grade, female, shanghai Laek laboratory animal Limited.
3.3 Test protocol:
(1) Drug administration information:
Preparing the medicine: the sample was taken, physiological saline was added thereto, and ultrasound was performed. Route of administration: oral gastric lavage administration; dosage of administration: 15mg/kg; frequency and duration of dosing: single administration.
(2) The test method comprises the following steps:
SD rats were randomly grouped after weight stratification, 3 rats per group, and fasted overnight prior to testing. For oral administration, 250. Mu.L of blood was taken from the jugular vein or orbital vein of the rat to a sample tube containing heparin sodium as an anticoagulant and placed in wet ice at 0, 0.167, 0.333, 0.5, 1,2, 4, 7 and 10 hours, and centrifuged at 4000 r.min -1 for 10 minutes, and plasma was separated for LC-MS analysis.
3.4 Test results and analysis:
the measured plasma concentration-time data were substituted into the Winnlin 8.2 program to calculate the major pharmacokinetic parameters. T max and C max were calculated using the measured values, the AUC 0-t and AUC inf values were calculated using the trapezoidal method, and T 1/2 was calculated from the concentration points at the ends of the elimination phases using the semilogarithmic plot method. The specific results are shown in Table 3.2 below.
TABLE 3.2 results of rat pharmaceutical experiments on Compound A hydrochloride form I
3.5 Test conclusion:
From the experimental results in the table, it can be seen that the compound a hydrochloride of the present invention can be rapidly absorbed after administration, and has good metabolic properties, and the exposure AUC and the maximum blood concentration C max are good.

Claims (8)

1. An acid salt of the compound (6 br,10 as) -8- (4- (4-fluorophenyl) -4-oxobutyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -one, characterized in that said acid salt is the hydrochloride salt.
2. The acid salt according to claim 1, wherein the acid salt is hydrochloride form i having an X-ray powder diffraction pattern comprising diffraction peaks at 10.33±0.2°, 12.95±0.2°, 23.43±0.2° in 2Θ; preferably, the X-ray powder diffraction pattern comprises diffraction peaks at 10.33+/-0.2 degrees, 12.95+/-0.2 degrees, 15.89+/-0.2 degrees, 23.43+/-0.2 degrees and 27.10 +/-0.2 degrees of 2 theta; preferably, the X-ray powder diffraction pattern comprises a diffraction peak at 10.33±0.2°、11.57±0.2°、11.98±0.2°、12.95±0.2°、15.38±0.2°、15.89±0.2°、20.82±0.2°、23.43±0.2°、24.23±0.2°、27.10±0.2° degrees 2-theta; preferably, the X-ray powder diffraction pattern comprises a diffraction peak at 6.91±0.2°、8.38±0.2°、10.33±0.2°、11.57±0.2°、11.98±0.2°、12.95±0.2°、15.38±0.2°、15.89±0.2°、16.76±0.2°、17.96±0.2°、20.82±0.2°、23.43±0.2°、24.23±0.2°、25.48±0.2°、26.03±0.2°、27.10±0.2°、27.76±0.2°、28.15±0.2°、28.88±0.2°、29.26±0.2°、30.47±0.2°、31.34±0.2°、32.07±0.2°、32.89±0.2°、33.82±0.2°、35.91±0.2°、37.02±0.2°、43.11±0.2° degrees 2-theta.
3. The acid salt according to any one of claims 1-2, wherein the acid salt is hydrochloride form i having an X-ray powder diffraction pattern substantially as shown in figure 1.
4. An acid salt according to any of claims 1-3, characterized in that the acid salt is hydrochloride form i having a DSC profile with an endothermic peak at 187.92 ± 5 ℃, preferably having a DSC profile as shown in figure 2 and/or having a TGA profile as shown in figure 3.
5. A process for the preparation of an acid salt according to any one of claims 1 to 4, characterized in that it comprises in particular the following steps:
(1) Weighing a proper amount of compound (6 bR,10 aS) -8- (4- (4-fluorophenyl) -4-oxo-butyl) -3,6 b-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxalin-2 (3H) -ketone free base, and dissolving the compound with a solvent 1;
(2) Weighing a proper amount of hydrochloric acid, and optionally dissolving with a solvent 2; the amount of hydrochloric acid is preferably 0.5 to 1.0 equivalent;
(3) Mixing the above two materials, stirring for crystallization, vacuum filtering, and vacuum drying to obtain target product;
Wherein:
The solvent 1 and the solvent 2 are respectively and independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, N-propanol, isopropanol, N-butanol, isobutanol, tertiary butanol, glacial acetic acid, acetone, butanone, 3-pentanone, N-hexane, cyclohexane, N-heptane, isopropyl ether, methyl tertiary butyl ether, petroleum ether, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1, 2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, 1, 2-dioxane, benzene or toluene; the solvent 1 and the solvent 2 are required to be mutually soluble when used.
6. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt as set forth in any one of claims 1-4, or a combination thereof, and one or more pharmaceutically acceptable carriers or excipients.
7. Use of an acid salt according to any one of claims 1-4, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for the involvement or modulation of 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters and/or dopamine receptors; preferably in the manufacture of a medicament involving or modulating a 5-HT2A receptor, a 5-hydroxytryptamine transporter, a dopamine D1 receptor and/or a dopamine D2 receptor, more preferably in the manufacture of a medicament involving or modulating a 5-HT2A receptor and/or a dopamine D2 receptor.
8. Use of an acid salt according to any one of claims 1-4, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for the treatment of a neuropsychiatric disorder selected from depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in dementia patients, parkinson's disease, alzheimer's disease, migraine, hyperactivity disorder, obsessive-compulsive disorder, social phobia, neurodegenerative disorders, bipolar disorders, post-traumatic stress syndrome, addictive disorders, withdrawal syndrome or attention deficit, preferably any one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in dementia patients, neurodegenerative disorders or bipolar disorders; such as major depression, and such as attention deficit hyperactivity disorder.
CN202311388058.3A 2022-10-26 2023-10-25 Hydrochloride and crystal form of heterocycle substituted condensed gamma-carboline derivative, and preparation method and application thereof Pending CN117924288A (en)

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