CN116041323A - Acid salt of Sigma-1 receptor agonist, crystal form thereof, preparation method and application thereof - Google Patents

Acid salt of Sigma-1 receptor agonist, crystal form thereof, preparation method and application thereof Download PDF

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CN116041323A
CN116041323A CN202211256445.7A CN202211256445A CN116041323A CN 116041323 A CN116041323 A CN 116041323A CN 202211256445 A CN202211256445 A CN 202211256445A CN 116041323 A CN116041323 A CN 116041323A
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cyclopropylmethyl
methylpyridin
tetrahydroisoquinolin
isopropyl
amino
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路苹
陈科
季明华
董达文
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Suzhou Enhua Biomedical Technology Co ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention provides an acid salt of a Sigma-1 receptor agonist or a crystal form thereof, and a preparation method and application thereof. In particular to 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one acid salt with high affinity to a sigma-1 receptor and a crystal form thereof, and relates to a preparation method of the acid salt and the crystal form and application of the acid salt and the crystal form in the field of medicines. The acid salt of the compound 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one and the crystal form thereof provided by the invention have improved physicochemical properties such as appearance, hygroscopicity and chemical stability.

Description

Acid salt of Sigma-1 receptor agonist, crystal form thereof, preparation method and application thereof
Technical Field
The invention belongs to the field of medical treatment, and relates to an acid salt of a Sigma-1 receptor agonist, a crystal form thereof, a preparation method and application thereof. In particular to 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one acid salt with high affinity to a sigma-1 receptor and a crystal form thereof, and also relates to a preparation method of the acid salt and the crystal form and application of the acid salt and the crystal form in the field of medicines.
Background
Sigma receptors (Sigma receptors) are cell surface receptors of the Central Nervous System (CNS) that may be associated with dysphoria, hallucinations, and cardiac stimulating effects of opioids. Sigma receptor ligands have been shown to be useful in the treatment of psychoses and dyskinesias, such as dystonia and tardive dyskinesia, as well as dyskinesias associated with huntington's disease or tic disorder, and parkinson's disease (Walker, j.m. et al, pharmacopoeia reviews,1990,42,355) through studies of the biology and function of sigma receptors. The known sigma receptor ligand, lincarbazol, has been reported to show clinical therapeutic effects on psychosis (Snyder, s.h., large, b.l.j. Neurops sychiatry1989,1, 7).
Sigma receptor has at least two subtypes, in which Sigma-1 receptor (Sigma 1 receptor) is an emerging drug target in recent years, and is a binding protein for various specific psychotropic drugs. Sigma-1 receptor is a ligand-regulated protein chaperone that acts by interacting with receptors such as NMDA: regulate NMDA, APMA plasma channels and downstream receptors, thereby regulating mitochondrial function, release of neurotransmitters such as 5-hydroxytryptamine, dopamine, and the like.
Known sigma-1 receptor agonists such as ospemiol, ifemetacin, SA-4503, ANAVEX2-73, etc. have been shown to have an antidepressant, anxiolytic effect clinically. Such as benzomorphinans (SKF 10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.), and the like, all have high affinity for Sigma-1 binding sites.
Currently, the prior art discloses different Sigma-1 receptor agonists, such as: igmesine, cutamesine, OPC-14523, opipramol, PRE-084, SA-4503, ANAVEX2-73, ANAVEX1-41, ANAVEX3-71d, etc. have obvious antidepressant effect; patent WO2017190109 discloses the structure of part of sigma receptor agonists and the use of CNS related diseases.
However, the most rapidly developed Igmesine has failed in clinical phase 3 experiments, and the marketed Opipramol is directed against sigma-1 targets, dopamine D2 receptor antagonists and histamine H1 receptor antagonists, and the multi-target effect brings about certain side effects.
Disclosure of Invention
The inventor researches and discovers that 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one has good affinity and selectivity to sigma-1 receptor, has good safety and metabolic stability, and has good application prospect in the treatment and prevention of central nervous diseases, in particular to anti-depression and anti-anxiety aspects. Related content is described in PCT/CN2021/103543, the entire contents of which are incorporated herein by reference.
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one has the structural formula:
Figure BDA0003889770950000021
there is no literature report on the compound 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in the form of an acid salt and its crystalline form.
The pharmaceutically active ingredient exhibits different physical properties depending on its solid form. The difference in physical properties may affect, for example, the method of producing a pharmaceutically active ingredient, the mode of administration, and the preparation, and in general, the physical properties can be changed by using a salt or a crystalline solid. Another important solid state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid. In particular, the solid state form of an orally administered active ingredient may also affect its solubility, bioavailability, stability, etc. The solid state physical properties of a polymorphic compound also include, for example, the flowability of the crushed solid, which can affect the ease of handling during processing into a pharmaceutical product, and the solid state form of the compound also affects its compressibility and storage stability.
The inventor finds that the compound shown in the formula I is usually sticky and gelatinous in the research process, is inconvenient to store and weigh, and is unfavorable for subsequent preparation development. The object of the present invention is to further study and develop different salts and/or crystalline solids of the compounds, making the active pharmaceutical compounds more favourable for pharmaceutical preparations.
To improve the physicochemical properties, such as the behavior, hygroscopicity and chemical stability, of the compound 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, the inventors have intensively studied the different solid forms of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one. Acid salts of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, crystalline forms thereof, and methods of preparation are provided.
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, defined as compound I, has the structure shown below:
Figure BDA0003889770950000031
the preparation process is described in PCT/CN 2021/103543.
In a first aspect the invention provides an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, said acid salt comprising an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid salt, hydroiodide or phosphate, more preferably hydrochloride; the organic acid salt is selected from the group consisting of p-toluenesulfonate, fumarate, tartrate, maleate, acetate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclohexaneaminosulfonate, gluconate, glucuronate, glutamate, isoascorbate, lactate, aspartate, malate, mandelate, methanesulfonate, ethanesulfonate, galactoate, glutarate, hippurate, lactobionate, ascorbate, aspartate, laurate, malonate, 1, 5-naphthalenedisulfonate, naphthalene-2-sulfonate, nicotinate, oleate, oxalate, palmitate, sebacate, stearate, succinate, trifluoroacetate, succinate, more preferably p-toluenesulfonate, fumarate, or maleate.
In a specific embodiment of the invention, the acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, wherein the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (compound I) to acid is from 1:1 to 2, preferably from 1:1 or 1:2.
in another aspect the invention provides an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, said acid salt being the hydrochloride salt selected from hydrochloride form I or hydrochloride form II, wherein the hydrochloride form I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 10.00 ° ± 0.2 °,11.99 ° ± 0.2 °,17.45 ° ± 0.2 °,23.15 ° ± 0.2 °,24.22 ° ± 0.2 ° and 26.58 ° ± 0.2 °;
preferably, peaks at diffraction angles (2θ) of 7.97 ° ± 0.2 °,9.19 ° ± 0.2 °,10.00 ° ± 0.2 °,11.99 ° ± 0.2 °,17.45 ° ± 0.2 °,20.92 ° ± 0.2 °,23.15 ° ± 0.2 °,24.22 ° ± 0.2 °, and 26.58 ° ± 0.2 °;
more preferably, the peak at the diffraction angle (2θ) of 7.97++0.2°, 9.19++0.2°, 10.00++0.2°,11.11±0.2°, 11.99++0.2°,12.64±0.2°,13.16±0.2°,16.94±0.2°, 17.45++0.2°,18.40±0.2°,20.39±0.2°, 20.92++0.2°,21.71±0.2°, 23.15++0.2°, 24.22++0.2°, 26.58++0.2° 28.79±0.2° isincluded.
Most preferably, the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in fig. 1, and the X-ray powder diffraction data are shown in table 1:
table 1:
Figure BDA0003889770950000032
Figure BDA0003889770950000041
the present invention provides a hydrochloride salt form II of compound I having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 9.17 ° ± 0.2 °,15.33 ° ± 0.2 °,16.17 ° ± 0.2 °,18.24 ° ± 0.2 °,18.77 ° ± 0.2 °,22.58 ° ± 0.2 ° and 24.10 ° ± 0.2 °.
Preferably, the hydrochloride form II, its X-ray powder diffraction pattern comprises peaks at diffraction angles (2θ) of 9.17°±0.2°,11.18°±0.2°,14.75°±0.2°,15.33°±0.2°,16.17°±0.2°,18.24°±0.2°,18.77°±0.2°,22.58°±0.2°,24.10°±0.2° and 29.52°±0.2°.
More preferably, the hydrochloride form II, the X-ray powder diffraction pattern of which comprises peaks at diffraction angles (2θ) of 9.17 ° ± 0.2 °,11.18 ° ± 0.2 °,14.75 ° ± 0.2 °,15.33 ° ± 0.2 °,16.17 ° ± 0.2 °,17.80±0.2 °,18.24 ° ± 0.2 °,18.77 ° ± 0.2 °,21.32 ±0.2 °,22.01±0.2 °,22.58 ° ± 0.2 °,23.48±0.2 °,24.10 ° ± 0.2 °,24.85±0.2° 27.46 ±0.2 °,28.67±0.2° and 29.52 ° ± 0.2 °.
Most preferably, the hydrochloride salt form II has an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angle (2θ) shown in fig. 2, and has X-ray powder diffraction data as shown in table 2:
Table 2:
Figure BDA0003889770950000042
Figure BDA0003889770950000051
the hydrochloride of the crystal form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one provided by the invention comprises a hydrochloride crystal form I and a hydrochloride crystal form II, and can be characterized by DSC, and the hydrochloride crystal form I is analyzed and identified by a differential scanning calorimeter, the scanning speed is 10 ℃/min, and the hydrochloride crystal form I comprises an endothermic peak with the peak temperature of 238.8+/-3 ℃; the hydrochloride form II comprises endothermic peaks with peak temperatures of 101.46 ℃ + -3 ℃ and 219.39 ℃ + -3 ℃.
In one embodiment of the invention, the 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is present in a salt-forming molar ratio with hydrochloric acid of 1:1 or 1:2.
in one embodiment of the present invention, there is provided an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, which is a p-toluenesulfonate salt selected from p-toluenesulfonate salt form I having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.78 ° ± 0.2 °,10.34 ° ± 0.2 °,11.50 ° ± 0.2 °,12.03 ° ± 0.2 °,14.00 ° ± 0.2 °,16.64 ° ± 0.2 °,17.66 ° ± 0.2 °,19.71 ° ± 0.2 °,20.86 ° ± 0.2 ° and 23.08 ° ± 0.2 °.
Preferably, the p-toluenesulfonate salt form I, its X-ray powder diffraction pattern comprises peaks at diffraction angles (2θ) of 7.78 ° ± 0.2 °,10.34 ° ± 0.2 °,11.50 ° ± 0.2 °,12.03 ° ± 0.2 °,14.00 ° ± 0.2 °,15.46 ±0.2 °,15.91±0.2 °,16.64 ° ± 0.2 °,17.66 ° ± 0.2 °,19.04±0.2 °,19.71 ° ± 0.2 °,20.86 ° ± 0.2 °,21.66±0.2 °,22.26±0.2 °,23.08 ° ± 0.2 ° and 24.58±0.2°.
Most preferably, the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 3, and has X-ray powder diffraction data as shown in table 3:
table 3:
Figure BDA0003889770950000052
Figure BDA0003889770950000061
the p-toluenesulfonate crystal form I can be characterized by DSC, and is analyzed and identified by a differential scanning calorimeter, the scanning speed is 10 ℃/min, and the p-toluenesulfonate crystal form I comprises an endothermic peak with the peak temperature of 203.15 +/-3 ℃.
Further preferred, the salt forming molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to p-toluenesulfonic acid is 1:1.
In one embodiment of the present invention, there is provided an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, which is the fumarate salt, including fumarate salt form I or fumarate salt form II, wherein,
The fumarate salt crystal form I has an X-ray powder diffraction pattern including peaks at diffraction angles (2 theta) of 7.90 DEG + -0.2 DEG, 10.36 DEG + -0.2 DEG, 11.89 DEG + -0.2 DEG, 12.44 DEG + -0.2 DEG, 15.89 DEG + -0.2 DEG, 17.73 DEG + -0.2 DEG, 19.91 DEG + -0.2 DEG, 22.15 DEG + -0.2 DEG, 23.98 DEG + -0.2 DEG and 28.04 DEG + -0.2 deg.
Preferably, the fumarate salt form I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.90 ° ± 0.2 °,10.36 ° ± 0.2 °,11.89 ° ± 0.2 °,12.44 ° ± 0.2 °,14.53±0.2 °,15.89 ° ± 0.2 °,17.08±0.2 °,17.73 ° ± 0.2 °,19.91 ° ± 0.2 °,20.38±0.2 °,22.15 ° ± 0.2 °,23.98 ° ± 0.2 °,24.54±0.2° and 28.04 ° ± 0.2 °.
Most preferably, the fumarate salt form I has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 4, and has X-ray powder diffraction data as shown in table 4:
table 4:
Figure BDA0003889770950000062
Figure BDA0003889770950000071
the fumarate salt form II, the X-ray powder diffraction pattern of which comprises peaks at diffraction angles (2θ) of 9.56 ° ± 0.2 °,12.50 ° ± 0.2 °,16.79 ° ± 0.2 °,21.60 ° ± 0.2 °,23.06 ° ± 0.2 ° and 25.79 ° ± 0.2 °.
Preferably, the fumarate salt form II, its X-ray powder diffraction pattern comprises peaks at diffraction angles (2θ) of 8.35°±0.2°,9.56°±0.2°,12.50°±0.2°,16.79°±0.2°,18.66°±0.2°,20.40°±0.2°,21.60°±0.2°,23.06°±0.2° and 25.79°±0.2°.
More preferably, the fumarate salt form II, its X-ray powder diffraction pattern comprises peaks at diffraction angles (2θ) of 8.35 ° ± 0.2 °,9.56 ° ± 0.2 °,12.50 ° ± 0.2 °,13.40±0.2 °,15.52±0.2 °,16.79 ° ± 0.2 °,18.66 ° ± 0.2 °,20.40 ° ± 0.2 °,21.60 ° ± 0.2 °,23.06 ° ± 0.2 ° and 25.79 ° ± 0.2 °.
Most preferably, the fumarate salt form II has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 5, and has X-ray powder diffraction data as shown in table 5:
table 5:
Figure BDA0003889770950000072
Figure BDA0003889770950000081
the fumarate crystal form I or the fumarate crystal form II can also be characterized by DSC, and can be analyzed and identified by a differential scanning calorimeter, the scanning speed is 10 ℃/min,
the fumarate salt crystal form I comprises endothermic peaks with peak temperatures of 115.47 +/-3 ℃ and 157.84 +/-3 ℃,
the fumarate salt form II contains an endothermic peak with a peak temperature of 180.03 ℃ + -3 ℃.
Further preferred, the acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is the fumarate salt, including fumarate salt form I or fumarate salt form II, wherein the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to fumarate salt is 1:1.
In one embodiment of the present invention, there is provided an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, said acid salt being a maleate salt selected from maleate salt form I,
the maleate salt form I, the X-ray powder diffraction pattern of which comprises peaks at diffraction angles (2θ) of 4.06 ° ± 0.2 °,8.11 ° ± 0.2 °,10.82 ° ± 0.2 °,12.18 ° ± 0.2 °,13.58 ° ± 0.2 °,16.27 ° ± 0.2 °,18.23 ° ± 0.2 °,20.38 ° ± 0.2 °,24.28 ° ± 0.2 ° and 28.68 ° ± 0.2 °.
Preferably, the maleate salt form I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 4.06 ° ± 0.2 °,8.11 ° ± 0.2 °,9.08±0.2 °,10.82 ° ± 0.2 °,12.18 ° ± 0.2 °,13.58 ° ± 0.2 °,16.27 ° ± 0.2 °,16.82±0.2 °,18.23 ° ± 0.2 °,20.38 ° ± 0.2 °,24.28 ° ± 0.2 °,28.21±0.2° and 28.68 ° ± 0.2 °.
Most preferably, the maleate salt form I has an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angle (2θ) shown in fig. 6, and has X-ray powder diffraction data as shown in table 6:
table 6:
Figure BDA0003889770950000082
Figure BDA0003889770950000091
further preferred, the acid salt of crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is the maleate salt selected from the maleate salt crystalline form I, wherein the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to maleic acid salification is 1:1.
The term "substantially identical" as used herein with respect to the position of the X-ray diffraction peak means that typical peak position and intensity variability are considered. For example, one skilled in the art will appreciate that peak position (2θ) will vary in measurement due to XRPD instrument differences, sometimes by as much as 0.2 °. Furthermore, those skilled in the art will appreciate that factors such as the method of sample preparation, the XRPD instrument, the sample crystallinity, the sample amount, and the preferred crystal orientation will result in a change in the relative peak intensities in the XRPD diffractogram of the sample.
In another aspect, the invention provides a process for preparing an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, comprising:
dissolving or dispersing 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one free base in an organic solvent, then adding a liquid of an inorganic or organic acid, or adding a solid of an inorganic or organic acid, or a solution of an acid, to prepare an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one; or alternatively, the process may be performed,
Adding 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to a solution of an acid to produce an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one; wherein the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to acid is 1:1 to 2.5. The molar ratio of the acid to be fed is related to the acid content of the prepared acid salt, for example, when the molar ratio of the preparation is 1:1, the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to acid was 1:1 to 1.1;
when the molar ratio of the preparation is 1:2, 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, and the acid are fed in a molar ratio of 1:2 to 2.5, preferably 1:2 to 2.1.
In another aspect of the invention, there is also provided a process for preparing an acid salt of crystalline 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, comprising:
Preparing an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to the procedure described previously;
collecting solid products precipitated in the salt forming reaction process, or creating supersaturated solution in a salt system to obtain the solid products, wherein the method for creating the supersaturated solution comprises the following steps: volatilizing the solvent, or adding an anti-solvent, or cooling to obtain a crystalline 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one acid salt;
and/or converting one form of the acid salt to another form of the salt by a process of form conversion. The crystal form conversion method comprises the following steps: the seeding is carried out by heating or suspending in a suitable solvent.
In the above method, suitable organic solvents used in the salification process include alcohols (e.g., methanol, ethanol, isopropanol), chlorinated alkanes (e.g., methylene chloride), ketones (e.g., acetone), ethers (e.g., diethyl ether), esters (e.g., ethyl acetate), alkanes (e.g., n-hexane, n-heptane), acetonitrile, benzene, amides or mixtures thereof, preferably methanol, ethanol, ethyl acetate, acetonitrile or mixtures thereof; the acid solution is an acid ethyl acetate solution or an acid acetonitrile solution.
For example, a process for the preparation of hydrochloride form I comprising:
adding 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one into dichloromethane, adding ethyl acetate solution of hydrochloric acid after complete dissolution, precipitating solid, concentrating under reduced pressure, and drying to obtain dark green solid;
wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to hydrochloric acid is 1:1-2.5, preferably 1:2-2.1.
For example, a process for the preparation of compound I hydrochloride form II comprising:
dissolving 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in ethanol, preferably by dropwise adding ethyl acetate for dilution, then adding concentrated hydrochloric acid, stirring at room temperature, centrifuging after the reaction is finished, and drying the solid in vacuum; wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to hydrochloric acid is 1:1-2.5, preferably 1:1-1.1.
For example, a process for the preparation of the p-toluenesulfonate salt form I of compound I, comprising:
dissolving 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in ethanol, then adding an acetonitrile solution of p-toluenesulfonic acid, stirring at room temperature, centrifuging after the reaction is finished, and drying the solid in vacuum;
Wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to p-toluenesulfonic acid is 1:1-2.5, preferably 1:1-1.1.
For example, a process for the preparation of crystalline form I of compound I fumarate salt, comprising:
dissolving 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in ethanol, then adding acetonitrile solution of fumaric acid, stirring at room temperature, centrifuging after the reaction is finished, and drying the solid in vacuum; wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to fumaric acid is 1:1 to 2.5, preferably 1:1 to 1.1.
For example, a process for the preparation of compound I fumarate salt form II comprising:
dissolving 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in ethanol, then adding ethyl acetate solution of fumaric acid, stirring at room temperature, centrifuging after the reaction is finished, and drying the solid in vacuum;
wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to fumaric acid is 1:1 to 2.5, preferably 1:1 to 1.1.
For example, a process for the preparation of compound I maleate form I comprising:
dissolving 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one in ethanol, then adding an acetonitrile solution of maleic acid, stirring at room temperature, centrifuging after the reaction is finished, and drying the solid in vacuum for 10 hours;
wherein the molar feed ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to maleic acid is 1:1 to 2.5, preferably 1:1 to 1.1.
In another aspect of the invention there is provided a pharmaceutical composition comprising an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to the invention, and a pharmaceutically acceptable carrier or excipient, preferably the acid salt is the hydrochloride, fumarate, maleate or p-toluenesulfonate salt of compound I, more preferably the acid salt is the hydrochloride of compound I.
In another embodiment of the invention, a pharmaceutical composition is provided comprising the crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one acid salt of the present invention and a pharmaceutically acceptable carrier or excipient; preferably, the acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is hydrochloride form I, hydrochloride form II, fumarate form I, fumarate form II, p-toluenesulfonate form I or maleate form I.
In another aspect of the invention, there is provided the use of an acid salt of said 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, or of said crystalline 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, or of said pharmaceutical composition in the preparation of a medicament for the treatment of neuropsychiatric disorders; preferably, the neuropsychiatric disease is selected from any one of depression and anxiety.
The present invention also provides a method of treating and/or preventing a sigma-1 receptor related disease or condition comprising administering to a subject in need thereof an acid salt of compound I or an acid salt of compound I in crystalline form, or a pharmaceutical composition comprising an acid salt of compound I or a crystalline form thereof, as described herein.
In another embodiment of the invention, the acid salt of compound I or the acid salt of compound I in crystalline form, or a pharmaceutical composition comprising the acid salt of compound I or the crystalline form thereof, according to the invention is used for the treatment and/or prophylaxis of a sigma-1 receptor related disease or condition. Further, the sigma-1 receptor related diseases are mental diseases such as depression, anxiety, alzheimer's disease and the like, preferably depression.
The beneficial effects are that: compared with the prior art, the acid salt of the compound I, particularly the hydrochloride, has obvious improvement on physicochemical properties, such as no obvious degradation, weak hygroscopicity, good crystal form stability, and good crystal form stability under a high-humidity environment, so that the drug property of the raw material can be kept stable under the conventional humidity storage condition, and the acid salt can be better used in clinical treatment. In addition, the acid salt of the compound I provided by the invention has better sigma-1 affinity and good drug effect in mice. Compared with the compound free alkali, the acid salt of the compound I provided by the invention is in a solid crystal form or a powder form, and is favorable for storage, weighing and subsequent preparation development.
Drawings
The technical scheme of the application is further described below with reference to the accompanying drawings and examples.
FIG. 1 is an XRPD pattern for hydrochloride form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 2 is an XRPD pattern for hydrochloride form II of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 3 is an XRPD pattern for p-toluenesulfonate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 4 is an XRPD pattern for fumarate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 5 is an XRPD pattern for fumarate salt form II of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 6 is an XRPD pattern for maleate form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
FIG. 7 is a crystalline form XRPD comparison of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one hydrochloride after 5 days and 10 days of standing at room temperature and humidity, respectively;
FIG. 8 is a crystalline form XRPD comparison plot of the hydrochloride salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one after 5 days and 10 days of standing at 40℃under 75% RH, respectively;
FIG. 9 is a crystalline form XRPD comparison of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one hydrochloride, after 5 days of standing at 25 ℃ + -1 ℃,80% + -4% RH humidity.
Detailed Description
Unless otherwise indicated, implied from the context, or common denominator in the art, all parts and percentages in the present application are based on weight and the test and characterization methods used are synchronized with the filing date of the present application. If the definition of a particular term disclosed in the prior art does not conform to any definition provided in this application, the definition of that term provided in this application controls.
The words "preferably," "preferred," "more preferred," "most preferred," and the like in the present disclosure refer to embodiments of the present disclosure that may provide certain benefits in some instances. However, other embodiments may be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention. "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. The sources of the components not mentioned in the present invention are all commercially available.
The term "crystalline form" as used herein means a crystal having a certain crystal form and comprising atoms, ions, molecules, and the like constituting a solid in a regular arrangement. Unless otherwise indicated, the term "crystal" in this specification is synonymous with "crystalline form" and "crystalline form". The crystallinity of the crystalline form can be measured by various techniques including, for example, X-ray powder diffraction measurement, moisture adsorption/desorption measurement, differential scanning calorimetry measurement, solution colorimetry measurement, dissolution characteristics, and the like.
The crystalline solid of the present invention may be single crystal, double crystal, polycrystal, etc., and is usually single crystal or a mixed crystal thereof. The crystal form (external shape) is not particularly limited, and may be, for example, triclinic, monoclinic, orthorhombic (rectangular), tetragonal, cubic, trigonal (rhombohedral), hexagonal, or the like, or may be spherulitic, skeletal, bark-like, needle-like (e.g., whisker-like) or the like. The size of the crystals is not particularly limited, and the average particle diameter of the crystals may be, for example, about 0.5 μm to 1mm, preferably about 1 to 500 μm, based on a laser diffraction method.
In addition, the acid salt of crystalline 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one may also undergo moisture adsorption due to changes in relative humidity, i.e., may also cause water molecules in the air to easily come in and go out of the crystalline solid in the lattice in the form of crystal water due to changes in external humidity; the above-mentioned crystalline solid may be interpreted as a crystalline solid which is substantially the same as the X-ray powder diffraction pattern when the X-ray powder diffraction pattern varies slightly with the variation of the moisture content, as long as the crystalline solid has the characteristic peaks described in the present specification. The water may be any of residual solvents such as crystal water and adhesion water; in a preferred embodiment of the invention, the acid salt of crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is free of water of crystallization.
The invention relates to a compound I and a compound 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -ketone, which refer to the same compound and can be mutually replaced, and both refer to a compound with the following structure:
Figure BDA0003889770950000141
the crystalline forms of the acid salts of the compounds I according to the invention are characterized by their X-ray powder diffraction pattern. That is, using Cu-K alpha radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta angle was obtained. The "2 theta or 2 theta angle" refers to a diffraction angle, and theta is a Bragg angle, and the unit is degree or degree; the error range of each characteristic peak 2 theta in the X-ray powder diffraction pattern may be + -0.3, + -0.2, + -0.1, preferably + -0.2.
The absolute and relative intensities of the peaks shown in the foregoing tables and figures may vary due to various factors, such as the effect of the selected orientation of the crystalline solid on the X-ray beam, the effect of coarse particles, the purity of the substance being analyzed, or the degree of crystallization 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=2dsinθ), and different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.
In addition to the aforementioned determination of the crystalline form of the acid salt of compound I by X-ray powder diffraction spectroscopy, the determination may also be performed by thermal analysis methods, including, for example, but not limited to DSC, TG/DTA, raman.
The "differential scanning calorimetric analysis" or "DSC" described in the present invention measures the transition temperature when the 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.
The X-ray powder diffraction patterns of the following examples were collected on an alis X-ray powder diffractometer of the family panaceae at a conventional temperature, for example 25 ℃. The X-ray powder diffraction method has the following parameters:
x-ray reflection parameters: cu, K alpha
Wavelength:
Figure BDA0003889770950000151
tube pressure: 40KV
Tube flow: 15mA
Step size: 0.0110 DEG
Scanning each step of time: 18.87s
Scanning range: from 3.0 to 40.0 DEG
Differential Scanning Calorimetric (DSC) plots were each collected on a TA DSC25 differential scanning calorimeter. The method parameters are as follows: rate of temperature rise: 10 ℃/min; protective gas: nitrogen gas.
Preparation of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one:
the preparation of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one was carried out according to the procedure described in examples 1 and 4 of PCT/CN2021/103543, the reaction equation being as follows:
Figure BDA0003889770950000152
(1) Synthesis of 7-bromo-2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinoline
7-bromo-1, 2,3, 4-tetrahydroisoquinoline (4.71 g,22.2 mmol), bromomethylcyclopropane (3.15 g,23.13 mmol) was dissolved in 150mL acetonitrile and the reaction was stirred magnetically overnight, after which the reaction was completed and purified by silica gel column chromatography (PE/EA=15/1) to give 5.8g (98.3% yield) of 7-bromo-2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinoline.
(2) Synthesis of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
Reactant 7-bromo-2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinoline (266 mg,1.0 mmol), 5- (isopropylamino) -1-methylpyridin-2 (1H) -one (182.8 mg,1.1 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (48 mg,0.10 mmol), pd 2 (dba) 3 (92mg，0.10mmol)，Cs 2 CO 3 (630 mg,1.9 mmol) and xylene (10 ml) were added sequentially to the flask and reacted at 100℃for 16 hours under nitrogen. After the reaction is finished, the liquid is applied Cooled to room temperature, filtered over celite, the filter cake was washed with EA (30 ml x 2) and DCM (50 ml x 2), the organic phases combined, concentrated, and purified by column chromatography (DCM/meoh=10:1) to give 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one as a greenish black gum, viscous material.
1 H NMR(400MHz,Methanol-d4)δ7.65(d,J＝2.8Hz,1H),7.47(d,J＝2.8Hz,0.5H),7.44(d,J＝2.9Hz,0.5H),7.20(d,J＝8.5Hz,1H),6.85(d,J＝9.4Hz,2H),6.74(d,J＝2.1Hz,1H),4.60(d,J＝15.4Hz,1H),4.38–4.25(m,2H),3.86(d,J＝16.4Hz,1H),3.78(s,3H),3.42(d,J＝6.2Hz,1H),3.27–3.05(m,4H),1.24(s,1H),1.18(d,J＝6.5Hz,6H),0.81(d,J＝8.1Hz,2H),0.50(q,J＝4.8Hz,2H).MS(ESI)m/z 352.3([M+H] + )。
Example 15 preparation of hydrochloride salt form I of- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
To a 200ml single-neck flask was added 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (4.9 g,13.94 mmol) and dichloromethane (50 ml) to complete dissolution, then ethyl acetate solution of hydrochloric acid (15 ml,2 mol/L) was added, and after ultrasonic treatment for 10min, a clear solid was precipitated, concentrated under reduced pressure, dried to give an dark green solid, HPLC:98.24%. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 1, and whose XRPD pattern is shown in fig. 1, is 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one hydrochloride, crystalline form I.
1 H NMR(400MHz,Methanol-d4)：δ7.64(d,J＝2.7Hz,1H),7.45(dd,J＝9.5,2.9Hz,1H),7.19(d,J＝8.4Hz,1H),6.84(d,J＝9.3Hz,2H),6.73(d,J＝2.4Hz,1H),4.60(d,J＝15.3Hz,1H),4.37–4.24(m,2H),3.86(d,J＝11.7Hz,1H),3.76(s,3H),3.45-3.34(m,5.2Hz,1H),3.29–3.14(m,3H),3.13-3.04(m,1H),1.30–1.22(m,1H),1.17(d,J＝6.5Hz,6H),0.85–0.77(m,2H),0.50(t,J＝5.0Hz,2H)。
The salt formation stoichiometry of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to hydrochloric acid was 1:2 as determined by chlorine content titration.
Analysis by a differential scanning calorimeter identified that there was an error margin of + -3 deg.c for an endothermic peak at a scan rate of 10 deg.c/min containing 238.8 deg.c (peak temperature). The hydrochloride crystal form I is an anhydrous crystal form.
Example 2: preparation of hydrochloride salt form II of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (1.5 g,4.268 mmol) was dissolved in ethanol (7 mL), 100. Mu.L of the above solution was taken and diluted by dropwise with 0.5mL of ethyl acetate, then 37% by mass hydrochloric acid (4.7. Mu.L) was added, the reaction was stirred at room temperature for 72 hours, centrifuged, and the solid was dried in vacuo for 4 hours. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 2, and whose XRPD pattern is shown in fig. 2, is 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, hydrochloride crystalline form II.
1 H NMR(400MHz,Methanol-d 4)：δ7.55(d,J＝2.7Hz,1H),7.30(dd,J＝9.5,2.8Hz,1H),7.06(d,J＝8.6Hz,1H),6.68(dd,J＝8.6,2.6Hz,1H),6.61(d,J＝9.5Hz,1H),6.50(d,J＝2.6Hz,1H),4.33(s,2H),3.60(s,3H),3.54–3.51(m,1H),3.16–2.99(m,4H),1.28–1.19(m,1H),1.17(s,3H),1.16(s,3H),0.85–0.73(m,2H),0.51–0.42(m,2H)。
The error margin of + -3 deg.c was found by differential scanning calorimeter analysis at a scan rate of 10 deg.c/min, containing endothermic peaks of 101.46 and 219.39 deg.c (peak temperature).
Example 3: preparation of p-toluenesulfonate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (1.5 g,4.268 mmol) was dissolved in ethanol (7 mL), 10.3mg of p-toluenesulfonic acid was weighed into 0.5mL of acetonitrile, 100. Mu.L of the above solution was continuously added dropwise, the reaction was stirred at room temperature for 60 hours, centrifuged, and the solid was dried in vacuo for 10 hours. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 3, and whose XRPD pattern is shown in fig. 3, is the p-toluenesulfonate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one.
1 H NMR (400 MHz, methanol-d 4): delta 7.67 (d, j=7.8 hz, 2H), 7.56 (d, j=2.7 hz, 1H), 7.30 (dd, j=9.5, 2.8hz, 1H), 7.22 (d, j=7.9 hz, 2H), 7.06 (d, j=8.6 hz, 1H), 6.69 (dd, j=8.6, 2.6hz, 1H), 6.61 (d, j=9.5 hz, 1H), 6.50 (d, j=2.5 hz, 1H), 4.62-4.44 (m, 1H), 4.37-4.17 (m, 2H), 3.90-3.74 (m, 1H), 3.59 (s, 3H), 3.42-3.32 (m, 1H), 3.23-3.07 (m, 3H), 3.06-2.94 (m, 1H), 2.37 (s, 1.25-1H), 1.18 (m, 1H), 4.37-4.17 (m, 2H), 1.9 hz, 1.9 (m, 1H). The salt formation chemical ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to p-toluenesulfonic acid was 1:1 by nuclear magnetic hydrogen spectrum analysis.
The error margin of + -3 deg.c was found by differential scanning calorimeter analysis at a scan rate of 10 deg.c/min, containing an endothermic peak of 203.15 deg.c (peak temperature). The p-toluenesulfonate salt is in the anhydrous crystalline form.
Example 4: preparation of fumarate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (1.5 g,4.268 mmol) was dissolved in ethanol (7 mL), 6.2mg of fumaric acid was weighed, 0.5mL of acetonitrile was added, 100. Mu.L of the above solution was further added dropwise, the reaction was stirred at room temperature for 60 hours, centrifuged, and the solid was dried in vacuo for 10 hours. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 4, and whose XRPD pattern is shown in fig. 4, is the fumarate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one.
1 H NMR(400MHz,Methanol-d4)：δ7.56(d,J＝2.8Hz,1H),7.30(dd,J＝9.5,2.8Hz,1H),7.05(d,J＝8.6Hz,1H),6.70–6.65(m,1H),6.65(s,2H),6.61(d,J＝9.5Hz, 1H), 6.49 (d, j=2.6 Hz, 1H), 4.36 (s, 2H), 3.60 (s, 3H), 3.57-3.53 (m, 1H), 3.13 (d, j=7.3 Hz, 2H), 3.07 (t, j=6.4 Hz, 2H), 1.26-1.18 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 0.84-0.74 (m, 2H), 0.50-0.42 (m, 2H). The salt formation stoichiometry of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to fumaric acid was 1:1 by nuclear magnetic hydrogen spectrometry.
The error margin of + -3 deg.c was found by differential scanning calorimeter analysis at a scan rate of 10 deg.c/min, containing endothermic peaks of 115.47 and 157.84 deg.c (peak temperature). The fumarate is in an anhydrous crystalline form.
Example 5: preparation of fumarate salt form II of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (1.5 g,4.268 mmol) was dissolved in ethanol (7 mL), 6.3mg of fumaric acid was weighed, 0.5mL of ethyl acetate was added, 100. Mu.L of the above solution was further added dropwise, the reaction was stirred at room temperature for 60 hours, centrifuged, and the solid was dried in vacuo for 10 hours. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 5, and whose XRPD pattern is shown in fig. 5, is the fumarate salt form II of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one.
1 H NMR(400MHz,Methanol-d4)：δ7.56(d,J＝2.8Hz,1H),7.30(dd,J＝9.5,2.8Hz,1H),7.05(d,J＝8.6Hz,1H),6.69–6.65(m,1H),6.64(s,2H),6.61(d,J＝9.5Hz,1H),6.49(d,J＝2.6Hz,1H),4.36(s,2H),3.59(s,3H),3.56–3.52(m,1H),3.12(d,J＝7.3Hz,2H),3.07(t,J＝6.4Hz,2H),1.26–1.18(m,1H),1.17(s,3H),1.15(s,3H),0.83–0.72(m,2H),0.46(q,J＝5.2Hz,2H)。
The salt formation stoichiometry of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to fumaric acid was 1:1 by nuclear magnetic hydrogen spectrometry.
The error margin of + -3 deg.c was found by differential scanning calorimeter analysis at a scan rate of 10 deg.c/min, containing an endothermic peak of 180.03 deg.c (peak temperature). The fumarate is in an anhydrous crystalline form.
Example 6: preparation of maleate salt form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one
5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one (1.5 g,4.268 mmol) was dissolved in ethanol (7 mL), 6.3mg of maleic acid was weighed into 0.5mL of acetonitrile, 100. Mu.L of the above solution was further added dropwise, the reaction was stirred at room temperature for 60 hours, centrifuged, and the solid was dried in vacuo for 10 hours. Identified by an aeis X-ray powder diffraction (XRPD) analysis, whose XRPD data are shown in table 6, and whose XRPD pattern is shown in fig. 6, is maleate form I of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one.
1 H NMR(400MHz,Methanol-d4)：δ7.28(d,J＝2.7Hz,1H),7.02(dd,J＝9.5,2.8Hz,1H),6.77(d,J＝8.6Hz,1H),6.39(dd,J＝8.6,2.6Hz,1H),6.32(d,J＝9.5Hz,1H),6.21(d,J＝2.6Hz,1H),5.93(s,2H),4.11(s,2H),3.31(s,3H),3.06-2.99(m,1H),2.88(d,J＝7.3Hz,2H),2.80(t,J＝6.5Hz,2H),1.06-0.92(m,1H),0.88(s,3H),0.87(s,3H)0.60–0.44(m,2H),0.22–0.16(m,2H)。
The salt formation stoichiometry of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to maleic acid was 1:1 by nuclear magnetic hydrogen spectrometry.
Test case
Test example 1: study of Properties
The appearance of the 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one bulk drug is a dark green colloid and a sticky substance, which is not beneficial to the use in the subsequent preparation development process.
After the acid salt is prepared, the appearance is crystalline or powdery solid, and the acid salt can be conveniently stored, weighed and used for processing subsequent preparations.
Test example 2: moisture-wicking test of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one salt
Taking a proper amount of samples of different salt forms of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, spreading the samples in a glass bottle with the thickness of about 1mm, placing an opening of the glass bottle in a closed environment with the temperature of 25+/-1 ℃ and the relative humidity of 80+/-4%, and examining the wettability of each salt form after constant humidity for 5 days. The results of the wettability of the hydrochloride are shown in table 7 and fig. 9.
Table 7:
Figure BDA0003889770950000191
XRPD detection showed that hydrochloride form I did not change after 5 days of standing at 80% ± 4% rh humidity as shown in fig. 9. The results show that the acid salt of compound I provided by the present invention has little or no hygroscopicity.
Test example 3: stability test of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one salt
Samples of appropriate amounts of different salt forms of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one were taken, tiled in glass vials to a thickness of about 1.5mm, the glass vials were placed open at 25 ℃ + -3 ℃ and 60% + -5% relative humidity (i.e., room temperature, room humidity) and 40 ℃ and 75% relative humidity, respectively, sampled at 5 days and 10 days, subjected to XRPD assays while HPLC content (w/w,%) assays were performed, and compared to the results for 0 day to evaluate the stability of the salt forms.
As an example of the hydrochloride, the physical and chemical stability of the hydrochloride was good at room temperature, room humidity and 75% RH at 40℃and the test results are shown in Table 8.
Table 8:
Figure BDA0003889770950000201
the hydrochloride form I as shown in fig. 7 and 8 did not change at room temperature, room humidity and 40 ℃ under 75% rh conditions for 10 days.
Test example 4 Sigma-1 agonist function test
According to the literature report ([ J ]. Syntase, 2005,55 (3): 192-195.), phenytoin can alter the configuration of the sigma-1 receptor, in the presence of phenytoin, the Ki value of an agonist is smaller than the normal Ki value and the Ki value of an inhibitor is greater than the normal Ki value.
The specific procedure in reference ([ J ]. Syntase, 2005,55 (3): 192-195.) is to take compound I hydrochloride as an example to test the Ki value of the compound of the present invention, and the phenytoin group Ki value test method is to add phenytoin to the test tube additionally and to test the Ki value after the phenytoin addition. Normal Ki values/phenytoin group Ki values >1, can be determined as agonists.
Table 9 shows that the ratio of compound I hydrochloride (normal Ki/phenytoin group Ki) >1 is an agonist.
TABLE 9 Ki values and ratios of Normal to phenytoin groups
Ki value (nM)
Sigma-1 (Normal Ki) 49.62
Sigma-1 (phenytoin group Ki) 47.88
Ratio of 1.04
Test example 5: in vivo efficacy test of mice
Forced Swim Test (FST) in mice: male ICR mice, weighing 18-22g, were used, and were divided into vehicle control group, positive control group (duloxetine, 15 mg/kg), and test group (acid salt of Compound I, 30, 60, 90 mg/kg). The test group, the vehicle group and the positive control group were intraperitoneally injected with the test substance or the vehicle 30 minutes before the formal swimming, and then the forced swimming test was performed on the mice. The mice were placed in a clear glass cylinder (15 cm water depth, 23-25 ℃ water temperature) for 6 minutes and the activity status of the mice was video recorded, and the cumulative immobility time results of the mice after 4 minutes after 6 minutes of forced swimming period were analyzed using Forced Swim ScanTM 2.0.0 software after the end of the experiment.
Taking compound I hydrochloride as an example, duloxetine group (positive control) showed very significant efficacy (p < 0.0001) in the forced swimming model of mice, compound I hydrochloride had no efficacy at 30mg/kg, significant efficacy at 60mg/kg (p < 0.05) and very significant efficacy at 90mg/kg (p < 0.0001).

Claims (15)

1. An acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that said acid salt is selected from the group consisting of hydrochloride, p-toluenesulfonate, fumarate, or maleate, preferably said acid salt is hydrochloride or p-toluenesulfonate.
2. The acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to claim 1, characterized in that the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to the acid is from 1:1 to 2, preferably from 1:1.
3. a crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the acid salt is selected from hydrochloride form I or hydrochloride form II,
the hydrochloride form I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 10.00 ° ± 0.2 °,11.99 ° ± 0.2 °,17.45 ° ± 0.2 °,23.15 ° ± 0.2 °,24.22 ° ± 0.2 ° and 26.58 ° ± 0.2 °;
the hydrochloride form II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 9.17 ° ± 0.2 °,15.33 ° ± 0.2 °,16.17 ° ± 0.2 °,18.24 ° ± 0.2 °,18.77 ° ± 0.2 °,22.58 ° ± 0.2 ° and 24.10 ° ± 0.2 °;
further preferred is the crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that,
The hydrochloride form I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 7.97 ° ± 0.2 °,9.19 ° ± 0.2 °,10.00 ° ± 0.2 °,11.99 ° ± 0.2 °,17.45 ° ± 0.2 °,20.92 ° ± 0.2 °,23.15 ° ± 0.2 °,24.22 ° ± 0.2 °, and 26.58 ° ± 0.2 °;
the hydrochloride form II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.17 ° ± 0.2 °,11.18 ° ± 0.2 °,14.75 ° ± 0.2 °,15.33 ° ± 0.2 °,16.17 ° ± 0.2 °,18.24 ° ± 0.2 °,18.77 ° ± 0.2 °,22.58 ° ± 0.2 °,24.10 ° ± 0.2 ° and 29.52 ° ± 0.2 °.
4. The crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one of claim 3,
the hydrochloride form I, having an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angles (2θ) shown in fig. 1;
the hydrochloride form II having an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angles (2θ) shown in fig. 2; and/or the number of the groups of groups,
the acid salt of the crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is characterized by the fact that, when characterized by DSC, it is identified by differential scanning calorimeter analysis, the scanning rate is 10 ℃/min,
The hydrochloride crystal form I comprises an endothermic peak with a peak temperature of 238.8+/-3 ℃;
the hydrochloride form II comprises endothermic peaks with peak temperatures of 101.46 ±3 ℃ and 219.39 ±3 ℃.
5. A crystalline form of an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the acid salt is selected from the group consisting of p-toluenesulfonate crystalline form I, whose X-ray powder diffraction pattern comprises peaks at diffraction angles (2Θ) of 7.78 ° ± 0.2 °,10.34 ° ± 0.2 °,11.50 ° ± 0.2 °,12.03 ° ± 0.2 °,14.00 ° ± 0.2 °,16.64 ° ± 0.2 °,17.66 ° ± 0.2 °,19.71 ° ± 0.2 °,20.86 ° ± 0.2 ° and 23.08 ° ± 0.2 °;
further preferred is the crystalline form of the acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I comprises peaks at diffraction angles (2θ) of 7.78 ° ± 0.2 °,10.34 ° ± 0.2 °,11.50 ° ± 0.2 °,12.03 ° ± 0.2 °,14.00 ° ± 0.2 °,15.46 ±0.2 °,15.91±0.2°,16.64 ° ± 0.2 °,17.66 ° ± 0.2 °,19.04±0.2 °,19.71 ° ± 0.2 °,20.86 ° ± 0.2 °,21.66±0.2 °,22.26±0.2 °,23.08 ° ± 0.2 ° and 24.58±0.2°.
6. The acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one of claim 5 wherein the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I is essentially the same as the peak at the diffraction angle (2Θ) shown in figure 3; and/or the number of the groups of groups,
an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one characterized by an endothermic peak having a peak temperature of 203.15 ℃ ± 3 ℃ as characterized by DSC, identified by differential scanning calorimeter analysis, at a scan rate of 10 ℃/min.
7. A crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the acid salt is selected from fumarate form I or fumarate form II,
the fumarate salt form I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.90 ° ± 0.2 °,10.36 ° ± 0.2 °,11.89 ° ± 0.2 °,12.44 ° ± 0.2 °,15.89 ° ± 0.2 °,17.73 ° ± 0.2 °,19.91 ° ± 0.2 °,22.15 ° ± 0.2 °,23.98 ° ± 0.2 ° and 28.04 ° ± 0.2 °;
The fumarate salt form II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 9.56 ° ± 0.2 °,12.50 ° ± 0.2 °,16.79 ° ± 0.2 °,21.60 ° ± 0.2 °,23.06 ° ± 0.2 ° and 25.79 ° ± 0.2 °;
preferably, the crystalline form of the acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is characterized in that,
the fumarate salt form I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.90 ° ± 0.2 °,10.36 ° ± 0.2 °,11.89 ° ± 0.2 °,12.44 ° ± 0.2 °,14.53±0.2 °,15.89 ° ± 0.2 °,17.08±0.2 °,17.73 ° ± 0.2 °,19.91 ° ± 0.2 °,20.38 ° ± 0.2 °,22.15 ° ± 0.2 °,23.98 ° ± 0.2 °,24.54 ° ± 0.2 ° and 28.04 ° ± 0.2 °;
the fumarate salt form II, the X-ray powder diffraction pattern of which comprises peaks at diffraction angles (2θ) of 8.35 ° ± 0.2 °,9.56 ° ± 0.2 °,12.50 ° ± 0.2 °,16.79 ° ± 0.2 °,18.66 ° ± 0.2 °,20.40 ° ± 0.2 °,21.60 ° ± 0.2 °,23.06 ° ± 0.2 ° and 25.79 ° ± 0.2 °.
8. The crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one of claim 7,
The fumarate salt form I, having an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angles (2θ) shown in fig. 4;
the fumarate salt form II having an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angles (2θ) shown in fig. 5; and/or the number of the groups of groups,
the acid salt of the crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one is characterized by the fact that, when characterized by DSC, it is identified by differential scanning calorimeter analysis, the scanning rate is 10 ℃/min,
the fumarate salt crystal form I comprises endothermic peaks with peak temperatures of 115.47 +/-3 ℃ and 157.84 +/-3 ℃;
the fumarate salt form II contains an endothermic peak with a peak temperature of 180.03 ℃ + -3 ℃.
9. An acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the acid salt is selected from maleate form I, whose X-ray powder diffraction pattern comprises peaks at diffraction angles (2Θ) of 4.06 ° ± 0.2 °,8.11 ° ± 0.2 °,10.82 ° ± 0.2 °,12.18 ° ± 0.2 °,13.58 ° ± 0.2 °,16.27 ° ± 0.2 °,18.23 ° ± 0.2 °,20.38 ° ± 0.2 °,24.28 ° ± 0.2 ° and 28.68 ° ± 0.2 °;
Further preferred, the crystalline form of the acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the maleate salt form I, the X-ray powder diffraction pattern of which comprises peaks at diffraction angles (2θ) of 4.06 ° ± 0.2 °,8.11 ° ± 0.2 °,9.08 ° ± 0.2 °,10.82 ° ± 0.2 °,12.18 ° ± 0.2 °,13.58 ° ± 0.2 °,16.27 ° ± 0.2 °,16.82±0.2°,18.23 ° ± 0.2 °,20.38 ° ± 0.2 °,24.28 ° ± 0.2 °,28.21±0.2°, and 28.68 ° ± 0.2 °;
still further preferred is the acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one, characterized in that the maleate salt form I has an X-ray powder diffraction pattern substantially identical to the peaks at the diffraction angles (2θ) shown in figure 6.
10. A process for the preparation of an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to any of claims 1 to 2, comprising:
dissolving or dispersing 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one free base in an organic solvent, then adding a liquid of an inorganic or organic acid, or adding a solid of an inorganic or organic acid, or a solution of an acid, to prepare an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one; or alternatively
Adding 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to a solution of an acid to produce an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
wherein the molar ratio of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one to acid is fed as 1:1 to 2.5.
11. A process for the preparation of an acid salt of crystalline form 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to any one of claims 3 to 9 comprising:
(1) Preparing an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one using the method of claim 10;
(2) Collecting solid products precipitated during the salt forming reaction of step (1) or obtaining solid products by creating a supersaturated solution in a salt system, the method of creating a supersaturated solution comprising: volatilizing the solvent, or adding an anti-solvent, or cooling to obtain the crystalline acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one;
And/or converting one form of the acid salt to another form of the salt by a process of form conversion.
12. The preparation method according to any one of claims 10 to 11, wherein the organic solvent used in the salification process is methanol, ethanol, isopropanol, methylene chloride, acetone, diethyl ether, ethyl acetate, such as n-hexane, n-heptane, acetonitrile or a mixture thereof, preferably ethanol, ethyl acetate, acetonitrile or a mixture thereof.
13. The method according to any one of claims 10 to 12, wherein the acid solution is an acid ethyl acetate solution or an acid acetonitrile solution.
14. A pharmaceutical composition comprising an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one of any of claims 1 to 2, or an acid salt of crystalline 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one of any of claims 3 to 9, and a pharmaceutically acceptable carrier or excipient.
15. Use of an acid salt of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to any of claims 1 to 2, or of a crystalline form of 5- ((2- (cyclopropylmethyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) (isopropyl) amino) -1-methylpyridin-2 (1H) -one according to any of claims 3 to 9, or of a pharmaceutical composition according to claim 14, for the preparation of a medicament for the treatment of neuropsychiatric diseases; preferably, the neuropsychiatric disease is selected from any one of depression and anxiety.
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