CN112876477B - Crystalline forms of octahydropyrrolo [3,4-c ] pyrrole derivatives - Google Patents

Crystalline forms of octahydropyrrolo [3,4-c ] pyrrole derivatives Download PDF

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CN112876477B
CN112876477B CN202011334388.0A CN202011334388A CN112876477B CN 112876477 B CN112876477 B CN 112876477B CN 202011334388 A CN202011334388 A CN 202011334388A CN 112876477 B CN112876477 B CN 112876477B
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金传飞
许腾飞
张英俊
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Guangdong HEC Pharmaceutical
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Abstract

The invention relates to crystalline forms of octahydropyrrolo [3,4-c ] pyrrole derivatives. The invention also relates to a pharmaceutical composition containing the crystal form and application of the crystal form or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving diseases related to orexin receptors.

Description

Crystalline forms of octahydropyrrolo [3,4-c ] pyrrole derivatives
Technical Field
The invention belongs to the technical field of medicines, relates to a crystal form of an octahydropyrrolo [3,4-c ] pyrrole derivative, and particularly relates to a crystal form of (5- (5-chlorobenzo [ d ] oxazole-2-yl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazole-2-yl) phenyl) methanone and application thereof, and further relates to a pharmaceutical composition containing the crystal form.
Background
Orexin (orexin), also known as hypothalamin, orexin, which includes orexin a and orexin B (or hypothalamin-1 and hypothalamin-2), is a neuropeptide secreted by the hypothalamus with its main physiological roles: 1. appetite regulation, orexin can activate feeding-regulating neurons, significantly promote feeding, and have a dose-dependent response; 2. participating in the regulation of energy metabolism, and the orexin can remarkably increase the metabolic rate; 3. participating in sleep-wake regulation, orexin can inhibit rapid eye movement sleep, prolong wake time, and block orexin effect to promote sleep; 4. the medicine is involved in endocrine regulation, and the influence of the orexin on the endocrine of pituitary hormone is obvious; 5. associated with feelings of reward, learning, and memory; 6. promoting gastric acid secretion; 7. promoting the increase of drinking water; 8. raising blood pressure; 9. plays an important role in reward systems and drug addiction mechanisms (Piper et al, The novel broad neuro-peptide, orexin-A, models The sleep-wave cycle of rates, Eur.J.Neuroscience,2000,12(2), 726-730; and Sakurai, T.et al, The neural circuit of orexin, Maintaining sleep and wakefulness. Nature Review Neuroscience,2007,8: 171181).
Orexin produces a physiological effect by acting on an orexin receptor (OXR). The orexin receptor is a G-protein coupled receptor of two types, respectively called OX 1 Receptors and OX 2 Receptor of which OX 1 The receptor selectively binds orexin A, whereas OX 2 The receptor binds to orexin A and orexin B (Sakurai T.et al, Orexins and orexin receptors: a family of hypothalamic neurones)ptides and G protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573-585)。OX 1 Receptors and OX 2 Receptors are present almost exclusively in brain tissue and are selectively expressed in the brain, where OX is present 1 The receptor is expressed in high density in locus coeruleus (blue spot), which is the initiation of noradrenergic neurons, and OX 2 The receptors are expressed in high density in the tuberous papillary nucleus, which is the initiation of histaminergic neurons. OX 1 Receptors and OX 2 The expression of both receptors can be seen in the central suture, which is the initiation of serotonergic neurons; OX 1 Receptors and OX 2 Expression of both receptors can also be seen in the ventral tegmental area, which is the initiation of dopaminergic neurons. In addition, OX 2 Receptor expression can also be seen in brainstem cholinergic neurons responsible for the regulation of rapid eye movement sleep and have an effect on their nuclear activity (Marcus, j.n. et al, Differential expression of organ receptors 1and 2in the rat brain. j.comp. neurol.,2001,435(1): 6-25; and Trivedi, p.et al, Distribution of organ receptor mRNA in the rat brain nerve, febs lewis., 1998,438(1-2): 71-75).
Thus, it can be seen that orexin receptors are pathologically important in relation to a variety of diseases such as sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neuropathies, depressive neuropathies, anxiety neuropathies, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorders, sexual dysfunction, psychosis, schizophrenia, manic depression, confusion, dementia, drug dependence, addiction, cognitive disorders, alzheimer's disease, parkinson's disease, movement disorders, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, cardiovascular diseases, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases and hypertension.
Different solid forms of a pharmaceutically active ingredient may have different properties. Different solid forms may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and also have different effects on the stability, bioavailability, therapeutic effect, etc. of the drug. Therefore, in drug development, the solid form problem of the drug should be fully considered.
International application WO 2017088759 a1 discloses the compound (5- (5-chlorobenzo [ d ] oxazol-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, which has orexin receptor antagonistic activity. However, no studies on the crystal form of the compound have been disclosed in the prior art.
The inventor researches the compound to find that the compound has poor water solubility, low oral bioavailability, poor stability and poor druggability, so that a solid form with better druggability needs to be searched.
Disclosure of Invention
Through a large number of experimental researches, the inventor finds that the crystal form II of the compound shown in the formula (I) has good stability, high exposure in a living body after oral administration, high bioavailability and high preparation purity of a product, namely, the physical properties and various properties of the crystal form II are more beneficial to the development of a preparation, so that the crystal form II has more excellent pharmacy.
In particular, the invention relates to a crystal form of a compound shown in a formula (I) and application of the crystal form or a pharmaceutical composition containing the crystal form in preparing a medicament for preventing, treating or alleviating diseases related to orexin receptors. The crystalline forms of the present invention may also be in the form of solvates, for example hydrates.
In one aspect, the invention provides a crystalline form of a compound of formula (I),
Figure BDA0002796729490000021
in some embodiments, the crystalline form of the present invention is form I.
In some embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.44 ° ± 0.2 °,7.78 ° ± 0.2 °,8.24 ° ± 0.2 °,12.69 ° ± 0.2 °,12.95 ° ± 0.2 °,14.08 ° ± 0.2 °,14.75 ° ± 0.2 °,15.03 ° ± 0.2 °,17.75 ° ± 0.2 °,19.71 ° ± 0.2 °,20.12 ° ± 0.2 °,20.81 ° ± 0.2 °,21.30 ° ± 0.2 °,21.89 ° ± 0.2 °,22.18 ° ± 0.2 °,23.27 ° ± 0.2 °,25.49 ° ± 0.2 °,25.85 ° ± 0.2 ° ± 0.08 ° ± 0.2 °,26.60 ° ± 0.2 °,27.21 ° ± 0.2 °,27.44 ° ± 0.2 °,27.70 ° ± 0.53 ° ± 0.2 °.
In some embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, form I of the present invention, wherein the differential scanning calorimetry trace of form I comprises an endothermic peak at 159.96 ℃ ± 3 ℃.
In some embodiments, form I of the present invention is characterized by a differential scanning calorimetry trace substantially as shown in figure 2.
In some embodiments, the crystalline form of the present invention is crystalline form II.
In some embodiments, the crystalline form II of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,15.92 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °.
In some embodiments, the crystalline form II of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,14.49 ° ± 0.2 °,15.92 ° ± 0.2 °,16.00 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,18.42 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,21.45 ° ± 0.2 °,23.59 ° ± 0.2 °,24.00 ° ± 0.2 °,24.26 ° ± 0.2 °,24.75 ° ± 0.2 °,25.07 ° ± 0.2 °,26.26 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °,30.03 ° ± 0.2 °,31.20 ° ± 0.2 °,31.56 ° ± 0.2 °,34.24 ° ± 0.2 °,38.78 ° ± 0.2 °.
In some embodiments, the crystalline form II of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,13.08 ° ± 0.2 °,14.49 ° ± 0.2 °,15.18 ° ± 0.2 °,15.92 ° ± 0.2 °,16.00 ° ± 0.2 °,16.61 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,18.42 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,21.45 ° ± 0.2 °,23.59 ° ± 0.2 °,24.00 ° ± 0.2 °,24.26 ° ± 0.2 °,24.75 ° ± 0.2 °,25.07 ° ± 0.2 °,26.26 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °,28.02 ° ± 0.2 °,28.31 ° ± 0.2 °, 30.31 ° ± 0.2 °, 30.2.2 ° ± 0.3 ° ± 0.2 °, 26.38 ° ± 0.2.38 ° ± 0.38 ° ± 0.2 °, 26.35 ° ± 0.2 °,26.2 ° ± 0.2.2.2 °,26 ° ± 0.12 ° ± 0.38 ° ± 0.2.2 °, 26.12 ° ± 0.12 ° ± 0.2.12 ° ± 0.12 ° ± 0.2 °,26.2 ° ± 0.2 °.
In some embodiments, the crystalline form II of the present invention, characterized in that the crystalline form II has an X-ray powder diffraction pattern substantially as shown in figure 4.
In some embodiments, crystalline form II of the present invention is characterized by a differential scanning calorimetry trace of form II comprising an endothermic peak at 182.86 ℃ ± 3 ℃.
In some embodiments, the crystalline form II of the present invention, wherein the crystalline form II has a differential scanning calorimetry pattern substantially as shown in figure 5.
In some embodiments, the crystalline form of the present invention is form X.
In some embodiments, form X of the present invention, wherein the form X has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.97 ° ± 0.2 °,12.20 ° ± 0.2 °,13.82 ° ± 0.2 °,15.68 ° ± 0.2 °,16.79 ° ± 0.2 °,17.48 ° ± 0.2 °,18.42 ° ± 0.2 °,20.05 ° ± 0.2 °,20.85 ° ± 0.2 °,22.33 ° ± 0.2 °,23.03 ° ± 0.2 °,23.87 ° ± 0.2 °,24.61 ° ± 0.2 °,25.72 ° ± 0.2 °,26.97 ° ± 0.2 °,27.48 ° ± 0.2 °,28.05 ° ± 0.2 °,28.77 ° ± 0.2 °,29.49 ° ± 0.2 °,30.29 ° ± 0.2 °,32.96 ° ± 0.2 °,33.35 ° ± 0.2 °, 30.3 ° ± 0.2 °,32 ° ± 0.2 °, 32.3 ° ± 0.2 ° ± 0.3 ° ± 0.2 °,32 ° ± 0.2 °.
In some embodiments, form X of the present invention is characterized by having an X-ray powder diffraction pattern substantially as shown in figure 6.
In some embodiments, crystalline form X of the present invention is characterized by a differential scanning calorimetry trace comprising an endothermic peak at 176.58 ℃ ± 3 ℃.
In some embodiments, form X of the present invention is characterized by a differential scanning calorimetry pattern substantially as shown in figure 7.
In some embodiments, the crystalline form of the present invention is form XI.
In some embodiments, form XI of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.44 ° ± 0.2 °,7.76 ° ± 0.2 °,8.28 ° ± 0.2 °,12.69 ° ± 0.2 °,14.14 ° ± 0.2 °,15.05 ° ± 0.2 °,16.55 ° ± 0.2 °,17.44 ° ± 0.2 °,17.77 ° ± 0.2 °,19.12 ° ± 0.2 °,19.35 ° ± 0.2 °,19.69 ° ± 0.2 °,20.14 ° ± 0.2 °,20.45 ° ± 0.2 °,20.74 ° ± 0.2 °,21.35 ° ± 0.2 °,21.95 ° ± 0.2 °,22.20 ° ± 0.2 °,23.25 ° ± 0.2 °,23.82 ° ± 0.2 °,24.90 ° ± 0.2 °,25.46 ° ± 0.2 °,25.82 ° ± 0.2 ° ± 0.19 ° ± 0.2 °,27.41 ° ± 0.2 °, 52 ° ± 0.2 ° ± 2 ° ± 0.2 °, 52 ° ± 2 °.
In some embodiments, form XI of the present invention is characterized by an X-ray powder diffraction pattern substantially as shown in figure 8.
In some embodiments, form XI of the present invention is characterized by a differential scanning calorimetry pattern comprising endothermic peaks at 149.48 ℃ ± 3 ℃ and 160.27 ℃ ± 3 ℃.
In some embodiments, form XI of the present invention is characterized by a differential scanning calorimetry pattern substantially as shown in figure 9.
In some embodiments, the crystalline form of the present invention is crystalline form XII.
In some embodiments, crystalline form XII of the present invention is characterized by an X-ray powder diffraction pattern of crystalline form XII having diffraction peaks at the following 2 Θ angles: 6.36 ° ± 0.2 °,7.25 ° ± 0.2 °,11.41 ° ± 0.2 °,11.89 ° ± 0.2 °,13.32 ° ± 0.2 °,13.76 ° ± 0.2 °,14.15 ° ± 0.2 °,15.10 ° ± 0.2 °,16.67 ° ± 0.2 °,18.06 ° ± 0.2 °,18.23 ° ± 0.2 °,18.86 ° ± 0.2 °,19.04 ° ± 0.2 °,19.35 ° ± 0.2 °,20.09 ° ± 0.2 °,20.43 ° ± 0.2 °,20.72 ° ± 0.2 °,21.42 ° ± 0.2 ± 0.61 ° ± 0.2 °,23.48 ° ± 0.2 °,23.86 ° ± 0.2 °,23.59 ° ± 0.2 °,24.59 ° ± 0.2 ± 0.22 ° ± 0.2 °, 0.2 ° ± 0.2 °,23.65 ° ± 0 ° ± 0.2 °,23.86 ° ± 0.2 °,23.2 ° ± 0.2 °, 24.25 ° ± 0.25 ° ± 0 ° ± 0.2 °.
In some embodiments, crystalline form XII of the present invention is characterized by having an X-ray powder diffraction pattern substantially as shown in figure 10.
In some embodiments, crystalline form XII of the present invention is characterized by a differential scanning calorimetry trace of form XII comprising an endothermic peak at 162.58 ℃ ± 3 ℃.
In some embodiments, form XII of the present invention is characterized by a differential scanning calorimetry pattern substantially as shown in figure 11.
In some embodiments, the crystalline form of the present invention is form XIII.
In some embodiments, the crystalline form XIII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.18 ° ± 0.2 °,8.28 ° ± 0.2 °,12.37 ° ± 0.2 °,13.45 ° ± 0.2 °,14.26 ° ± 0.2 °,14.87 ° ± 0.2 °,17.48 ° ± 0.2 °,17.90 ° ± 0.2 °,19.35 ° ± 0.2 °,19.95 ° ± 0.2 °,20.71 ° ± 0.2 °,21.23 ° ± 0.2 °,21.45 ° ± 0.2 °,22.11 ° ± 0.2 °,23.16 ° ± 0.2 °,24.95 ° ± 0.2 °,25.55 ° ± 0.2 °,26.82 ° ± 0.2 °,27.07 ° ± 0.2 °,27.35 ° ± 0.2 °,28.40 ° ± 0.2 °,28.94 ° ± 0.2 °,29.40 ° ± 0.99.2 °.
In some embodiments, the crystalline form XIII of the present invention is characterized by having an X-ray powder diffraction pattern substantially as shown in figure 12.
In some embodiments, the crystalline form XIII of the present invention is characterized by a differential scanning calorimetry trace of form XIII comprising endothermic peaks at 146.79 ℃ ± 3 ℃ and 164.21 ℃ ± 3 ℃.
In some embodiments, the crystalline form XIII of the present invention is characterized by having a differential scanning calorimetry pattern substantially as shown in figure 13.
In some embodiments, the crystalline form of the present invention is form XIV.
In some embodiments, crystalline form XIV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.25 ° ± 0.2 °,8.06 ° ± 0.2 °,12.62 ° ± 0.2 °,14.02 ° ± 0.2 °,14.79 ° ± 0.2 °,17.28 ° ± 0.2 °,17.65 ° ± 0.2 °,19.69 ° ± 0.2 °,19.87 ° ± 0.2 °,20.64 ° ± 0.2 °,20.80 ° ± 0.2 °,21.62 ° ± 0.2 °,23.22 ° ± 0.2 °,24.31 ° ± 0.2 °,25.46 ° ± 0.2 °,25.77 ° ± 0.2 °,26.71 ° ± 0.2 °,27.23 ° ± 0.2 °,28.42 ° ± 0.2 °,28.74 ° ± 0.2 °,29.82 ° ± 0.2 °,30.78 ° ± 0.2 °,32.95 ° ± 0.2 °,24.26 ° ± 0.2 °.
In some embodiments, crystalline form XIV of the present invention, characterized in that the crystalline form XIV has an X-ray powder diffraction pattern substantially as shown in figure 14.
In some embodiments, crystalline form XIV of the present invention is characterized by a differential scanning calorimetry trace comprising endothermic peaks at 124.04 ℃ ± 3 ℃ and 163.38 ℃ ± 3 ℃.
In some embodiments, crystalline form XIV of the present invention, characterized in that crystalline form XIV has a differential scanning calorimetry pattern substantially as shown in figure 15.
In some embodiments, the crystalline form of the present invention is crystalline form XV.
In some embodiments, crystalline form XV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.37 ° ± 0.2 °,8.03 ° ± 0.2 °,12.72 ° ± 0.2 °,13.89 ° ± 0.2 °,14.85 ° ± 0.2 °,17.26 ° ± 0.2 °,17.58 ° ± 0.2 °,17.77 ° ± 0.2 °,19.72 ° ± 0.2 °,20.20 ° ± 0.2 °,20.47 ° ± 0.2 °,20.99 ° ± 0.2 °,21.45 ° ± 0.2 °,21.64 ° ± 0.2 °,23.12 ° ± 0.2 °,24.30 ° ± 0.2 °,25.26 ° ± 0.2 °,25.57 ° ± 0.2 °,27.09 ° ± 0.2 °,27.23 ° ± 0.2 °,28 ° ± 0.2 °,28.91 ° ± 0.2 °,29.98 ° ± 0.2.65 ° ± 0.2 °.
In some embodiments, crystalline form XV of the present invention, characterized in that said crystalline form XV has an X-ray powder diffraction pattern substantially as shown in figure 16.
In some embodiments, crystalline form XV of the present invention, characterized in that said differential scanning calorimetry trace of form XV comprises endothermic peaks at 127.06 ℃ ± 3 ℃ and 165.38 ℃ ± 3 ℃.
In some embodiments, crystalline form XV according to the present invention, characterized in that crystalline form XV has a differential scanning calorimetry pattern substantially as shown in figure 17.
In another aspect, the invention relates to a pharmaceutical composition comprising any one of the crystalline forms described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In one aspect, the invention relates to the use of said crystalline form or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of diseases related to orexin receptors.
In some of these embodiments, the orexin receptor-related disorder of the present invention is sleep disorder, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorders, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, delirium, dementia, drug dependence, addiction, cognitive disorder, alzheimer's disease, parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease or hypertension.
In another aspect, the invention relates to the use of said crystalline form or said pharmaceutical composition for the preparation of a medicament for antagonizing orexin receptors.
In one aspect, the present invention also provides an amorphous form of the compound of formula (I) having an X-ray powder diffraction pattern substantially as shown in figure 3.
In another aspect, the invention also relates to a method for preparing a crystalline or amorphous form of the compound of formula (I).
The solvent used in the method for preparing the crystalline form or amorphous form of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to such an extent that does not affect the properties thereof is included in the present invention. In addition, many equivalent modifications, substitutions, or equivalents in the various solvent, solvent combinations, and ratios of solvent combinations described herein are contemplated as falling within the scope of the present invention. The present invention provides the preferred solvent for each reaction step.
The experiments for the preparation of the crystalline forms of the invention are described in detail in the examples section. Meanwhile, the invention provides pharmacological property test experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, hygroscopicity experiments and the like of the crystal form. Experiments prove that the crystal form II has unexpected technical advantages: 1) the crystal form II is very stable, does not generate crystal transformation under the common conditions (such as placing in an open way at normal temperature or stirring in water at normal temperature), is very stable under the conditions of high temperature and high humidity, and has basically no change in crystal form, appearance and purity; 2) compared with the compound shown in the formula (I) disclosed in the prior art, the compound is taken through an oral capsule, and has higher blood concentration and exposure in dogs, thereby having better pharmacokinetic property. Therefore, the crystal form II has better pharmacological properties and higher stability, and is more suitable for pharmaceutical use.
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of an additive such as a co-crystallizing anti-molecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.
By "antisolvent" is meant a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" refers to a compound having a solvent on the surface, in the crystal lattice, or on and in the crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, among others.
X-ray powder diffraction (XRPD) can detect information such as change, crystallinity, crystal structure state and the like of a crystal form, and is a common means for identifying the crystal form. In some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as provided herein in the figures. Also, the 2 θ measurement of the XRPD pattern may be subject to experimental error, and the 2 θ measurement of the XRPD pattern may vary slightly from instrument to instrument and from sample to sample, so the 2 θ values cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program 2 O 3 ) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peak has an error capacity of + -3 ℃ according to the condition of the instrument used in the testAnd (4) limiting.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the variation in the quality of the TGA measurements varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown" means 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.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
The invention relates to crystalline forms of the (5- (5-chlorobenzo [ d ] oxazol-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, which exist in a substantially pure crystalline form.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern.
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with 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% is explicitly disclosed, wherein "+/-" means plus or minus.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃,25 ℃,27.5 ℃, and the like.
Pharmaceutical compositions, formulations, administration and uses of the crystalline forms of the invention
The pharmaceutical composition of the invention is characterized by comprising a crystal form of the compound shown in the formula (I) and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the crystalline form of the compound in the pharmaceutical composition of the present invention is effective to detectably treat or reduce central nervous system dysfunction in a patient. The pharmaceutical compositions of the present invention may also optionally comprise other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable quantities of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-Ash 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any of the other ingredients of a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a crystalline form of a compound of the invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the crystalline forms of the compounds of the present invention may be prepared, for example, by mixing at ambient temperature and atmospheric pressure.
The compounds of the present invention or crystalline forms thereof are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation administration, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a compound of the present invention or a crystalline form thereof. Embodiments of the present invention encompass the treatment of diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound or crystalline form of the present invention or a pharmaceutical composition comprising a compound or crystalline form thereof.
In one embodiment, the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the compound of the present invention or a crystalline form thereof may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a compound of the present invention or a crystalline form thereof may be administered orally. In another embodiment, a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a compound of the present invention or a crystalline form thereof may be administered by inhalation. In yet another embodiment, the compound of the present invention or a crystalline form thereof or comprising the compound of the present invention or a crystalline form thereof may be administered intranasally.
In one embodiment, a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a compound of the present invention or a crystalline form thereof may be administered once or several times at different time intervals within a specified time period according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a compound of the invention or a crystalline form thereof, or a pharmaceutical composition comprising a compound of the invention or a crystalline form thereof, depend on the pharmacokinetic properties of the compound or crystalline form thereof, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, a suitable dosing regimen for a compound of the invention or a crystalline form thereof, or a pharmaceutical composition comprising a compound of the invention or a crystalline form thereof, including the duration of the regimen, will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.
The compound of the invention or its crystalline forms may be administered concurrently with, or before or after, one or more other therapeutic agents. The compounds of the invention or their crystalline forms may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the form of the same pharmaceutical composition.
The pharmaceutical compositions and combinations of the present invention may be in unit dosage forms containing from about 1 to about 1000mg, or from about 1 to about 500mg of the active ingredient for an individual of from about 50 to about 70 kg. A therapeutically effective amount of a compound or crystalline form, pharmaceutical composition or combination thereof will depend upon the species, weight, age and condition of the subject, the disease (disorder) or condition being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).
The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.
In one embodiment, the amount of the compound in a therapeutically effective dose of a compound of the present invention or a crystalline form thereof is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg of the principal active ingredient or a combination of principal ingredients per dosage unit form.
The compound or the crystal form and the pharmaceutical composition thereof provided by the invention can be used for preparing medicaments for preventing, treating or alleviating diseases related to the orexin receptors in mammals including human beings, and can also be used for preparing medicaments for antagonizing the orexin receptors.
In particular, the amount of the compound in the compositions of the invention is effective to detectably selectively antagonize orexin receptors, and the compounds of the invention or crystalline forms thereof are useful as agents for treating diseases associated with orexin receptors.
The compounds of the present invention or crystalline forms thereof may be used in, but are in no way limited to, the prevention, treatment, or amelioration of diseases associated with orexin receptors by administering to a patient an effective amount of a compound of the present invention or a crystalline form or composition thereof. The diseases related to orexin receptors are sleep disorders, depression, anxiety disorders, panic disorders, obsessive compulsive disorders, affective neuropathies, depressive neuropathies, anxiety neuropathies, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorders, sexual dysfunction, psychosis, schizophrenia, manic depression, confusion, dementia, drug dependence, addiction, cognitive disorders, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, cardiovascular diseases, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases or hypertension, etc.
In addition to being beneficial for human therapy, the compounds of the present invention or crystalline forms and pharmaceutical compositions thereof may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Other examples of animals include horses, dogs, and cats.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound of formula (I).
FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of form I of the compound of formula (I).
FIG. 3 is an amorphous X-ray powder diffraction (XRPD) pattern of a compound of formula (I).
Fig. 4 is an X-ray powder diffraction (XRPD) pattern of crystalline form II of the compound of formula (I).
FIG. 5 is a Differential Scanning Calorimetry (DSC) profile of form II of the compound of formula (I).
Figure 6 is an X-ray powder diffraction (XRPD) pattern of form X of the compound of formula (I).
FIG. 7 is a Differential Scanning Calorimetry (DSC) chart of form X of the compound of formula (I).
Figure 8 is an X-ray powder diffraction (XRPD) pattern of form XI of the compound of formula (I).
Figure 9 is a Differential Scanning Calorimetry (DSC) profile of the compound of formula (I) in crystalline form XI.
Figure 10 is an X-ray powder diffraction (XRPD) pattern of crystalline form XII of the compound of formula (I).
Figure 11 is a Differential Scanning Calorimetry (DSC) profile of form XII of the compound of formula (I).
Figure 12 is an X-ray powder diffraction (XRPD) pattern of crystalline form XIII of the compound of formula (I).
FIG. 13 is a Differential Scanning Calorimetry (DSC) profile of a crystalline form XIII of the compound of formula (I).
Figure 14 is an X-ray powder diffraction (XRPD) pattern of crystalline form XIV of the compound of formula (I).
FIG. 15 is a Differential Scanning Calorimetry (DSC) profile of crystalline form XIV of the compound of formula (I).
Figure 16 is an X-ray powder diffraction (XRPD) pattern of crystalline form XV of the compound of formula (I).
FIG. 17 is a Differential Scanning Calorimetry (DSC) profile of crystalline form XV of the compound of formula (I).
Figure 18 shows a graph comparing the X-ray powder diffraction (XRPD) pattern of form II of compound of formula (I) after standing for 0 and 10 days at high temperature, high humidity and light conditions according to example 11, experiment B.
Fig. 19 is a dynamic moisture sorption (DVS) diagram for crystalline form II of the compound of formula (I).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. A powder sample is prepared into a thin layer on a monocrystalline silicon sample holder, and is placed on a rotary sample table to be analyzed in steps of 0.0167 DEG within the range of 3-60 deg. Data Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data.
The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of sample was accurately weighed into a specially made aluminum crucible with a lid and analyzed from room temperature to about 300 c using a linear heating device of 10 c/min. During use, the DSC cell was purged with dry nitrogen.
The solubility of the invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the type of a chromatographic column is Agilent XDB-C18(4.6 multiplied by 50mm,5 mu m). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the ratio of mobile phase A: acetonitrile-0.01M ammonium acetate 10:90(V: V), analytical method: acetonitrile-mobile phase a ═ 70:30(V: V), run time: for 10 minutes.
The moisture absorption of the invention is measured by adopting a DVS INT-Std type dynamic moisture and gas adsorption analyzer of Surface Measurement Systems company in England, and the humidity test range is as follows: 0% to 95%, air flow: 200mL/min, temperature: 25 ℃, test point: one test point was taken per liter of 5% humidity.
Detailed description of the preferred embodiment
The specific synthesis method of the compound (5- (5-chlorobenzo [ d ] oxazole-2-yl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazole-2-yl) phenyl) methanone shown as the formula (I) refers to example 3 in international application WO 2017088759A 1.
Examples
Example 1 crystalline form I of the invention
1. Preparation of form I
The compound of formula (I) (307g) was prepared by the method described in example 3 of International application WO 2017088759A 1, dissolved in DMF (614mL), heated to 80 ℃ and stirred for 0.5h to dissolve, then slowly cooled to room temperature, crystallized, filtered with suction, the residue was washed with water (50 mL. times.2) and dried by blowing at 70 ℃ to give a white-like solid powder.
2. Identification of form I
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.44 °,7.78 °,8.24 °,12.69 °,12.95 °,14.08 °,14.75 °,15.03 °,17.75 °,19.71 °,20.12 °,20.81 °,21.30 °,21.89 °,22.18 °,23.27 °,25.49 °,25.85 °,26.08 °,26.60 °,27.21 °,27.44 °,27.70 °,28.53 °, with an error tolerance of ± 0.2 °.
(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 159.96 ℃, with a margin of error of ± 3 ℃.
Example 2 inventive amorphous form
1. Preparation of amorphous form
Adding the crystal form I (500mg) of the compound shown in the formula (I) into DCM (5.0mL), dissolving at room temperature, then carrying out reduced pressure rotary evaporation, separating out a solid, and drying to obtain an off-white solid powder.
2. Identification of amorphous form
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 3.
Example 3 crystalline form II of the invention
1. Preparation of form II
Adding the crystal form I (200mg) of the compound shown in the formula (I) into ethyl acetate (2.0mL), heating to 75 ℃ under stirring, suspending and stirring for 24h, stopping reaction, performing suction filtration, and drying to obtain white-like solid powder which is the target crystal form.
2. Identification of Crystal form II
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 10.43 °,12.31 °,13.08 °,14.49 °,15.18 °,15.92 °,16.00 °,16.61 °,16.90 °,17.90 °,18.42 °,20.52 °,21.04 °,21.45 °,23.59 °,24.00 °,24.26 °,24.75 °,25.07 °,26.26 °,26.53 °,26.83 °,28.02 °,28.31 °,29.31 °,30.03 °,30.42 °,31.20 °,31.56 °,32.25 °,32.80 °,33.63 °,34.24 °,35.54 °,36.41 °,36.96 °,38.33 °,38.78 °, with an error tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endothermic peak at 182.86 ℃, with a margin of error of ± 3 ℃.
Example 4 form X of the invention
1. Preparation of form X
Adding the crystal form I (60mg) of the compound shown in the formula (I) into ethylene glycol dimethyl ether (2.0mL), suspending and stirring at room temperature for 5 days, stopping reaction, performing suction filtration, and drying to obtain white-like solid powder which is a target crystal form.
2. Identification of form X
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.97 °,12.20 °,13.82 °,15.68 °,16.79 °,17.48 °,18.42 °,20.05 °,20.85 °,22.33 °,23.03 °,23.87 °,24.61 °,25.72 °,26.97 °,27.48 °,28.05 °,28.77 °,29.49 °,30.29 °,32.05 °,32.96 °,33.35 °,34.90 °,36.21 °,36.82 °,39.33 °, with an error tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endothermic peak at 176.58 ℃, with a margin of error of ± 3 ℃.
Example 5 crystalline form XI of the invention
1. Preparation of form XI
Adding the crystal form I (60mg) of the compound shown in the formula (I) into acetonitrile (1.0mL), suspending and stirring at room temperature for 5 days, stopping reaction, performing suction filtration, and drying to obtain white-like solid powder serving as a target crystal form.
2. Identification of form XI
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.44 °,7.76 °,8.28 °,12.69 °,14.14 °,15.05 °,16.55 °,17.44 °,17.77 °,19.12 °,19.35 °,19.69 °,20.14 °,20.45 °,20.74 °,21.35 °,21.95 °,22.20 °,23.25 °,23.82 °,24.90 °,25.46 °,25.82 °,27.19 °,27.41 °,27.52 °,29.58 °,32.96 °,35.29 °,38.58 °, and an error tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 149.48 ℃ and 160.27 ℃, with a margin of error of ± 3 ℃.
Example 6 crystalline form XII according to the invention
1. Preparation of form XII
Adding amorphous (50mg) of the compound shown in the formula (I) into 4-methyl-2-pentanone (1.0mL), suspending and stirring at room temperature for 24h, stopping reaction, performing suction filtration, and drying to obtain white-like solid powder which is the target crystal form.
2. Identification of form XII
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 6.36 °,7.25 °,11.41 °,11.89 °,13.32 °,13.76 °,14.15 °,15.10 °,16.67 °,18.06 °,18.23 °,18.86 °,19.04 °,19.35 °,20.09 °,20.43 °,20.72 °,21.42 °,22.61 °,23.48 °,23.65 °,23.86 °,24.59 °,25.22 °,27.89 °,28.49 °,29.51 °,30.22 °,32.95 °, with a tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endothermic peak at 162.58 ℃, with a margin of error of ± 3 ℃.
Example 7 crystalline form XIII according to the invention
1. Preparation of form XIII
Crystalline form I of the compound of formula (I) (50mg) was added to acetone (1.0mL) and suspended and stirred at 50 ℃ for 24 h. Stopping reaction, carrying out suction filtration, and drying to obtain white solid powder which is the target crystal form.
2. Identification of form XIII
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 7.18 °,8.28 °,12.37 °,13.45 °,14.26 °,14.87 °,17.48 °,17.90 °,19.35 °,19.95 °,20.71 °,21.23 °,21.45 °,22.11 °,23.16 °,24.95 °,25.55 °,26.82 °,27.07 °,27.35 °,28.40 °,28.94 °,29.40 °,29.99 °, with a tolerance of ± 0.2 °.
(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 146.79 ℃ and 164.21 ℃, with a margin of error of ± 3 ℃.
Example 8 crystalline form XIV of the invention
1. Preparation of crystalline form XIV
An amorphous form (50mg) of the compound represented by the formula (I) was added to butanone (1.0mL), and the mixture was suspended and stirred at room temperature for 24 hours. Stopping reaction, performing suction filtration, and drying to obtain white solid powder as a target crystal form.
2. Identification of crystalline form XIV
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.25 °,8.06 °,12.62 °,14.02 °,14.79 °,17.28 °,17.65 °,19.69 °,19.87 °,20.64 °,20.80 °,21.62 °,23.22 °,24.31 °,25.46 °,25.77 °,26.71 °,27.23 °,28.42 °,28.74 °,29.82 °,30.78 °,32.95 °,24.26 °, with a tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 124.04 ℃ and 163.38 ℃, with a margin of error of ± 3 ℃.
Example 9 crystalline form XV of the present invention
1. Preparation of crystalline form XV
An amorphous form (50mg) of the compound represented by the formula (I) was added to ethyl formate (1.0mL), and the mixture was suspended and stirred at room temperature for 24 hours. Stopping reaction, carrying out suction filtration, and drying to obtain white solid powder which is the target crystal form.
2. Identification of crystalline form XV
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 7.37 °,8.03 °,12.72 °,13.89 °,14.85 °,17.26 °,17.58 °,17.77 °,19.72 °,20.20 °,20.47 °,20.99 °,21.45 °,21.64 °,23.12 °,24.30 °,25.26 °,25.57 °,27.09 °,27.23 °,28.28 °,28.91 °,29.98 °,34.65 °, with a tolerance of ± 0.2 °.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 127.06 ℃ and 165.38 ℃, with a margin of error of ± 3 ℃.
Example 10 pharmacokinetic experiments of the crystalline forms of the invention
The test samples were filled into capsules for oral administration.
3 male Beagle dogs (8-12 kg) were orally administered to capsules containing test samples at a dose of 5mg/kg, and blood was collected at time points of 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of the appropriate range is established according to the sample concentration, and the concentration of the sample to be tested in the plasma sample is determined in MRM mode by using LC-MS/MS model AB SCIEX API4000, and quantitative analysis is performed. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. The results of the experiment are shown in table 1.
TABLE 1 pharmacokinetic experimental data for the crystalline form of the invention
Test sample T max (h) C max (ng/ml) AUC last (h*ng/ml)
Example 3 (Crystal form II) 11.3 433 4310
A compound of formula (I) 1.5 108 661
And (4) experimental conclusion:
as can be seen from Table 1, compared with the compound shown in formula (I), the crystal form II has higher exposure in Beagle dogs and better pharmacokinetic properties.
Example 11 stability test of the crystalline form of the invention
1. Stability test experiment A
At room temperature, respectively weighing a sample to be detected in an EP tube, adding water (1.5mL), suspending and stirring at room temperature for 24h, filtering, drying, and respectively carrying out X-ray powder diffraction (XRPD) analysis and identification. The experimental result shows that the crystal form II of the invention does not change when stirred in water at room temperature, while other crystal forms such as the crystal forms XIII, XIV and XV change when stirred in water. Namely, the crystal form II of the invention has stable structure and is suitable for industrial production and preparation development.
2. Stability test experiment B
Taking a proper amount of sample to be tested, and respectively irradiating the sample under the condition of (4500 +/-500 lx and ultraviolet light is more than or equal to 0.7 w/m) 2 ) Placing the sample under the conditions of high humidity (25 ℃, 75% +/-5% RH, 90% +/-5% RH) and high temperature (40 ℃ +/-2 ℃, 60 ℃ +/-2 ℃ and humidity control), carrying out influencing factor experiments, sampling on the 10 th day, carrying out XRPD detection, and inspecting the stability of the crystal form of the sample. The results of the experiment are shown in FIG. 18.
The experimental conclusion is that: according to experimental results, under the conditions of high temperature (40 ℃ or 60 ℃), high humidity (25 ℃, RH 75 +/-5% or RH 90% +/-5%) and illumination, the XRPD pattern of the crystal form II has no obvious change, namely, the form of the crystal form II is kept unchanged. Therefore, the crystal form II has better stability under various lofting conditions and is suitable for pharmaceutical application.
EXAMPLE 12 hygroscopicity assay for the crystalline form of the invention
A proper amount of a sample (namely, the crystal form of the invention) is taken, and the hygroscopicity of the sample is tested by adopting a dynamic moisture adsorption instrument.
The dynamic water sorption (DVS) profile of the hygroscopicity assay for form II of the invention is substantially as shown in figure 19. As can be seen from FIG. 19, the hygroscopicity of the crystal form II of the present invention is very low at different humidities, and the hygroscopicity increased by about 0.06% under the condition of 95% RH; according to the specification of hygroscopicity characteristics and the defined standard of hygroscopicity increase (the guiding principle of hygroscopicity test of 9103 medicaments in the pharmacopoeia 2015 edition of China general rules, see table 2in detail), the crystal form II belongs to non-hygroscopicity. That is, the crystalline form II of the present invention is not susceptible to deliquescence due to high humidity.
TABLE 2 hygroscopicity characterization and definition of hygroscopicity increase (25 ℃ C. + -1 ℃ C., 80% + -2% relative humidity)
Figure BDA0002796729490000171
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (9)

1. A crystalline form II of a compound of formula (I),
Figure FDA0003503648360000011
characterized in that the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at the following 2 theta angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,15.92 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °.
2. The crystalline form II according to claim 1, characterized in that it has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,14.49 ° ± 0.2 °,15.92 ° ± 0.2 °,16.00 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,18.42 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,21.45 ° ± 0.2 °,23.59 ° ± 0.2 °,24.00 ° ± 0.2 °,24.26 ° ± 0.2 °,24.75 ° ± 0.2 °,25.07 ° ± 0.2 °,26.26 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °,30.03 ° ± 0.2 °,31.20 ° ± 0.2 °,31.56 ° ± 0.2 °,34.24 ° ± 0.2 °,38.78 ° ± 0.2 °.
3. Form II according to claim 1 or 2, characterized in that it has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 10.43 ° ± 0.2 °,12.31 ° ± 0.2 °,13.08 ° ± 0.2 °,14.49 ° ± 0.2 °,15.18 ° ± 0.2 °,15.92 ° ± 0.2 °,16.00 ° ± 0.2 °,16.61 ° ± 0.2 °,16.90 ° ± 0.2 °,17.90 ° ± 0.2 °,18.42 ° ± 0.2 °,20.52 ° ± 0.2 °,21.04 ° ± 0.2 °,21.45 ° ± 0.2 °,23.59 ° ± 0.2 °,24.00 ° ± 0.2 °,24.26 ° ± 0.2 °,24.75 ° ± 0.2 °,25.07 ° ± 0.2 °,26.26 ° ± 0.2 °,26.53 ° ± 0.2 °,26.83 ° ± 0.2 °,28.02 ° ± 0.2 °,28.31 ° ± 0.2 °, 30.31 ° ± 0.2 °, 30.2.2 ° ± 0.3 ° ± 0.2 °, 26.38 ° ± 0.2.38 ° ± 0.38 ° ± 0.2 °, 26.35 ° ± 0.2 °,26.2 ° ± 0.2.2.2 °,26 ° ± 0.12 ° ± 0.38 ° ± 0.2.2 °, 26.12 ° ± 0.12 ° ± 0.2.12 ° ± 0.12 ° ± 0.2 °,26.2 ° ± 0.2 °.
4. The crystalline form II of claim 1 or 2, characterized in that the crystalline form II has an X-ray powder diffraction pattern substantially as shown in figure 4.
5. A crystalline form II according to claim 1, characterized in that said differential scanning calorimetry pattern in form II comprises an endothermic peak at 182.86 ℃ ± 3 ℃.
6. A crystalline form II according to claim 1 or 5, characterized in that it has a differential scanning calorimetry pattern substantially as shown in figure 5.
7. A pharmaceutical composition comprising the crystalline form II of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
8. Use of the crystalline form II of any one of claims 1-6 or the pharmaceutical composition of claim 7 in the manufacture of a medicament for preventing, treating or ameliorating a disease associated with an orexin receptor.
9. The use according to claim 8, wherein the orexin receptor-related disease is sleep disorder, depression, anxiety disorder, panic disorder, obsessive compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorders, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, manic depression, dementia, drug dependence, addiction, cognitive disorder, alzheimer's disease, parkinson's disease, movement disorder, eating disorder, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease or hypertension.
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CN102781942A (en) * 2009-10-23 2012-11-14 詹森药业有限公司 Disubstituted octahy-dropyrrolo [3,4-c]pyrroles as orexin receptor modulators
CN106749269A (en) * 2015-11-23 2017-05-31 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4 c] azole derivatives and application thereof

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