Crystal form of compound, and preparation method therefor and use thereof

Abstract

To provide a crystal form of a compound, and a preparation method therefor and use thereof.SOLUTION: The present invention discloses a crystal form A of a compound, where the compound is S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine, and an X-ray powder diffraction pattern of the crystal form A includes three or more 2θ values selected from the group consisting of: 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.171±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0.2°, 24.391±0.2°, and 25.321±0.2°. The crystal form A of the compound of the present invention does not contain water and a solvent, has high stability and low hygroscopicity, and is suitable for pharmaceuticals.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically to crystal forms of compounds, methods for producing the same, and uses thereof. It relates to.

Background Art

[0002] In Patent Document 1, a method for producing an S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazoline α-AR antagonist is disclosed. 10,11-dimethoxy-6H-dibenzo[a,g]quinazoline α-AR 1A -AR An antagonist is disclosed.

Chemical Formula

[0003] Benign prostatic hyperplasia is a physiological disease commonly seen in middle-aged and elderly men. More than half of the men over 50 years old in the world suffer from prostatic lesions, and it has become one of the main diseases in the urinary system of the elderly. Currently, several 5α-reductase inhibitors and α1-adrenergic receptor (α1-AR) antagonists are used in the treatment of benign prostatic hyperplasia, but these pharmaceuticals have some problems to be solved in terms of efficacy and safety, and the side effects such as sexual dysfunction and orthostatic hypotension have greatly restricted the exertion of the therapeutic effects of these pharmaceuticals. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. It has become one of the main diseases in the urinary system of the elderly. Currently, several 5α-reductase inhibitors and α1-adrenergic receptor (α1-AR) antagonists are used in the treatment of benign prostatic hyperplasia, but these pharmaceuticals have some problems to be solved in terms of efficacy and safety, and the side effects such as sexual dysfunction and orthostatic hypotension have greatly restricted the exertion of the therapeutic effects of these pharmaceuticals. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. Currently, several 5α-reductase inhibitors and α1-adrenergic receptor (α1-AR) antagonists are used in the treatment of benign prostatic hyperplasia, but these pharmaceuticals have some problems to be solved in terms of efficacy and safety, and the side effects such as sexual dysfunction and orthostatic hypotension have greatly restricted the exertion of the therapeutic effects of these pharmaceuticals. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. R) antagonists are used in the treatment of benign prostatic hyperplasia, but these pharmaceuticals have some problems to be solved in terms of efficacy and safety, and the side effects such as sexual dysfunction and orthostatic hypotension have greatly restricted the exertion of the therapeutic effects of these pharmaceuticals. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. In terms of efficacy and safety, and the side effects such as sexual dysfunction and orthostatic hypotension have greatly restricted the exertion of the therapeutic effects of these pharmaceuticals. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. By side effects such as sexual dysfunction and orthostatic hypotension, the exertion of the therapeutic effects of these pharmaceuticals has been greatly restricted. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. Therefore, the development of safer and more effective new pharmaceuticals is of great significance in meeting the dosing requirements in the clinic of BPH patients. It has great significance.

[0004] Various crystal forms of pharmaceuticals can affect dissolution and absorption in the body, and thereby may affect the clinical therapeutic effect and safety of pharmaceuticals to a certain extent. Especially in the case of poorly soluble oral solid or semi-solid preparations, the influence of crystal forms becomes even greater. It may affect the clinical therapeutic effect and safety of pharmaceuticals to a certain extent. Especially in the case of poorly soluble oral solid or semi-solid preparations, the influence of crystal forms becomes even greater. Or semi-solid preparations, the influence of crystal forms becomes even greater.

[0005] Therefore, it was necessary to develop a crystalline form of a compound with high stability, low hygroscopicity, and easy processability. There was.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a crystalline form of a compound of Formula 1 with high stability, low hygroscopicity, and easy processability. To do.

Means for Solving the Problems

[0008] The present invention provides crystalline Form A of the compound of Formula 1.

Chemical

[0009] The powder X-ray diffraction pattern of crystalline Form A is the following group: 12.21 ± 0.2°, 13.381 ± 0.2°, 15.181 ± 0.2°, 16.1 71 ± 0.2°, 17.101 ± 0.2°, 19.801 ± 0.2°, 21.511 ± 0 .2°, 24.391 ± 0.2°, 25.321 ± 0.2° and contains three or more 2 θ values.

[0010] Furthermore, the powder X-ray diffraction pattern of crystalline Form A is the following group: 12.21 ± 0.2°, 13.381 ± 0.2°, 15.181 ± 0.2°, 16.1 71 ± 0.2°, 17.101 ± 0.2°, 19.801 ± 0.2°, 21.511 ± 0 including 2θ values selected from 0.2°, 24.391 ± 0.2°, 25.321 ± 0.2° .

[0011] Furthermore, the powder X-ray diffraction pattern of crystalline form A is in the following group: 12.21 ± 0.1°, 13.381 ± 0.1°, 15.181 ± 0.1°, 16.1 71 ± 0.1°, 17.101 ± 0.1°, 19.801 ± 0.1°, 21.511 ± 0 .1°, 24.391 ± 0.1°, 25.321 ± 0.1° and includes three or more 2 θ values.

[0012] Furthermore, the relative intensities corresponding to the peak positions of the aforementioned 2θ values are as follows.

Table 1

[0013] Furthermore, crystalline form A is in the following group: 7.2 Å ± 0.2 Å, 6.6 Å ± 0.2 Å, 5.8 Å ± 0.2 Å, 5.5 Å ± 0.2 Å, 5.2 Å ± 0.2 Å, 4.5 Å ± 0.2 Å, 4.1 Å ± 0.2 Å, 3.6 Å ± 0.2 Å, 3.5 Å ± 0.2 Å and includes characteristic peaks having three or more lattice plane spacing d values.

[0014] Furthermore, crystalline form A basically has the XRPD pattern shown in Figure 2, or the powder X-ray diffraction pattern of crystalline form A is basically as shown in Table 1. The 2θ value of each peak of the characteristic peak has an error range of ±0.2° selectively, preferably an error range of ±0.1°.

[0015] Furthermore, crystalline form A is in the following group: 1) There is no weight loss before the decomposition of the compound of formula 1 in the TGA diagram of crystalline form A, 2) The DSC diagram of crystalline form A has a characteristic absorption peak at a peak value of 172 ± 5 °C (or ± 3 °C, or ± 1 °C) (pe ak), 3) The moisture absorption weight increase of crystalline form A at a relative humidity of 0 - 95% is ≦ 1%, preferably 0 .4% ± 0.3%, and has one or more characteristics selected therefrom.

[0016] In another preferred example, the IR diagram of crystalline form A includes three or more characteristic absorption peaks represented by the following wavelengths λ: 3599 ± 2 cm , 3001 ± 2 cm -1 , 2934 ± 2 cm -1 , 2835 ± 2 cm -1 , 2789 ± 2 cm -1 , 2789 ± 2 cm -1 , 1611 ± 2 cm -1 , 1520 ± 2 cm -1 , 1485 ± 2 cm -1 , 1452 ± 2 cm -1 , 1348 ± 2 cm -1 , 1248 ± 2 cm -1 , 1217 ± 2 cm -1 , 1107 ± 2 cm -1 , 1030 ± 2 c m -1 , 995 ± 2 cm -1 , 926 ± 2 cm -1 , 856 ± 2 cm -1 . Preferably, each characteristic absorption peak has an error range of ± 1 cm -1 .

[0017] Furthermore, crystalline form A has one or more characteristics selected from the following group: 1) Crystalline form A basically has the TGA diagram shown in Figure 3, 2) Crystalline form A basically has the DSC diagram shown in Figure 4, 3) Crystalline form A basically has the DVS diagram shown in Figure 5, 4) Crystalline form A basically has the IR diagram shown in Figure 6, and has one or more characteristics selected therefrom.

[0018] The present invention further provides a crystalline composition, which comprises any one of the above-mentioned crystalline forms A.

[0019] In another preferred example, calculated based on the total weight of the crystalline composition, the weight content of crystalline form A is 60 to 99.999%, preferably 80 to 99.999%, more preferably 90 to 9 9.999%.

[0020] In another preferred example, the crystalline composition further comprises a crystalline compound of the compound of formula 1 in amorphous form A or an amorphous compound of formula 1.

[0021] The present invention further provides a method for producing the above-mentioned crystalline form A, and the method comprises a step of suspending the compound of formula 1 in an inert solvent, stirring and filtering to obtain crystalline form A. including.

[0022] In another preferred example, the inert solvent is selected from isopropanol or normal hexane. selected.

[0023] In another preferred example, the weight-to-volume ratio of the compound of formula 1 in the inert solvent is 10 to 1. 00 mg / mL, preferably 15 to 50 mg / mL, more preferably 20 to 40 mg / mL.

[0024] In another preferred example, the stirring has one or more characteristics selected from the following group. (1) The stirring time is 12 to 48 h, preferably 18 to 36 h. (2) The stirring temperature is 25 ± 5 °C.

[0025] The present invention further provides the use of any one of the above-mentioned crystalline forms A or the above-mentioned crystalline composition, and They can be used to produce pharmaceuticals for the prevention and / or treatment of benign prostatic hyperplasia. It is possible.

[0026] The present invention further provides a pharmaceutical comprising any one of the above-described crystalline form A or the above-described crystal composition and a pharmaceutically acceptable carrier. It provides a pharmaceutical product.

[0027] In another preferred example, the carrier is selected from the following group: fillers, disintegrants, lubricants, or a combination thereof.

[0028] In another preferred example, the filler is selected from the following group: pregelatinized starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, or a combination thereof. It is possible.

[0029] In another preferred example, the disintegrant is selected from the following group: carboxymethyl cellulose and its salts, croscarmellose and its salts, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, or a combination thereof. It is possible.

[0030] In another preferred example, the lubricant is selected from the following group: magnesium stearate, calcium stearate, or a combination thereof.

[0031] It should be understood that within the scope of the present invention, each of the above-described technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form a new or suitable technical solution. For convenience of space, they will not be discussed one by one here. For the convenience of the paper width, it will not be discussed one by one here. It is not.

Brief Description of the Drawings

[0032]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

BEST MODE FOR CARRYING OUT THE INVENTION

[0033] The present inventors have, through extensive and advanced research, numerous screenings and tests, arrived at providing crystalline form A of the compound of formula 1. Crystalline form A does not contain water and a solvent, has high stability and low hygroscopicity, is easy to process, and is suitable for pharmaceuticals. The present invention has been completed based on this. Unless otherwise defined, the meanings of all technical and scientific terms used in this specification are the same as those generally understood by those skilled in the art to which this invention pertains.

[0034] TERMS Unless otherwise defined, the meanings of all technical and scientific terms used in this specification are the same as those generally understood by those skilled in the art to which this invention pertains. The term "about" as used in this specification, when used in connection with a specifically recited numerical value, means that the value may vary by up to 1% from the recited value. For example, in this specification

[0035] when used in connection with a specifically recited numerical value, means that the value may vary by up to 1% from the recited value. For example, in this specification ​​The expression "about 100" used in the specification includes all values between 99 and 101 (e.g., 99 .1, 99.2, 99.3, 99.4, etc.).

[0036] As used herein, the terms "comprising" or "including" can be open-ended, semi-closed chain or closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0037] As used herein, the terms "compound of formula 1", "S-(-)-2,3-methylenedioxy- 5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a, g]quinazoline" are used interchangeably.

[0038] As used herein, the term "n or more" includes n and any positive integer greater than n (n, n + 1,... etc.), where the upper limit Nup is the number of all values in the group . For example, "one or more" includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,... each positive integer up to the upper limit Nup and also includes ranges such as "two or more", "three or more", "four or more", "five or more", "six or more", "seven or more", "eight or more", "nine or more", "ten or more", "eleven or more", "twelve or more", "thirteen or more", "fourteen or more", "fifteen or more", . For example, "three or more" includes 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,... each positive integer up to the upper limit Nup and also includes ranges such as "four or more", "five or more", "six or more", "seven or more ", "8 or more", "9 or more", "10 or more", "11 or more", "12 or more", Ranges such as "13 or more", "14 or more", "15 or more" are also included.

[0039] As used herein, the term "inert solvent" refers to a solvent that does not react with the compound of Formula 1 of the present invention. All solvents used in the method for producing crystalline Form A of the present invention preferably do not react with the compound of Formula 1. compound.

[0040] Unless otherwise specified, the terms "room temperature" or "ambient temperature" mean that the temperature is 4 to 32 °C, preferably 25 ± 5 °C.

[0041] Crystal Polymorph Solids exist in either an amorphous or crystalline form. In the case of the crystalline form, the molecules are arranged within a three-dimensional crystal lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different space lattice arrangements (such properties are called "crystal polymorphism"), forming crystals with different crystal forms, and these various crystal forms are called "crystal polymorphs". Different crystal polymorphs of a given substance can differ from each other in one or more physical attributes (solubility, dissolution rate, true specific gravity, crystal form, deposition mode, fluidity, and / or solid-state stability).

[0042] As used herein, the terms "crystalline Form A", "crystalline Form A of the compound of Formula 1", "crystalline Form A of the present invention", "crystalline Form A of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazoline" can be used interchangeably.

[0043] Crystal Form A The present invention provides crystalline Form A of the compound of Formula 1.​​​​​​​​​​ [Chemical]

[0044] The powder X-ray diffraction pattern of crystalline form A includes three or more 2θ values selected from the following groups: 12.21 ± 0.2°, 13.381 ± 0.2°, 15.181 ± 0.2°, 16.1 71 ± 0.2°, 17.101 ± 0.2°, 19.801 ± 0.2°, 21.511 ± 0 .2°, 24.391 ± 0.2°, 25.321 ± 0.2°. It includes.

[0045] Furthermore, the powder X-ray diffraction pattern of crystalline form A includes three or more 2θ values selected from the following groups: 12.21 ± 0.1°, 13.381 ± 0.1°, 15.181 ± 0.1°, 16.1 71 ± 0.1°, 17.101 ± 0.1°, 19.801 ± 0.1°, 21.511 ± 0 .1°, 24.391 ± 0.1°, 25.321 ± 0.1°. It includes.

[0046] Furthermore, the relative intensities corresponding to the peak positions of the aforementioned 2θ values are as follows. [Table 2]

[0047] Furthermore, crystalline form A includes characteristic peaks having three or more lattice plane spacing d values selected from the following groups: 7.2 Å ± 0.2 Å, 6.6 Å ± 0.2 Å, 5.8 Å ± 0.2 Å, 5.5 Å ± 0.2 Å, 5.2 Å ± 0.2 Å, 4.5 Å ± 0.2 Å, 4.1 Å ± 0.2 Å, 3.6 Å ± 0.2 Å, 3.5 Å ± 0.2 Å. It includes.

[0048] Furthermore, crystalline form A basically has the XRPD pattern shown in Figure 2, or the crystalline form The powder X-ray diffraction pattern of A is basically as shown in Table 1. The characteristic peaks at the 2θ values each have a 2θ value with a selective error range of ±0.2°, or preferably ±0. 1° error range.

[0049] Furthermore, crystalline form A has one or more characteristics selected from the following group: 1) There is no weight loss before the decomposition of the compound of formula 1 in the TGA diagram of crystalline form A, 2) The DSC diagram of crystalline form A has a characteristic absorption peak at a peak value of 172 ± 5 °C (or ±3 °C, or ±1 °C) (pe ak), 3) The moisture absorption weight increase of crystalline form A at a relative humidity of 0 to 95% is ≦1%, preferably 0 .4% ± 0.3%.

[0050] In another preferred example, the IR diagram of crystalline form A includes three or more characteristic absorption peaks represented by the following wavelengths λ: 3599 ± 2 cm -1 , 3001 ± 2 cm -1 , 2934 ± 2 cm -1 , 2835 ± 2 cm -1 , 2789 ± 2 cm -1 , 1611 ± 2 cm -1 , 1520 ± 2 cm -1 , 1485 ± 2 cm -1 , 1452 ± 2 cm -1 , 1348 ± 2 cm -1 , , 1248 ± 2 cm -1 , 1217 ± 2 cm -1 , 1107 ± 2 cm -1 , 1030 ± 2 c m -1 , 995 ± 2 cm -1 , 926 ± 2 cm -1 , 856 ± 2 cm -1 . Preferably, each characteristic absorption peak has an error range of ±1 cm -1 .

[0051] Furthermore, crystalline form A belongs to the following group: 1) Crystalline form A basically has the TGA diagram shown in Figure 3; 2) Crystalline form A basically has the DSC diagram shown in Figure 4; 3) Crystalline form A basically has the DVS diagram shown in Figure 5; 4) Crystalline form A basically has the IR diagram shown in Figure 6, and has one or more characteristics selected from these.

[0052] Crystalline composition The present invention further provides a crystalline composition, which contains crystalline form A described in the first aspect of the present invention in it.

[0053] In another preferred example, calculated based on the total weight of the crystalline composition, the weight content of crystalline form A is 60 to 99.999%, preferably 80 to 99.999%, more preferably 90 to 9 9.999%.

[0054] In another preferred example, the crystalline composition further contains a crystalline compound of the compound of formula 1 in amorphous form A or an amorphous compound of formula 1.

[0055] Crystal By operating the solution to exceed the solubility limit of the target compound, crystallization on a production scale can be completed. This can be achieved in various ways, for example, by dissolving the compound at a relatively high temperature and then cooling the solution to below the saturation limit. Alternatively, the volume of the liquid may be reduced by boiling, atmospheric evaporation, vacuum drying or several other methods. By adding an antisolvent or a compound to a poorly soluble solvent or a mixture containing such a solvent, the solubility of the target compound can be reduced. Also, the method of adjusting the pH value to reduce the solubility can also be selected as an option.

[0056] For example, if the simultaneous occurrence of salt formation and crystallization is desired and the solubility of the salt in the reaction medium is smaller than that of the raw material, the desired salt can be directly crystallized by adding an appropriate acid or alkali. Similarly, in a medium where the solubility of the final desired form is lower than that of the reactants, the final product can be directly crystallized by completion of the synthesis reaction.

[0057] Optimization of crystallization may include inoculating the crystallization medium with crystals of the desired form as seed crystals. Also, in many crystallization methods, combinations of the above methods are used. As one example, the target compound is dissolved in a solvent at a high temperature, and then an appropriate volume of an antisolvent is added in a controlled manner to bring the system below the saturation level. Here, seed crystals of the desired form are added (and the integrity of the seed crystals is maintained), and the system is cooled to complete crystallization.

[0058] Method for producing crystalline form A The present invention further provides a method for producing the above-mentioned crystalline form A, the method comprising suspending the compound of formula 1 in an inert solvent, and performing stirring and filtration to obtain crystalline form A.

[0059] In another preferred example, the inert solvent is selected from isopropanol or normal hexane.

[0060] In another preferred example, the weight / volume ratio of the compound of formula 1 in the inert solvent is 10-1 00 mg / mL, preferably 15-50 mg / mL, more preferably 20-40 mg / mL.

[0061] ​​​In another preferred example, the stirring has one or more characteristics selected from the following group. (1) The stirring time is 12 to 48 h, preferably 18 to 36 h. (2) The stirring temperature is 25 ± 5°C.

[0062] Preferably, the raw material of the various production methods described above is the compound of formula 1 in amorphous form.

[0063] Usually, the crystalline form A obtained by the various production methods described above can be subjected to processes such as filtration and drying in a conventional manner in this field as required. and drying and other steps can be performed.

[0064] Preferably, the filtration can be selected from filtration after centrifugation, pressure filtration or vacuum filtration ( but not limited to). Drying can be selected from vacuum drying or drying by a dryer (but not limited to).

[0065] Pharmaceutical composition and use The pharmaceutical composition of the present invention contains a safe and effective amount of crystalline form A of the compound of formula 1 and a pharmaceutically acceptable carrier.

[0066] The "active ingredient" in the present invention refers to the compound of formula 1 described in the present invention, preferably, the crystalline form A of the present invention.

[0067] Usually, in terms of the total weight of the active ingredient, the weight content ratio of crystalline form A is 60 to 99.999 %, preferably 80 to 99.999%, more preferably 90 to 99.999%.

[0068] The crystalline form A, crystalline composition and pharmaceutical composition of the present invention can be used for the prevention and / or treatment of benign prostatic hyperplasia.

[0069] Here, the "safe and effective amount" means sufficient to significantly improve the disease state, but serious side effects Refers to the amount of a compound that does not lead to the occurrence of use. Usually, a pharmaceutical composition contains 1 to 2000 mg of the crystalline form A / agent of the present invention, and more preferably contains 10 to 500 mg of the compound / agent of the present invention. Preferably, the above-mentioned "agent" is one capsule or tablet. "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. The "compatibility" mentioned here means that each component in the composition can be miscible with the compound of the present invention and with each other without significantly reducing the medicinal effect of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as TWEEN (registered trademark), etc.), wetting agents (such as sodium dodecyl sulfate, etc.), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0070] There are no special restrictions on the method of using the compound or pharmaceutical composition of the present invention. Representative methods of use include, but are not limited to, oral, rectal administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration), and topical administration. In the treatment of the crystalline form A of the present invention, the general range of the effective amount is about 1 to 2000 mg / day.

[0071]

[0072]

[0071] There are no special restrictions on the method of using the compound or pharmaceutical composition of the present invention. Representative methods of use include, but are not limited to, oral, rectal administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration), and topical administration.

[0072]

[0072] In the treatment of the crystalline form A of the present invention, the general range of the effective amount is about 1 to 2000 mg / day.​ Approx. 10~1000mg / day, Approx. 10~500mg / day, Approx. 10~250mg / day, Approx. 10 A therapeutically effective amount is one or more doses of the compound. However, the particular use of the compounds of the invention for any particular patient may vary. The dosage will depend on the age, sex, weight, general health condition, diet, individual response, and dosage of the patient to be treated. the duration of administration, the severity of the disease to be treated, the activity of the specific compound used, the dosage form, the method of administration, and It should be understood that the effectiveness of treatment in a given situation will depend on a variety of factors, including concomitant medications. The amount can be determined using routine tests and is within the skill and judgment of the clinician or physician. In any situation, the above-mentioned compounds or compositions may be administered in multiple doses based on the individual circumstances of the patient. and is administered in a manner capable of delivering a therapeutically effective dose.

[0073] The main advantages of the present invention include: (1) The crystalline form A of the compound of formula 1 of the present invention does not contain water and solvent, and has high stability and low absorption. It has good moisture resistance and is very suitable for pharmaceuticals. (2) The crystalline form A of the compound of formula 1 of the present invention is dissolved in water during the pharmaceutical manufacturing process, such as individual packaging. It is difficult to lift, easy to collect, and does not produce waste. It also contributes to protecting the physical health of the operator. do. (3) The crystalline form A of the compound of formula 1 of the present invention can be produced by a simple method and is suitable for large-scale industrial production. Suitable for childbirth. EXAMPLES

[0074] The present invention will be described in more detail below with reference to specific examples. It is to be understood that these are merely illustrative of the invention and are not intended to limit the scope of the invention. want to. For test methods where specific conditions are not specified in the following examples, usually follow conventional conditions or the conditions recommended by the manufacturer. Unless otherwise explained, percentages and parts were calculated based on weight.

[0075] Inspection Method X-ray Diffraction (XRD) is a method for analyzing the structure of a substance in terms of the spatial distribution of internal atoms by utilizing the diffraction of X-rays formed by crystals. When X-rays having a certain wavelength are irradiated onto a crystalline substance, scattering occurs when the X-rays hit regularly arranged atoms or ions in the crystal, and the scattered X-rays are enhanced in phase in a specific direction, thereby showing a specific diffraction phenomenon corresponding to the crystal structure. In the present invention, the test parameters of XRD are as follows. Instrument model: Bruker D8 advance, Target: Cu-Kα (40 kV, 40 mA), Distance from sample to detector: 30 cm, Scanning range: 3° to 40° (2 theta value), Scanning step size: 0.1 s.

[0076]

[0077] Thermo Gravimetric Analysis (TGA) is one of the analytical techniques for measuring the mass change of a substance with temperature under conditions where the temperature is controlled by a program. Thermogravimetric analysis can obtain the heat quantity generated by the thermal change of the sample, and is suitable for examining the loss of crystal solvent or crystal water molecules in crystalline substances, the sublimation and decomposition processes of the sample, and values, and can also effectively determine whether the substance contains crystal solvent or crystal water molecules.

[0078] In the present invention, the test parameters of TGA are as follows. Instrument model: Netzsch TG 209F3, temperature range: 30 - 400 °C, scanning rate: 10 K / min, purge gas flow rate: 25 mL / min, shielding gas flow rate: 15 mL / min.

[0079] Differential Scanning Calorimetry (DSC) employs a programmed control of heating or cooling, and measures the change in enthalpy difference between a sample and an inert reference substance ( α-Al2O3 is often used) as a function of temperature. DSC examination is suitable for the analysis of the melting and decomposition state, mixed crystal state, crystal transition state, etc. of a sample.

[0080] In the present invention, the test parameters of DSC are as follows. Instrument model: Perkin Elmer DSC 8500, nitrogen gas flow rate: 20 mL / min, temperature range: 50 - 2 00 °C, scanning rate: 10 °C / min.

[0081] Infra-red Spectrometry (IR) is an analytical method that has been used for the identification and discrimination of crystalline substances since the earliest times. Since the covalent bonds of molecules with different crystal forms have different electrical environments, the strength of the covalent bonds may also change, and the change in the strength of the covalent bonds will inevitably result in differences in the IR spectra of different crystal forms.

[0082] In the present invention, the test parameters of IR are as follows. Instrument model: Nicolet 6700 Fourier Transform Infrared Spectrometer, single point ATR method, resolution 4.0 c m -1 .

[0083] Dynamic vapor sorption (DVS) test / hygroscopicity test is to quickly measure the increase and decrease of the moisture content of the sample caused by the flowing carrier gas, place the sample on a highly sensitive · highly stable microelectronic balance, and then measure the increase / decrease of the mass of the material to inspect the adsorption / desorption of water vapor, thereby determining the hygroscopicity of the sample.

[0084] In the present invention, the test parameters of DVS are as follows. Instrument model: SMS DVS Intrinsic, 0~95%RH, temperature: 25°C.

[0085] Polarizing microscope In the present invention, the instrument model of the polarizing microscope is XPV-400E.

[0086] Example 1 S-(-)-2,3-Methylenedioxy-5,8,13,13a-tetrahydro-10 ,11-dimethoxy-6H-dibenzo[a,g]quinazoline crystal form A was prepared.

[0087] 15 mg of S-(-)-2,3-Methylenedioxy-5,8,13,13a-tetrahydro -10,11-dimethoxy-6H-dibenzo[a,g]quinazoline was dissolved in 1 mL of isopropanol and stirred at room temperature under the condition of 25°C for at least 24 hours for equilibration. Filter it, place the obtained solid in a vacuum dryer, and perform vacuum drying to obtain S-(-)-2,3-Methylenedioxy -5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo [a,g]quinazoline crystal form A crystals.

[0088] The crystal form A of the crystals obtained in Example 1 was subjected to polarizing microscope imaging, XRPD, TG It was tested by A, DSC, DVS, IR, Raman, etc. The results of the property evaluation are as shown in FIGS. 1 to 7.

[0089] Figure 1 is a polarized light micrograph of crystalline form A. From Figure 1, it can be seen that crystalline form A is a massive crystal. It can be understood.

[0090] Figure 2 is the XRPD pattern of crystalline form A (the peak table is as shown in Table 1).

[0091]

Table 3

[0092] Figure 3 is the TGA diagram of crystalline form A. From Figure 3, it can be seen that there is no weight loss before the decomposition of the compound in crystalline form A, indicating that crystalline form A does not contain water or other solvents. It shows that crystalline form A does not contain water or other solvents.

[0093] Figure 4 is the differential scanning calorimetry (DSC) diagram of crystalline form A. From Figure 4, it can be seen that the DSC corresponding to crystalline form A shows an onset of about 170.3 °C and a melting peak value temperature of 172.5 °C. It can be seen. It can be seen.

[0094] Figure 5 is the dynamic vapor sorption (DVS) diagram of crystalline form A. From Figure 5, it can be seen that crystalline form A is in the range of relative humidity 0 to 95%, the change in hygroscopicity is as small as about 0.6%, and the weight change is small, indicating that crystalline form A has low hygroscopicity. It can be seen that the change in hygroscopicity is as small as about 0.6% and the weight change is small, indicating that crystalline form A has low hygroscopicity. It shows that crystalline form A has low hygroscopicity.

[0095] Figure 6 is the infrared absorption (IR) spectrum of crystalline form A. From Figure 6, it can be seen that crystalline form A has peaks at 359 9 ± 2 cm -1 、3001 ± 2 cm -1 、2934 ± 2 cm -1 、2835 ± 2 cm -1 、2789 ± 2 cm -1 、1611 ± 2 cm-1 , 1520 ± 2 cm -1 , 1485 ± 2 cm -1 , 1452 ± 2 cm -1 , 1348 ± 2 cm -1 , 1248 ± 2 cm -1 , 12 17 ± 2 cm -1 , 1107 ± 2 cm -1 , 1030 ± 2 cm -1 , 995 ± 2 cm -1 , 926 ± 2 cm -1 , 856 ± 2 cm -1 is found to have characteristic absorption peaks at .

[0096] Example 2 S-(-)-2,3-Methylenedioxy-5,8,13,13a-tetrahydro-10 ,11-dimethoxy-6H-dibenzo[a,g]quinazoline crystal form A was prepared.

[0097] 215 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetra hydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazoline was dissolved in 1 mL of normal hexane, stirred at room temperature under 25 °C conditions, and equilibrated for at least 24 hours. Filtered, and the obtained solid was placed in a vacuum dryer and vacuum dried to obtain crystals of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazoline crystal form A.

[0098] The XRPD results of the obtained product were basically the same as those of Example 1.

[0099] Comparative Example 1 S-(-)-2,3-Methylenedioxy-5,8,13,13a-tetrahydro-10 ​​The crystalline form B of 11-dimethoxy-6H-dibenzo[a,g]quinazoline crystals was prepared.

[0100] 15 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro -10,11-dimethoxy-6H-dibenzo[a,g]quinazoline was dissolved in 1 mL of methanol and stirred at room temperature under 25 °C conditions for at least 24 hours for equilibration. It was filtered, and the obtained solid was placed in a vacuum dryer and vacuum-dried to obtain the crystalline form B.

[0101] The XRPD results of the obtained product are as shown in Figure 7.

[0102] Comparative Example 2 The crystalline form C of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 ,11-dimethoxy-6H-dibenzo[a,g]quinazoline crystals was prepared.

[0103] 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro -10,11-dimethoxy-6H-dibenzo[a,g]quinazoline was dissolved in 200 μL of ethanol and 100 μL of normal hexane, mixed and dissolved, and slowly volatilized and dried at 25 °C to obtain the crystalline form C.

[0104] The XRPD results of the obtained product are as shown in Figure 8.

[0105] Comparative Example 3 The crystalline form D of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 ,11-dimethoxy-6H-dibenzo[a,g]quinazoline crystals was prepared.

[0106] 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro 10,11-Dimethoxy-6H-dibenzo[a,g]quinazoline was dissolved in 200 μL of isoprop anol and 600 μL of chloroform, mixed and dissolved, and slowly volatilized at 25 °C to dryness to obtain crystalline form D.

[0107] The XRPD results of the obtained product are as shown in Figure 9.

[0108] Conversion experiment between crystalline forms Conversion experiments were carried out among four crystalline forms of Form A, Form B, Form C, and Form D. The experimental conditions and results are as follows.

Table 4

[0109] 5 mg of each sample was taken and stirred with 1 mL of solvent under the condition of 25 °C. The experimental conditions and results are as follows.

Table 5

[0110]

[0111] From the results of this crystalline form conversion, it can be seen that Form A is the most stable crystalline form. Observation of hygroscopicity Using a dynamic vapor sorption measurement device (DVS), the adsorption and desorption conditions of the sample's moisture at a relative humidity of 0 - 95% at a temperature of 25 °C were observed to determine the hygroscopicity of different crystalline forms. The experimental results are as follows.

Table 6

[0112]

[0113] Preparation of pharmaceutical composition and study of stability​​​​

Table 7

[0114] 2. Preparation Process (1) Weigh polyvinylpyrrolidone K30 according to the formula, dissolve it in 80% ethanol, and obtain the binder. (2) Mix the raw drug (crystalline forms A / B / C / D) uniformly with the pharmaceutical additives of sucrose / lactose / crospovidone (CL-M), add the binder, and prepare the soft material . (3) Granulate with a 20-mesh sieve. (4) Dry at 50 °C and control the moisture content to less than 2.0%. (5) Screen with a 20-mesh sieve and remove fine particles with an 80-mesh sieve. (6) Collect the granules. (7) Perform primary packaging.

[0115] 3. Stability Research Data According to the above process, prepare 4 lots of pilot-scale samples of Sample A, Sample B, Sample C, and Sample D. According to the stability test guidelines for raw drugs and drug preparations in Appendix XIX C of Part II of the Chinese Pharmacopoeia 2015 Edition, perform accelerated stability tests and observations on the above 4 lots of samples. .

[0116] Accelerated stability test conditions: Pack the above samples respectively with a polyester / aluminum / polyethylene composite film for pharmaceutical packaging, leave them for 6 months under the conditions of a temperature of 40 °C and a relative humidity of 75%, sample once at the 0th, 1st, 3rd, and 6th months during the test period, and inspect based on the stability observation items. .

[0117]

Table 8

[0118] The results show that the granules prepared from crystalline form A have better stability than those prepared from other crystalline forms, and their dissolution rate is significantly higher than that of the granules prepared from other crystalline forms. Moreover, crystalline form A shows that the change of granule-related substances is much smaller than that of other crystalline forms. That is, the granules prepared from crystalline form A have better stability than those prepared from other crystalline forms, and their dissolution rate is significantly higher than that of the granules prepared from other crystalline forms. Moreover, crystalline form A shows that the change of granule-related substances is much smaller than that of other crystalline forms. That is, the granules prepared from crystalline form A have better stability than those prepared from other crystalline forms, and their dissolution rate is significantly higher than that of the granules prepared from other crystalline forms. Moreover, crystalline form A shows that the change of granule-related substances is much smaller than that of other crystalline forms. .

[0119] Thus, crystalline form A described in the present invention does not contain water or a solvent, is a columnar crystal, has good physical stability, and crystalline form A has low hygroscopicity at a relative humidity of 0 to 95%, indicating that it is very suitable for processing into pharmaceuticals. In addition, crystalline form A of the present invention is not likely to fly up, is easy to collect, and is less likely to cause waste during the pharmaceutical manufacturing process such as individual packaging, and contributes to the protection of the health of the operator's body. Thus, crystalline form A described in the present invention does not contain water or a solvent, is a columnar crystal, has good physical stability, and crystalline form A has low hygroscopicity at a relative humidity of 0 to 95%, indicating that it is very suitable for processing into pharmaceuticals. In addition, crystalline form A of the present invention is not likely to fly up, is easy to collect, and is less likely to cause waste during the pharmaceutical manufacturing process such as individual packaging, and contributes to the protection of the health of the operator's body. Thus, crystalline form A described in the present invention does not contain water or a solvent, is a columnar crystal, has good physical stability, and crystalline form A has low hygroscopicity at a relative humidity of 0 to 95%, indicating that it is very suitable for processing into pharmaceuticals. In addition, crystalline form A of the present invention is not likely to fly up, is easy to collect, and is less likely to cause waste during the pharmaceutical manufacturing process such as individual packaging, and contributes to the protection of the health of the operator's body. Thus, crystalline form A described in the present invention does not contain water or a solvent, is a columnar crystal, has good physical stability, and crystalline form A has low hygroscopicity at a relative humidity of 0 to 95%, indicating that it is very suitable for processing into pharmaceuticals. In addition, crystalline form A of the present invention is not likely to fly up, is easy to collect, and is less likely to cause waste during the pharmaceutical manufacturing process such as individual packaging, and contributes to the protection of the health of the operator's body. Thus, crystalline form A described in the present invention does not contain water or a solvent, is a columnar crystal, has good physical stability, and crystalline form A has low hygroscopicity at a relative humidity of 0 to 95%, indicating that it is very suitable for processing into pharmaceuticals. In addition, crystalline form A of the present invention is not likely to fly up, is easy to collect, and is less likely to cause waste during the pharmaceutical manufacturing process such as individual packaging, and contributes to the protection of the health of the operator's body.

[0120] All documents mentioned in the present invention are incorporated herein by reference in the same manner as if each document was individually cited as a reference. It should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and their equivalent forms also fall within the scope defined by the claims appended to this application. All documents mentioned in the present invention are incorporated herein by reference in the same manner as if each document was individually cited as a reference. It should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and their equivalent forms also fall within the scope defined by the claims appended to this application. All documents mentioned in the present invention are incorporated herein by reference in the same manner as if each document was individually cited as a reference. It should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and their equivalent forms also fall within the scope defined by the claims appended to this application. All documents mentioned in the present invention are incorporated herein by reference in the same manner as if each document was individually cited as a reference. It should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and their equivalent forms also fall within the scope defined by the claims appended to this application.

Claims

1. Crystalline form A of the compound of formula 1, 【Chemistry 1】 The powder X-ray diffraction pattern of the crystalline form A is the following group: Crystalline form A of the compound of formula 1, characterized in that it contains five or more 2θ values ​​selected from 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.171±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0.2°, 24.391±0.2°, and 25.321±0.2°.

2. The powder X-ray diffraction pattern of the crystalline form A is 2. The crystalline form A of claim 1, characterized in that it comprises 2θ values ​​selected from the group consisting of 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.171±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0.2°, 24.391±0.2°, and 25.321±0.2°.

3. The relative intensity corresponding to the peak position of the 2θ value is 【Table 1】

4. 2. The crystalline form A according to claim 1, characterized in that the crystalline form A comprises characteristic peaks having five or more lattice plane d-spacings selected from the following group: 7.2 ű0.2 Å, 6.6 ű0.2 Å, 5.8 ű0.2 Å, 5.5 ű0.2 Å, 5.2 ű0.2 Å, 4.5 ű0.2 Å, 4.1 ű0.2 Å, 3.6 ű0.2 Å, and 3.5 ű0.2 Å.

5. 2. The crystalline form A of claim 1, wherein the crystalline form A has an XRPD pattern essentially as shown in FIG.

6. The crystalline form A is selected from the group consisting of: 1) there is no weight loss before decomposition of the compound of formula 1 in the TGA diagram of said crystalline form A; 2) The DSC diagram of the crystalline form A has a characteristic absorption peak at a peak value of 172±5° C.; 3) the hygroscopic weight gain of said crystalline form A at a relative humidity of 0 to 95% is ≦1%, preferably 0.4%±0.3%.

7. A crystalline composition comprising crystalline form A of any one of claims 1 to 6.

8. A method for preparing crystalline form A according to any one of claims 1 to 6, comprising the steps of: suspending the compound of formula 1 in an inert solvent, stirring and filtering to obtain said crystalline form A; The method for producing crystalline form A according to any one of claims 1 to 6, wherein the inert solvent is selected from isopropanol and normal hexane.

9. Use of crystalline form A according to any one of claims 1 to 6 or the crystalline composition according to claim 7 for the manufacture of a medicament for the prevention and / or treatment of benign prostatic hyperplasia.

10. 8. A pharmaceutical composition comprising crystalline form A of any one of claims 1 to 7 and a pharma- ceutically acceptable carrier.

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