CN112638907B - Crystalline form of an opioid receptor (MOR) agonist and methods of preparation - Google Patents
Crystalline form of an opioid receptor (MOR) agonist and methods of preparation Download PDFInfo
- Publication number
- CN112638907B CN112638907B CN201980053697.XA CN201980053697A CN112638907B CN 112638907 B CN112638907 B CN 112638907B CN 201980053697 A CN201980053697 A CN 201980053697A CN 112638907 B CN112638907 B CN 112638907B
- Authority
- CN
- China
- Prior art keywords
- form iii
- crystalline form
- mor
- ray powder
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
Abstract
The present disclosure provides crystalline forms of an opioid receptor (MOR) agonist and methods of preparation. In particular, the present disclosure provides (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [ 4.5)]Decyl-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine fumarate and preparation method thereof. The III crystal form of the compound disclosed in the formula (I) has good crystal form stability and can be better used for clinical treatment.
Description
This application claims priority from chinese patent application 201811186743.7 filed as 2018/10/12. The present application refers to the above-mentioned chinese patent application in its entirety.
Technical Field
The present disclosure provides a crystalline form III of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine fumarate and methods of preparation, use of the crystalline form III in pharmaceutical compositions and use of the crystalline form III, compositions in the preparation of a medicament for the treatment and/or prevention of a disease associated with an opioid receptor (MOR) agonist.
Background
Opioid receptors are important G Protein Coupled Receptors (GPCRs), are target points for combination of endogenous opioid peptides and opioid drugs, have a regulating effect on nervous system immunity and endocrine system after being activated, and are the strongest and commonly used central analgesics at present. Endogenous opioid peptides are opioid active substances naturally produced in mammals, and currently known endogenous opioid peptides are roughly classified into enkephalins, endorphins, dynorphins and neokephalins (Pharmacol Rev 2007; 59: 88-123). The central nervous system has its corresponding opioid receptors, i.e., μ (MOR), δ (DOR), κ (KOR), etc. MOR is the target of action of opioid analgesics such as endogenous enkephalin and morphine.
Opioid drugs, when used for a long period of time, produce tolerance and side effects such as respiratory depression and constipation, which have been shown to be closely related to the function of β -arrestin. In order to reduce the side effect of opioid drugs, a drug can be designed based on negative beta-arrestin preferential ligands of MOR, so that the beta-arrestin mediated side effect is reduced, and the therapeutic effect is enhanced, in the research of the oxaspiro derivative as MOR selective drug, TrevenaInc research finds that the activity is poor when the aryl benzyl position is substituted (j.med.chem.2013, 56, 8019-one 8031), but WO2017063509 finds that an MOR compound which shows high activity, remarkably improved Emax and obviously improved hERG after the aryl benzyl position is cyclized and has a single configuration, and the structure is shown as formula (II):
the crystal structure of the compound used as a medicinal active ingredient often affects the chemical and physical stability of the medicament, and the difference of crystallization conditions and storage conditions can cause the change of the crystal structure of the compound and is sometimes accompanied by the generation of other forms of crystal forms. Generally speaking, amorphous drug products do not have regular crystal structures and often have other defects, such as poor product stability, difficult filtration, easy caking, poor flowability, and the like. Therefore, it is necessary to improve various properties of the compound represented by the formula (II).
Disclosure of Invention
The disclosure provides a crystal form III of a compound shown as a formula (I), an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta angle has characteristic peaks at 6.44, 10.16, 11.99, 13.65, 14.00, 16.43, 17.05, 19.56, 21.40 and 22.64,
in some embodiments, the crystalline form III is provided having an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ angles, having characteristic peaks at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94, and 29.26.
In some embodiments is provided the crystalline form III having characteristic peaks at diffraction angle 2 Θ angles of 6.44, 7.11, 9.78, 10.16, 11.99, 12.90, 13.22, 13.65, 14.00, 14.38, 14.82, 15.32, 16.08, 16.43, 17.05, 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 20.92, 21.40, 22.64, 22.91, 23.18, 23.94, 24.50, 25.32, 25.88, 26.67, 28.47, 29.26, 30.16, 30.96, 32.52, 33.38, 35.74, 37.02, 40.38, 41.19, and 42.41.
In other embodiments, there is provided crystalline form III having an X-ray powder diffraction pattern, expressed in terms of diffraction angle, 2 Θ, as shown in figure 1.
The present disclosure also provides a method of preparing form III, the method comprising:
dissolving a free compound shown as a formula (I) in a solvent, adding fumaric acid, heating to slightly boil, cooling and crystallizing to obtain a crystal form III; the micro-boiling temperature is selected from 40 ℃ to the boiling point of the solvent, the solvent is preferably an alcohol solvent, and the alcohol solvent is preferably isopropanol.
On the other hand, in some embodiments, the preparation method of the crystalline form of the present disclosure further comprises the steps of filtering, washing or drying.
The present disclosure provides a pharmaceutical composition, which is prepared from the crystal form of compound III shown in formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the crystal form III of the compound of formula (I) or the pharmaceutical preparation of the present disclosure may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
In addition, the pharmaceutical compositions of the present disclosure may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, e.g., oral, parenteral, rectal, pulmonary, or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, oral solid preparations such as tablets, capsules, pills, granules and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. When formulated into oral preparations, the pharmaceutical preparations may further contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be manufactured by a conventional method in the existing pharmaceutical field. When preparing injection, the pharmaceutical preparation can be added with no additive, or added with proper additive according to the nature of the medicine. When used for rectal administration, the pharmaceutical preparation may be formulated into suppositories and the like. For pulmonary administration, the pharmaceutical formulation may be formulated as an inhalant or a spray. In certain preferred embodiments, the crystalline form III of the compound of formula (I) of the present disclosure is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline form III of the compound of formula (I) of the present disclosure is present in a pharmaceutical composition or medicament in the form of a unit dose.
The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned form III or the form III prepared by the aforementioned method with a pharmaceutically acceptable carrier, diluent, or excipient.
The disclosure also provides the use of said form III, pharmaceutical compositions of form III in the manufacture of a medicament for the treatment of a disease associated with opioid receptor (MOR) agonist mediation.
The use according to the present disclosure, wherein said MOR receptor agonist mediated related disorder is selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, cardiovascular disorders and respiratory disorders, preferably pain.
The disclosure also provides a crystal form III of the compound shown in the formula (I) and application of the crystal form III pharmaceutical composition in preparing a medicament for preventing or treating pain and pain-related diseases.
Pain according to the present disclosure is selected from post-operative pain, cancer-induced pain, neuropathic pain, traumatic pain or inflammation-induced pain.
The cancer described in the present disclosure is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia, and leukemia.
The disclosure also provides a crystal form III of the compound shown in the formula (I) and application of the crystal form III pharmaceutical composition in preparing medicines for exciting or antagonizing MOR receptors. Further, the present application provides a method of inhibiting a disease associated with an opioid receptor (MOR) agonist comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the crystalline form III compound of formula (I) of the present disclosure, or a pharmaceutical composition of the present disclosure.
In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain.
And performing structure determination and crystal form research on the III crystal form of the compound shown in the formula (I) through an X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The method for recrystallization of form III is not particularly limited, and can be carried out by a usual recrystallization procedure. For example, the compound represented by the formula (I) as a raw material is dissolved in an organic solvent, and then an anti-solvent is added to the solution to crystallize the compound, and after completion of crystallization, the crystals are filtered and dried to obtain desired crystals.
The crystallization method disclosed by the invention comprises room-temperature crystallization, cooling crystallization, crystal seed addition induction crystallization and the like.
The starting materials used in the preparation method of the crystal forms disclosed in the present disclosure may be any form of the compound represented by formula (I), and specific forms include, but are not limited to: amorphous, random crystalline, and the like.
Detailed description of the disclosure
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present disclosure, definitions and explanations of some of the relevant terms are provided below. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "C1-6 alkyl" as used herein means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, and specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
As used herein, "hydroxy" refers to a group such as-OH.
As used in this disclosure, "cyano" refers to a group such as-CN.
The "ether solvent" according to the present disclosure means a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether or 1, 4-dioxane.
The term "alcoholic solvent" as used in this disclosure means a group derived by substituting one or more "hydroxyl groups" for one or more hydrogen atoms of "C1-6 alkyl", wherein the "hydroxyl groups" and "C1-6 alkyl" are as defined above, and specific examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
The "mixed solvent" in the disclosure refers to a solvent formed by mixing one or more different organic solvents according to a certain proportion, or a solvent formed by mixing an organic solvent and water according to a certain proportion; the mixed solvent is preferably a mixed solvent of alcohols and ethers; the mixed solvent of the alcohols and the ethers is preferably a mixed solvent of methanol and diethyl ether, and the ratio is preferably 1: 10.
The "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-ka radiation, wherein,
the term "X-ray powder diffraction pattern or XRPD" as used in this disclosure refers to the pattern of X-rays according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-rays,
the order n of diffraction is any positive integer, one order of diffraction peak is taken, n is 1, when X-ray is incident on a certain atomic plane with d lattice plane spacing of a crystal or a part of crystal sample at grazing angle theta (complementary angle of incidence, also called Bragg angle), the condition can be metBragg equation, and the set of X-ray powder diffraction patterns is thus determined.
The differential scanning calorimetry or DSC in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference substance during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemical changes related to the thermal effect and obtain the phase change information of the sample.
The term "2 theta or 2 theta angle" as used in this disclosure means the diffraction angle, theta is the Bragg angle, and is in degrees or degrees, and the error range for 2 theta is + -0.3, and may be-0.30, -0.29, -0.28, -0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.02, 0.19, 0.20, 0.23, 0.27, 0.20, 0.23, 0.26, 0.23, 0.20, 0.23, 0.20, 0.1, or more, 0.29, 0.30, more preferably ± 0.2.
The term "interplanar spacing or interplanar spacing (d value)" as used in this disclosure means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
In the present disclosure, the drying temperature is generally 25 ℃ to 100 ℃, preferably 40 ℃ to 70 ℃, and the drying can be carried out under normal pressure or reduced pressure. Preferably, the drying is carried out under reduced pressure.
Advantageous effects of the disclosure
Compared with the prior art, the technical scheme of the disclosure has the following advantages:
researches show that the III crystal form of the compound shown in the formula (I) prepared by the method has higher melting point, good solubility and higher purity, and the crystal form is not changed and has good crystal form stability through XRPD detection under the conditions of high temperature, high humidity and illumination; the III crystal form of the compound shown in the formula (I) obtained by the technical scheme disclosed by the invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
Figure 1 is an XRPD pattern of a crystalline form of compound III shown in formula (I).
FIG. 2 is a DSC chart of a crystal form III of the compound shown in the formula (I).
FIG. 3 is a TGA profile of a crystalline form of compound III represented by formula (I).
FIG. 4 is an XRPD pattern of the crystalline form of compound III of formula (I) after being left at 25 ℃ and 60% RH for 3 months.
FIG. 5 is an XRPD pattern of the crystalline form of compound III of formula (I) after being left for 3 months at 40 ℃ and 75% RH.
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present disclosure and do not limit the spirit and scope of the present disclosure.
Test conditions of the apparatus used for the experiment:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: TA Q2000
And (3) purging gas: nitrogen (50mL/min)
The heating rate is as follows: 10.0 ℃/min
Temperature range: 30-300 deg.C
2. X-ray Powder Diffraction Spectroscopy (XRPD)
The instrument model is as follows: rigaku ultimaIV X-ray powder diffractometer
Ray: monochromatic Cu-Kalpha ray
The scanning mode is as follows: θ/2 θ, scan range: 3-45 °
Voltage: 40kV, current: 40mA
3. Thermogravimetric Analyzer (TGA)
The instrument model is as follows: mettler Toledo TGA2 STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 20-250 deg.C
Comparative example 1 preparation of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (amorphous form of Compound 19)
First step of
(S) -1,2,3, 4-Tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a
(S) -1,2,3, 4-tetrahydro-1-naphthylamine 10a (3g, 20.41mmol, prepared by the method disclosed in "Angewandte Chemie-International Edition, 45(28)," 4641-one 4644, 2006 ") was dissolved in 100mL of dichloromethane, triethylamine (5.7mL, 40.82mmol) was added, di-tert-butyl dicarbonate (4.9g, 22.45mmol) was added, and the reaction was stirred for 12 hours. The reaction was washed successively with water (100mL), saturated sodium bicarbonate solution (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 11a (5.6g, a pale yellow oil) which was reacted without purification.
MS m/z(ESI)：248.3[M+1]
Second step of
(S) -4-carbonyl-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b
Crude tert-butyl (S) -1,2,3, 4-tetrahydronaphthalene-1-carbamate 11a (5.6g, 20.41mmol) was dissolved in 90mL of a mixed solvent of acetone and water (V/V ═ 2: 1), magnesium sulfate (5.5g, 45.66mmol) was added, potassium permanganate (7.22g, 45.66mmol) was slowly added with stirring, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane and ethyl acetate as eluents to give the title product 11b (3.1g, off-white solid) in yield: 52 percent.
MS m/z(ESI)：262.3[M+1]
The third step
(1S,4S) -4-hydroxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a
(S) -tert-butyl 4-carbonyl-1, 2,3, 4-tetrahydronaphthalene-1-carbamate 11b (100mg, 0.883mmol) was dissolved in 5mL of toluene, cooled to 0 ℃ and (R) -2-methyl-CBS-oxazaborolidine (0.1mL, 0.076mmol) was added and stirred for 5 minutes, borane methyl sulfide (0.88mL, 0.76mmol) was added and stirred for reaction for 2 hours. The reaction was quenched by the addition of 50mL of saturated sodium chloride solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to give the title product 14a (60mg, white solid) in 60% yield.
MS m/z(ESI)：208.3[M-55]
The fourth step
(1S,4S) -4-ethoxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 19a
Crude tert-butyl (1S) -4-hydroxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamate 14a (850mg, 3.23mmol), silver oxide (76mg, 0.33mmol) and iodoethane (1.3mL, 16.15mmol) were dissolved in dichloromethane (30mL) and the reaction was stirred for 48 hours. Filtration and concentration of the filtrate under reduced pressure gave the crude title product 19a (800mg, yellow oil) which was reacted without purification.
MS m/z(ESI)：236.1[M-55]
The fifth step
(1S,4S) -4-ethoxy-1, 2,3, 4-tetrahydronaphthalen-1-amine 19b
Crude compound 19a (698mg, 2.4mmol) was dissolved in 4mL of dichloromethane, 8mL of a solution of 4M hydrogen chloride in 1, 4-dioxane was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, slurried with ethyl acetate (30mL), filtered, the cake was dissolved in a mixed solvent of dichloromethane and methanol (20mL, V: V ═ 5: 1), the pH of the reaction mixture was adjusted to 7 to 8 with a saturated sodium bicarbonate solution, the reaction mixture was concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V: V ═ 5: 1) (30mL × 2), filtered, and the filtrate was concentrated under reduced pressure to give a crude title product 19b (310mg, yellow liquid), which was reacted without purification.
MS m/z(ESI)：191.1[M+1]
The sixth step
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine 19
(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde 5a (500mg, 1.85mmol, prepared by the method disclosed in patent application "WO 2012129495"), crude compound 19b (310mg, 1.85mmol) was dissolved in dichloroethane (30mL), reacted with stirring for 40 minutes, sodium triacetoxyborohydride (980mg, 4.63mmol) was added, and reacted with stirring for 2 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to give the title product 19(280mg, yellow viscous solid), yield: 35 percent.
Example 1
Preparation of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine fumarate (form III)
Dissolving (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridine-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine (2.6g, 5.96mmol) in isopropanol (10mL), heating to 80 ℃, adding fumaric acid (695mg, 5.96mmol) and isopropanol (10mL) into another reaction flask, heating to 80 ℃, stirring to dissolve, dropwise adding the solution, refluxing and stirring for reaction for 10 minutes, naturally cooling to 40 ℃, precipitating a white solid in the solution, cooling to room temperature again, and stirring for reaction for 1.5 hours. Filtering the reaction solution, eluting the filter cake with isopropanol (2mL × 5) and ethyl acetate (2mL × 3) in sequence, collecting the filter cake, and vacuum-drying to obtain a white solid product (2.0g, yield 60%), wherein the XRPD pattern of the crystal sample is shown in FIG. 1, the DSC pattern thereof is shown in FIG. 2, the onset point of the endothermic peak is about 175.44 ℃, the peak value is about 176.65 ℃, and the TGA pattern is shown in FIG. 3, indicating that the crystal form III is an anhydrate; the characteristic peak positions are shown in the following table:
MS m/z(ESI)：435.5[M+1]
1H-NMR(400MHz，DMSO-d6)δ8.49-8.61(m，1H)，7.68-7.80(m，1H)，7.41-7.53(m，1H)，7.28-7.37(m，1H)，7.15-7.28(m，4H)，6.51(s，2H)，4.25-4.38(m，1H)，3.88-4.01(m，1H)，3.51-3.69(m，3H)，3.40-3.51(m，1H)，2.52-2.64(m，1H)，2.29-2.46(m，2H)，2.08-2.22(m，1H)，1.85-2.08(m，3H)，1.23-1.85(m，12H)，1.11(t，3H)，0.92-1.03(m，1H)，0.56-0.71(m，1H).
table 1, III crystal form characteristic peaks
Example 2, stability study of crystal form III influencing factors
The sample of the form III obtained in example 1 was placed open and spread, and the chemical stability of the sample under the conditions of illumination (4500Lux), high temperature (40 ℃, 60 ℃), high humidity (RH 75%, RH 90%) was examined, the sampling time was 10 days and 17 days, the chemical purity and chiral purity of the sample were examined, and the purity by HPLC was shown in the following table.
And (3) test results:
TABLE 2 stability of influencing factors (HPLC purity) for the crystal modification III samples
And (4) test conclusion:
the III crystal form is placed in an open manner for 17 days under the conditions of illumination and high temperature (40 ℃, 60 ℃), the chemical purity and the chiral purity are obviously reduced, and the change of the chemical purity and the chiral purity is small when the III crystal form is placed in an open manner for 17 days under the conditions of high humidity (RH 75%, RH 90%); XRPD detects that the crystal form III is placed for 17 days under the conditions of illumination (4500Lux), high temperature (40 ℃, 60 ℃) and high humidity (RH 75%, RH 90%), the crystal form is not changed, and the stability of the crystal form III is better.
Example 3 long-term, accelerated stability study of form III
The crystal form III sample obtained in example 1 is placed in a dark place, sealed and flatly placed, the stability of the sample under long-term (25 ℃, 60% RH) and accelerated (40 ℃, 75% RH) is examined, the sampling time is examined to be 0.5 month, 1 month, 2 months and 3 months, and XRPD detects whether the crystal form is transformed.
And (3) test results:
TABLE 3 stability of the sample of form III (HPLC purity)
And (4) test conclusion:
the III crystal form has good stability after being placed for 3 months under the conditions of light shielding and sealing for a long time (25 ℃, 60% RH) and acceleration (40 ℃, 75% RH), the XRPD pattern after being placed for 3 months at 25 ℃ and 60% RH is shown in figure 4, the XRPD pattern after being placed for 3 months at 40 ℃ and 75% RH is shown in figure 5, the XRPD peak pattern of the III crystal form is basically unchanged, and the crystal form is stable.
Claims (10)
1. A crystalline form III of a compound of formula (I) characterized by: an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta has characteristic peaks at 6.44, 10.16, 11.99, 13.65, 14.00, 16.43, 17.05, 19.56, 21.40 and 22.64, wherein the error range of 2 theta of each characteristic peak is +/-0.30,
2. the crystalline form III according to claim 1, characterized by an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ angles, having characteristic peaks at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94, and 29.26, wherein each characteristic peak has an error in 2 Θ of ± 0.30.
3. The crystalline form III of claim 2, characterized by an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ angles, having characteristic peaks at 6.44, 7.11, 9.78, 10.16, 11.99, 12.90, 13.22, 13.65, 14.00, 14.38, 14.82, 15.32, 16.08, 16.43, 17.05, 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 20.92, 21.40, 22.64, 22.91, 23.18, 23.94, 24.50, 25.32, 25.88, 26.67, 28.47, 29.26, 30.16, 30.96, 32.52, 33.38, 35.74, 37.02, 40.38, 41.19, and 42.41, wherein each characteristic peak has a2 Θ error range of ± 0.30.
4. The crystalline form III according to any one of claims 1-3, characterized by an X-ray powder diffraction pattern expressed in diffraction angle 2 Θ angles as shown in figure 1.
5. A process for preparing the crystalline form III of any one of claims 1-4, comprising:
dissolving a free compound shown as a formula (I) in a solvent, adding fumaric acid, heating to slightly boil, cooling and separating out crystals to obtain a crystal form III; the micro-boiling temperature is selected from 40 ℃ to the boiling point of a solvent, and the solvent is isopropanol.
6. A pharmaceutical composition prepared from the crystalline form III of any one of claims 1-4, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
7. A process for preparing a pharmaceutical composition comprising the step of admixing the crystalline form III of any one of claims 1-4 or prepared by the process of claim 5 with a pharmaceutically acceptable carrier, diluent, or excipient.
8. Use of the crystalline form III according to any one of claims 1-4, or a pharmaceutical composition of the crystalline form III according to claim 6, in the manufacture of a medicament for the treatment of a disease associated with opioid receptor (MOR) agonist mediation.
9. The use according to claim 8, wherein said MOR receptor agonist-mediated related disorder is selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, cardiovascular disorders and respiratory disorders.
10. The use according to claim 9, wherein said MOR receptor agonist-mediated related disorder is selected from pain.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018111867437 | 2018-10-12 | ||
| CN201811186743 | 2018-10-12 | ||
| PCT/CN2019/110563 WO2020073985A1 (en) | 2018-10-12 | 2019-10-11 | Crystalline structure of mu opioid receptor (mor) agonist and preparation method therefor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112638907A CN112638907A (en) | 2021-04-09 |
| CN112638907B true CN112638907B (en) | 2022-04-12 |
Family
ID=70163634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980053697.XA Active CN112638907B (en) | 2018-10-12 | 2019-10-11 | Crystalline form of an opioid receptor (MOR) agonist and methods of preparation |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN112638907B (en) |
| TW (1) | TWI717859B (en) |
| WO (1) | WO2020073985A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017063509A1 (en) * | 2015-10-15 | 2017-04-20 | 江苏恒瑞医药股份有限公司 | Oxa spiro derivative, preparation method therefor, and applications thereof in medicines |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2688403T (en) * | 2011-03-23 | 2017-07-13 | Trevena Inc | Opioid receptor ligands and methods of using and making same |
| CA3057383A1 (en) * | 2017-04-14 | 2018-10-18 | Jiangsu Hengrui Medicine Co., Ltd. | Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof |
-
2019
- 2019-10-11 WO PCT/CN2019/110563 patent/WO2020073985A1/en active Application Filing
- 2019-10-11 CN CN201980053697.XA patent/CN112638907B/en active Active
- 2019-10-14 TW TW108136888A patent/TWI717859B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017063509A1 (en) * | 2015-10-15 | 2017-04-20 | 江苏恒瑞医药股份有限公司 | Oxa spiro derivative, preparation method therefor, and applications thereof in medicines |
Non-Patent Citations (1)
| Title |
|---|
| Structure-Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R) 9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain;Xiao-Tao Chen 等;《Journal of Medicinal Chemistry》;20130924;第8019-8031页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW202016099A (en) | 2020-05-01 |
| WO2020073985A1 (en) | 2020-04-16 |
| TWI717859B (en) | 2021-02-01 |
| CN112638907A (en) | 2021-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110049980B (en) | Salt of opioid receptor (MOR) agonist, fumarate I crystal form of salt and preparation method of fumarate I crystal form | |
| US10189837B2 (en) | Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt | |
| CN108727347B (en) | Crystal form of opioid receptor (MOR) agonist and preparation method thereof | |
| EP3248983B1 (en) | Crystal form a of obeticholic acid and preparation method therefor | |
| CN109937200B (en) | Crystal form of benzofuran derivative free alkali and preparation method thereof | |
| CN112638906B (en) | Crystalline form of an opioid receptor (MOR) agonist and methods of preparation | |
| WO2018072742A1 (en) | Crystalline form of free base of imidazo isoindole derivative and preparation method therefor | |
| EP3360858A1 (en) | Process for producing an aminopyrrolidine derivative | |
| CN112638907B (en) | Crystalline form of an opioid receptor (MOR) agonist and methods of preparation | |
| RU2779119C2 (en) | Salt of mu-opioid receptor (mor) agonist, crystal form i of its fumarate salt, and their production method | |
| CN115448895A (en) | Crystal form of vortioxetine prodrug, preparation method and application thereof | |
| TW201904972A (en) | Crystal form of imidazoisoindole derivative free base and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |