WO2023143205A1 - 7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法 - Google Patents

7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法 Download PDF

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WO2023143205A1
WO2023143205A1 PCT/CN2023/072433 CN2023072433W WO2023143205A1 WO 2023143205 A1 WO2023143205 A1 WO 2023143205A1 CN 2023072433 W CN2023072433 W CN 2023072433W WO 2023143205 A1 WO2023143205 A1 WO 2023143205A1
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crystal form
compound
formula
ray powder
present
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PCT/CN2023/072433
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颜小兵
来巍
钱文远
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南京明德新药研发有限公司
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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms

Definitions

  • the invention discloses a crystal form of a class of 7-azaspiro[4,5]decane-6,10-dione compounds and a preparation method thereof, and specifically discloses a preparation method of a compound of formula (I) and a crystal form thereof and apply.
  • Hypertrophic cardiomyopathy is a myocardial disease characterized by myocardial hypertrophy, which often invades the interventricular septum, the ventricular cavity becomes smaller, left ventricular blood filling is blocked, and left ventricular diastolic compliance decreases. According to whether the left ventricular outflow tract is obstructed, it is divided into obstructive and non-obstructive hypertrophic cardiomyopathy, which may be related to genetics.
  • the global incidence of HCM is about 1/500, and its clinical manifestations are diverse, ranging from asymptomatic to palpitations, exertional dyspnea, precordial pain, fatigue, syncope and even sudden death, and left heart failure in the late stage.
  • beta-receptor blockers or calcium channel blockers to improve symptoms, which cannot target the cause, delay the progression of myocardial hypertrophy, and do not improve the prognosis, so the therapeutic effect is limited.
  • Myosin and actin are the material basis of myocardial contraction, and myosin cross-bridges periodically combine with and dissociate from actin to drive myofilaments to slide, resulting in myocardial contraction.
  • Myosin has ATPase activity, which provides power for myocardial contraction by hydrolyzing ATP. Mutations in myosin can lead to prolongation of the binding time between myosin and actin, and damage the excessive contraction and relaxation of left ventricular myocardium, leading to hypertrophy and fibrosis of left ventricular myocardium, and HCM.
  • MYK-461 is an allosteric regulator of cardiac myosin, which slows down the rate of phosphate hydrolysis, reduces the binding time between myosin and actin, produces negative inotropic effects, and relieves myocardial hypertrophy caused by excessive contraction of left ventricular myocardium, etc.
  • Pathological changes However, the elimination in the body is slow, and the drug stays in the body for too long, which is not convenient for rapid dose adjustment. Therefore, the development of myosin inhibitors with better activity and more ideal pharmacokinetic properties has important clinical value and significance.
  • myocardial sarcomeres have been identified as drivers of a variety of cardiac diseases and conditions, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.
  • Myosin ATPase Inhibitors can also play a potential therapeutic role in alleviating the pathological process of the above diseases by inhibiting myocardial contraction.
  • the present invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200° and 22.420 ⁇ 0.200°;
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 26.259 ⁇ 0.200° and 28.056 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 26.259 ⁇ 0.200°, 27.261 ⁇ 0.200°, 28.056 ⁇ 0.200°, and 30.256 ⁇ 0.200°.
  • the above-mentioned A crystal form, in its X-ray powder diffraction pattern, is represented by 2 ⁇ angle, and contains at least 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 11.143 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 26.259 ⁇ 0.200°, 27.261 ⁇ 0.200°, 28.056 ⁇ 0.200°, and 30.256 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.200°, 16.522 ⁇ 0.200°, 17.053 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 23.909 ⁇ 0.200°, 26.259 ⁇ 0.200°, 27.261 ⁇ 0.200°, 28.056 ⁇ 0.200°, 30.256 ⁇ 0.200°, and 33.761 ⁇ 0.200°.
  • the above-mentioned A crystal form, in its X-ray powder diffraction pattern, is represented by 2 ⁇ angle, and contains at least 5, 6, 7, 8, 9, 10, 11 or 12 features selected from the following Diffraction peaks: 11.143 ⁇ 0.200°, 16.522 ⁇ 0.200°, 17.053 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 23.909 ⁇ 0.200°, 26.259 ⁇ 0.200°, 27.26 1 ⁇ 0.200°, 28.056 ⁇ 0.200°, 30.256 ⁇ 0.200° and 33.761 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.200°, 13.260 ⁇ 0.200°, 16.522 ⁇ 0.200°, 17.053 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 23.568 ⁇ 0.200°, 23.909 ⁇ 0.200°, 26.259 ⁇ 0.200°, 27.261 ⁇ 0.200°, 28.056 ⁇ 0.200°, 29.008 ⁇ 0.200°, 30 .256 ⁇ 0.200°, 33.761 ⁇ 0.200° and 35.404 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.200°, 13.260 ⁇ 0.200°, 14.860 ⁇ 0.200°, 16.163 ⁇ 0.200°, 16.522 ⁇ 0.200°, 17.053 ⁇ 0.200°, 17.537 ⁇ 0.200°, 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, 23.568 ⁇ 0.200°, 23.909 ⁇ 0.200°, 26.259 ⁇ 0.200°, 26 .726 ⁇ 0.200°, 27.261 ⁇ 0.200°, 28.056 ⁇ 0.200°, 29.008 ⁇ 0.200°, 30.256 ⁇ 0.200°, 31.219 ⁇ 0.200°, 31.646 ⁇ 0.200°, 32.037 ⁇ 0.200°, 32.438 ⁇ 0.200°, 32.807 ⁇ 0.200°, 33 .761 ⁇ 0.200°, 34.534 ⁇ 0.200°, 35.404 ⁇ 0.200°, 36.856 ⁇
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143 ⁇ 0.100°, 13.260 ⁇ 0.100°, 14.860 ⁇ 0.100°, 16.163 ⁇ 0.100°, 16.522 ⁇ 0.100°, 17.053 ⁇ 0.100°, 17.537 ⁇ 0.100°, 18.283 ⁇ 0.100°, 19.662 ⁇ 0.100°, 22.420 ⁇ 0.100°, 23.568 ⁇ 0.100°, 23.909 ⁇ 0.100°, 26.259 ⁇ 0.100°, 26.726 ⁇ 0.100°, 27.261 ⁇ 0.100°, 28.056 ⁇ 0.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.143°, 13.260°, 14.860°, 16.163°, 16.522°, 17.053°, 17.537°, 18.283 °, 19.662°, 22.420°, 23.568°, 23.909°, 26.259°, 26.726°, 27.261°, 28.056°, 29.008°, 30.256°, 31.219°, 31.646°, 32.037°, 32.438°, 32.807° , 33.761°, 34.534°, 35.404°, 36.856°, 37.813°, and 39.456°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 18.283 ⁇ 0.200°, 19.662 ⁇ 0.200°, 22.420 ⁇ 0.200°, and/or 11.143 ⁇ 0.200° , and/or 13.260 ⁇ 0.200°, and/or 14.860 ⁇ 0.200°, and/or 16.163 ⁇ 0.200°, and/or 16.522 ⁇ 0.200°, and/or 17.053 ⁇ 0.200°, and/or 17.537 ⁇ 0.200°, and /or 23.568 ⁇ 0.200°, and/or 23.909 ⁇ 0.200°, and/or 26.259 ⁇ 0.200°, and/or 26.726 ⁇ 0.200°, and/or 27.261 ⁇ 0.200°, and/or 28.056 ⁇ 0.200°, and/or 29.008 ⁇ 0.200°, and/or 30.256 ⁇ 0.200°, and/or 31.219 ⁇ 0.200°, and/or 31.646 ⁇ 0.200°, and/or 3
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 18.283 ⁇ 0.100°, 19.662 ⁇ 0.100°, 22.420 ⁇ 0.100°, and/or 11.143 ⁇ 0.100° , and/or 13.260 ⁇ 0.100°, and/or 14.860 ⁇ 0.100°, and/or 16.163 ⁇ 0.100°, and/or 16.522 ⁇ 0.100°, and/or 17.053 ⁇ 0.100°, and/or 17.537 ⁇ 0.100°, and /or 23.568 ⁇ 0.100°, and/or 23.909 ⁇ 0.100°, and/or 26.259 ⁇ 0.100°, and/or 26.726 ⁇ 0.100°, and/or 27.261 ⁇ 0.100°, and/or 28.056 ⁇ 0.100°, and/or 29.008 ⁇ 0.100°, and/or 30.256 ⁇ 0.100°, and/or 31.219 ⁇ 0.100°, and/or 31.646 ⁇ 0.100°, and/or 3
  • the XRPD spectrum of the above crystal form A is basically shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above crystal form A has peak endothermic peaks at 249.53 ⁇ 8°C and 306.12 ⁇ 8°C.
  • the differential scanning calorimetry curve of the above crystal form A has peak endothermic peaks at 249.53 ⁇ 3°C and 306.12 ⁇ 3°C.
  • the DSC spectrum of the above crystal form A is basically as shown in FIG. 2 .
  • the above crystal form A has a thermogravimetric analysis curve with a weight loss of 0.075% at 200 ⁇ 3°C and a weight loss of 0.164% at 250 ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is basically as shown in FIG. 3 .
  • the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 12.861 ⁇ 0.200°, 14.135 ⁇ 0.200°, 17.788 ⁇ 0.200°, 18.099 ⁇ 0.200°, 21.659 ⁇ 0.200°, 21.912 ⁇ 0.200°, 22.410 ⁇ 0.200°, and 25.218 ⁇ 0.200°.
  • the above-mentioned B crystal form in its X-ray powder diffraction pattern, is represented by 2 ⁇ angle, and contains at least 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 12.861 ⁇ 0.200°, 14.135 ⁇ 0.200°, 17.788 ⁇ 0.200°, 18.099 ⁇ 0.200°, 21.659 ⁇ 0.200°, 21.912 ⁇ 0.200°, 22.410 ⁇ 0.200°, and 25.218 ⁇ 0.200°.
  • the above-mentioned B crystal form, in its X-ray powder diffraction pattern, is represented by 2 ⁇ angle, and at least contains 5, 6, 7, 8, 9, 10, 11, 12, 13 selected from the following Or 14 characteristic diffraction peaks: 8.262 ⁇ 0.200°, 12.861 ⁇ 0.200°, 14.135 ⁇ 0.200°, 16.303 ⁇ 0.200°, 17.788 ⁇ 0.200°, 18.099 ⁇ 0.200°, 19.053 ⁇ 0.200°, 21.659 ⁇ 0.200°, 21.912 ⁇ 0.200°, 22.410 ⁇ 0.200°, 25.218 ⁇ 0.200°, 27.230 ⁇ 0. 200°, 27.526 ⁇ 0.200° and 28.132 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.240 ⁇ 0.200°, 8.262 ⁇ 0.200°, 9.189 ⁇ 0.200°, 10.841 ⁇ 0.200°, 12.861 ⁇ 0.200°, 13.269 ⁇ 0.200°, 14.135 ⁇ 0.200°, 14.651 ⁇ 0.200°, 15.907 ⁇ 0.200°, 16.303 ⁇ 0.200°, 16.770 ⁇ 0.200°, 17.788 ⁇ 0.200°, 18.099 ⁇ 0.200°, 19 .053 ⁇ 0.200°, 21.659 ⁇ 0.200°, 21.912 ⁇ 0.200°, 22.410 ⁇ 0.200°, 22.829 ⁇ 0.200°, 24.408 ⁇ 0.200°, 25.218 ⁇ 0.200°, 26.009 ⁇ 0.200°, 27.230 ⁇ 0.200°, 27.526 ⁇ 0.200°, 28 .132 ⁇ 0.200°, 29.630 ⁇ 0.200°, 32.150 ⁇ 0.200°, 32.961 ⁇ 0.200°,
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.240 ⁇ 0.100°, 8.262 ⁇ 0.100°, 9.189 ⁇ 0.100°, 10.841 ⁇ 0.100°, 12.861 ⁇ 0.100°,13.269 ⁇ 0.100°,14.135 ⁇ 0.100°,14.651 ⁇ 0.100°,15.907 ⁇ 0.100°,16.303 ⁇ 0.100°,16.770 ⁇ 0.100°,17.788 ⁇ 0.100°,18.099 ⁇ 0.100°,19 .053 ⁇ 0.100°, 21.659 ⁇ 0.100°, 21.912 ⁇ 0.100°, 22.410 ⁇ 0.100°, 22.829 ⁇ 0.100°, 24.408 ⁇ 0.100°, 25.218 ⁇ 0.100°, 26.009 ⁇ 0.100°, 27.230 ⁇ 0.100°, 27.526 ⁇ 0.100°, 28 .132 ⁇ 0.100°, 29.630 ⁇ 0.100°, 32.150 ⁇ 0.100°, 32.961 ⁇
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 17.788° ⁇ 0.200°, 18.099 ⁇ 0.200°, 21.659 ⁇ 0.200°, and/or 21.912 ⁇ 0.200° °, and/or 7.240 ⁇ 0.200°, and/or 8.262 ⁇ 0.200°, and/or 9.189 ⁇ 0.200°, and/or 10.841 ⁇ 0.200°, and/or 12.861 ⁇ 0.200°, and/or 13.269 ⁇ 0.200°, and/or 14.135 ⁇ 0.200°, and/or 14.651 ⁇ 0.200°, and/or 15.907 ⁇ 0.200°, and/or 16.303 ⁇ 0.200°, and/or 16.770 ⁇ 0.200°, and/or 19.053 ⁇ 0.200°, and/or or 22.410 ⁇ 0.200°, and/or 22.829 ⁇ 0.200°, and/or 24.408 ⁇ 0.200°, and/or 25.218 ⁇ 0.200°, and/or 26
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 17.788° ⁇ 0.100°, 18.099 ⁇ 0.100°, 21.659 ⁇ 0.100°, and/or 21.912 ⁇ 0.100° °, and/or 7.240 ⁇ 0.100°, and/or 8.262 ⁇ 0.100°, and/or 9.189 ⁇ 0.100°, and/or 10.841 ⁇ 0.100°, and/or 12.861 ⁇ 0.100°, and/or 13.269 ⁇ 0.100°, and/or 14.135 ⁇ 0.100°, and/or 14.651 ⁇ 0.100°, and/or 15.907 ⁇ 0.100°, and/or 16.303 ⁇ 0.100°, and/or 16.770 ⁇ 0.100°, and/or 19.053 ⁇ 0.100°, and/or or 22.410 ⁇ 0.100°, and/or 22.829 ⁇ 0.100°, and/or 24.408 ⁇ 0.100°, and/or 25.218 ⁇ 0.100°, and/or 26
  • the differential scanning calorimetry curve of the above crystal form B has an endothermic peak at 249.48 ⁇ 8°C.
  • the differential scanning calorimetry curve of the above crystal form B has an endothermic peak at 249.48 ⁇ 3°C.
  • the DSC spectrum of the above crystal form B is basically as shown in FIG. 6 .
  • the present invention also provides a preparation method of formula (I) compound A crystal form, comprising:
  • the above alcohol solvent is selected from methanol and ethanol.
  • the present invention also provides the preparation method of the compound of the above formula (I), the crystal form A of the compound of the formula (I), the crystal form B of the compound of the formula (I) or the crystal form A of the compound of the formula (I) in the preparation of LSD1-related Drug application for diseases.
  • the present invention also provides the application of the preparation method of the compound of the above formula (I), the crystal form A of the compound of the formula (I) or the crystal form A of the compound of the formula (I) in the preparation of medicines for treating LSD1-related diseases.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (I), the A crystal form of the above-mentioned compound of formula (I), the B crystal form of the above-mentioned compound of formula (I) and pharmaceutically acceptable Carrier.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (I) or A of the above-mentioned compound of formula (I) Crystal forms and pharmaceutically acceptable carriers.
  • the present invention also provides the above-mentioned compound of formula (I), the A crystal form of the above-mentioned compound of formula (I), the B crystal form of the above-mentioned compound of formula (I) or the application of the above-mentioned pharmaceutical composition in the preparation of cardiac myosin inhibitor drugs .
  • the present invention also provides the application of the above-mentioned compound of formula (I), crystal form A of the above-mentioned compound of formula (I) or the above-mentioned pharmaceutical composition in the preparation of a drug for cardiac myosin inhibitor.
  • the present invention also provides the compound of the above formula (I), the crystal form A of the compound of the formula (I), the crystal form B of the compound of the formula (I) or the above pharmaceutical composition in the preparation and treatment of heart failure and hypertrophic cardiomyopathy application.
  • the present invention also provides the application of the above-mentioned compound of formula (I), crystal form A of the above-mentioned compound of formula (I) or the above-mentioned pharmaceutical composition in the preparation and treatment of heart failure and hypertrophic cardiomyopathy.
  • the present invention also provides a method for treating diseases related to myocardial myosin inhibitors in a subject in need, the method comprising providing the subject with an effective dose of the compound of formula (I) defined in any of the above technical schemes , Form A of the compound of formula (I), form B of the compound of formula (I), or a pharmaceutical composition.
  • the present invention also provides a method for treating diseases related to myocardial myosin inhibitors in a subject in need, the method comprising providing the subject with an effective dose of the compound of formula (I) defined in any of the above technical schemes .
  • the present invention also provides a method for treating heart failure and hypertrophic cardiomyopathy in a subject in need, the method comprising providing the subject with an effective dose of the compound of formula (I) defined in any of the above technical schemes, formula ( I) Crystal form A of the compound, crystal form B of the compound of formula (I), or a pharmaceutical composition.
  • the differential scanning calorimetry (DSC) of the crystalline form of the present invention has experimental error and is slightly affected by the drying degree of the sample, between one machine and another machine and between one sample and another sample , the position and peak value of the endothermic peak may be slightly different, and the experimental error or difference may be less than or equal to 10°C, or less than or equal to 9°C, or less than or equal to 8°C, or less than or equal to 7°C, or less than or equal to 6°C, Or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method SXRD
  • the cultivated single crystal is collected with a Bruker D8venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method is ⁇ / ⁇ scanning.
  • the direct method ( Shelxs97) analysis of the crystal structure can confirm the absolute configuration.
  • TEA triethylamine
  • DIEA N,N-diisopropylethylamine
  • PE petroleum ether
  • EtOAc ethyl acetate
  • EA ethyl acetate
  • THF tetrahydrofuran
  • MeOH MTBE stands for methyl tert-butyl ether
  • DCM stands for dichloromethane
  • EtOH stands for ethanol
  • iPrOH stands for isopropanol
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • L-selectride stands for lithium tri-sec-butyl borohydride
  • TCFH stands for N,N,N,N-tetramethylchloroformamidine hexafluorophosphate
  • FA stands for formic acid
  • TFA stands for trifluoroacetic acid
  • ACN stands for acetonitrile
  • TLC thin layer chromatography
  • the second method of X-ray powder diffraction (X-ray powder diffractometer, XRPD) of the present invention is acquired by the D2Phaser type of Bruker Instruments, and the test parameters are shown in Table 4.
  • DSC Differential Scanning Calorimeter
  • DSC Differential Scanning Calorimeter
  • Thermogravimetric Analyzer (Thermal Gravimetric Analyzer, TGA) method one of the present invention, test parameter is shown in Table 7.
  • Fig. 1 the XRPD spectrogram of the Cu-K ⁇ radiation of formula (I) compound A crystal form
  • Fig. 2 the DSC spectrogram of formula (I) compound A crystal form
  • Fig. 3 TGA spectrogram of formula (I) compound A crystal form
  • FIG. 4 Single crystal X-ray diffraction (SC-XRD) three-dimensional structure ellipsoid diagram of the compound of formula (I);
  • Fig. 5 XRPD spectrogram of Cu-K ⁇ radiation of formula (I) compound B crystal form
  • Step A To a solution of 1-1 (5g, 32.02mmol, 4.07mL, 1eq) in THF (50mL) was added 1-2 (4.66g, 38.43mmol, 1.2eq) and tetraethyl titanate at 20°C Ester (21.92g, 96.07mmol, 19.92mL, 3eq), the reaction solution was stirred at 60°C for 16 hours, ethyl acetate (100mL) was added to the reaction solution, after cooling to 0°C, water (20mL) was slowly added, and stirred for 0.5 hours, filtered, and the filtrate was washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-3.
  • Step C Add HCl/MeOH (200mmol.50mL, 7.92eq) to the MeOH (50mL) solution of 1-4 (6.6g) at 20°C, stir the reaction solution for 16 hours and concentrate to obtain the salt of compound 1-5 salt.
  • Step F Under nitrogen protection, sodium methoxide (1M, 6.43ml, 1eq) was added to a solution of 1-9 (0.648g, 1.53mmol, 1eq) in MeOH (7.6mL), and the reaction solution was stirred at 20°C for 16 hours , adding 1M dilute hydrochloric acid to the reaction solution to adjust the pH to about 5, then adding EA (20mL) for extraction, the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-10.
  • Step G Add hydrochloric acid (4M, 4mL, 17.40eq) to a solution of 1-10 (348mg, 919.74 ⁇ mol, 1eq) in 1,4-dioxane (4mL), and stir the reaction solution at 50°C for 16 hours, Add EA (30mL) to the reaction solution, then add 1M sodium hydroxide aqueous solution to adjust the pH to about 8, after liquid separation, the organic phase is washed with saturated brine (50mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated, leaving Add MeOH (10mL) to the compound and stir for 20 minutes, filter, and dry the filter cake under high vacuum to obtain the compound of formula (I).
  • Embodiment 4 Single crystal X-ray diffraction detection analysis of the compound of formula (I)
  • X-ray light source high-intensity micro-focus rotating anode light source
  • Tube current 50mA
  • Goniometer four-axis (Kappa, ⁇ , 2 ⁇ , ⁇ ) goniometer;
  • Detector Large-area photon II detector, the effective area of the detector is 14cm ⁇ 10cm;
  • Cardiac actin (Cytoskeleton, Cat.#AD99-A)
  • the compound of the present invention is to the inhibitory effect IC of myocardial myosin ATPase activity IC 50 value test result
  • Animals in group 1 were given a dose of 0.2 mg/kg and a concentration of 0.2 mg/mL by single injection through the tail vein, and animals in group 2 were given a compound with a dose of 1 mg/kg and a concentration of 0.2 mg/mL by intragastric administration.
  • Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose.
  • the compound of the present invention has good in vivo pharmacokinetic properties in rats.

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Abstract

本发明公开了一类7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法，具体公开了式(I)化合物及其晶型的制备方法和应用。

Description

7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法
本申请主张如下优先权：
CN202210103134.0，2022年01月27日；
CN202211017556.2，2022年08月23日。
技术领域
本发明公开了一类7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法，具体公开了式(I)化合物及其晶型的制备方法和应用。
背景技术
肥厚型心肌病是一种以心肌肥厚为特征的心肌疾病，常侵及室间隔，心室内腔变小，左心室血液充盈受阻，左心室舒张期顺应性下降。根据左心室流出道有无梗阻分为梗阻性及非梗阻性肥厚型心肌病，可能与遗传等有关。HCM全球发病率约1/500，其临床表现多样，可以无症状，也可以有心悸、劳力性呼吸困难、心前区闷痛、易疲劳、晕厥甚至猝死，晚期出现左心衰的表现。
目前HCM治疗药物有限，主要通过β受体阻滞剂或钙通道阻滞剂来改善症状，无法针对病因，延缓心肌肥厚进展，也不改善预后，治疗效果有限。
肌球蛋白和肌动蛋白是心肌收缩的物质基础，肌球蛋白横桥周期性地与肌动蛋白结合、解离，驱动肌丝滑动，导致心肌收缩。肌球蛋白具有ATP酶活性，通过水解ATP为心肌收缩提供动力。肌球蛋白变异会导致肌球蛋白与肌动蛋白结合时间延长，左心室心肌过度收缩和舒张受损，导致左心室心肌肥大、纤维化，引发HCM。MYK-461是心肌肌球蛋白别构调控剂，其减慢磷酸水解速度、降低肌球蛋白与肌动蛋白结合时间，产生负性肌力效应，缓解因左心室心肌过度收缩所致心肌肥大等病理改变。但体内消除缓慢，药物在体内停留时间过长，不便于快速调节剂量。因此，开发具有更好活性、更理想药代动力学特性的肌球蛋白抑制剂具有重要临床价值和意义。
此外，心肌肌节的异常已鉴别为多种心脏疾病及病状的驱动原因，如射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛和限制性心肌病等，肌球蛋白ATP酶抑制剂通过抑制心肌收缩，也可以在缓解上述疾病病理过程中发挥潜在治疗效应。
发明内容
本发明提供式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：18.283±0.200°、19.662±0.200°和22.420±0.200°；
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°和28.056±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°和30.256±0.200°。
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的5、6、7或8个特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°和30.256±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、16.522±0.200°、17.053±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、23.909±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°、30.256±0.200°和33.761±0.200°。
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的5、6、7、8、9、10、11或12个特征衍射峰：11.143±0.200°、16.522±0.200°、17.053±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、23.909±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°、30.256±0.200°和33.761±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、13.260±0.200°、16.522±0.200°、17.053±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、23.568±0.200°、23.909±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°、29.008±0.200°、30.256±0.200°、33.761±0.200°和35.404±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、13.260±0.200°、14.860±0.200°、16.163±0.200°、16.522±0.200°、17.053±0.200°、17.537±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、23.568±0.200°、23.909±0.200°、26.259±0.200°、26.726±0.200°、27.261±0.200°、28.056±0.200°、29.008±0.200°、30.256±0.200°、31.219±0.200°、31.646±0.200°、32.037±0.200°、32.438±0.200°、32.807±0.200°、33.761±0.200°、34.534±0.200°、35.404±0.200°、36.856±0.200°、37.813±0.200°和39.456±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.100°、13.260±0.100°、14.860±0.100°、16.163±0.100°、16.522±0.100°、17.053±0.100°、17.537±0.100°、 18.283±0.100°、19.662±0.100°、22.420±0.100°、23.568±0.100°、23.909±0.100°、26.259±0.100°、26.726±0.100°、27.261±0.100°、28.056±0.100°、29.008±0.100°、30.256±0.100°、31.219±0.100°、31.646±0.100°、32.037±0.100°、32.438±0.100°、32.807±0.100°、33.761±0.100°、34.534±0.100°、35.404±0.100°、36.856±0.100°、37.813±0.100°和39.456±0.100°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143°、13.260°、14.860°、16.163°、16.522°、17.053°、17.537°、18.283°、19.662°、22.420°、23.568°、23.909°、26.259°、26.726°、27.261°、28.056°、29.008°、30.256°、31.219°、31.646°、32.037°、32.438°、32.807°、33.761°、34.534°、35.404°、36.856°、37.813°和39.456°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：18.283±0.200°、19.662±0.200°、22.420±0.200°、和/或11.143±0.200°、和/或13.260±0.200°、和/或14.860±0.200°、和/或16.163±0.200°、和/或16.522±0.200°、和/或17.053±0.200°、和/或17.537±0.200°、和/或23.568±0.200°、和/或23.909±0.200°、和/或26.259±0.200°、和/或26.726±0.200°、和/或27.261±0.200°、和/或28.056±0.200°、和/或29.008±0.200°、和/或30.256±0.200°、和/或31.219±0.200°、和/或31.646±0.200°、和/或32.037±0.200°、和/或32.438±0.200°、和/或32.807±0.200°、和/或33.761±0.200°、和/或34.534±0.200°、和/或35.404±0.200°、和/或36.856±0.200°、和/或37.813±0.200°、和/或39.456±0.200°。
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：18.283±0.100°、19.662±0.100°、22.420±0.100°、和/或11.143±0.100°、和/或13.260±0.100°、和/或14.860±0.100°、和/或16.163±0.100°、和/或16.522±0.100°、和/或17.053±0.100°、和/或17.537±0.100°、和/或23.568±0.100°、和/或23.909±0.100°、和/或26.259±0.100°、和/或26.726±0.100°、和/或27.261±0.100°、和/或28.056±0.100°、和/或29.008±0.100°、和/或30.256±0.100°、和/或31.219±0.100°、和/或31.646±0.100°、和/或32.037±0.100°、和/或32.438±0.100°、和/或32.807±0.100°、和/或33.761±0.100°、和/或34.534±0.100°、和/或35.404±0.100°、和/或36.856±0.100°、和/或37.813±0.100°、和/或39.456±0.100°。
本发明的一些方案中，上述A晶型的XRPD图谱基本如图1所示。
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。
表1式(I)化合物A晶型的XRPD图谱解析数据

本发明的一些方案中，上述A晶型，其差示扫描量热曲线在249.53±8℃和306.12±8℃处具有吸热峰的峰值。
本发明的一些方案中，上述A晶型，其差示扫描量热曲线在249.53±3℃和306.12±3℃处具有吸热峰的峰值。
本发明的一些方案中，上述A晶型，其DSC图谱基本如图2所示。
本发明的一些方案中，上述A晶型，其热重分析曲线在200±3℃时失重达0.075％，在250±3℃时失重达0.164％。
本发明的一些方案中，上述A晶型，其TGA图谱基本如图3所示。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.861±0.200°、14.135±0.200°、17.788±0.200°、18.099±0.200°、21.659±0.200°、21.912±0.200°、22.410±0.200°和25.218±0.200°。
本发明的一些方案中，上述B晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的5、6、7或8个特征衍射峰：12.861±0.200°、14.135±0.200°、17.788±0.200°、18.099±0.200°、21.659±0.200°、21.912±0.200°、22.410±0.200°和25.218±0.200°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.262±0.200°、12.861±0.200°、14.135±0.200°、16.303±0.200°、17.788±0.200°、18.099±0.200°、19.053±0.200°、21.659±0.200°、21.912±0.200°、22.410±0.200°、25.218±0.200°、27.230±0.200°、27.526±0.200°和28.132±0.200°。
本发明的一些方案中，上述B晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的5、6、7、8、9、10、11、12、13或14个特征衍射峰：8.262±0.200°、12.861±0.200°、14.135±0.200°、 16.303±0.200°、17.788±0.200°、18.099±0.200°、19.053±0.200°、21.659±0.200°、21.912±0.200°、22.410±0.200°、25.218±0.200°、27.230±0.200°、27.526±0.200°和28.132±0.200°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.240±0.200°、8.262±0.200°、9.189±0.200°、10.841±0.200°、12.861±0.200°、13.269±0.200°、14.135±0.200°、14.651±0.200°、15.907±0.200°、16.303±0.200°、16.770±0.200°、17.788±0.200°、18.099±0.200°、19.053±0.200°、21.659±0.200°、21.912±0.200°、22.410±0.200°、22.829±0.200°、24.408±0.200°、25.218±0.200°、26.009±0.200°、27.230±0.200°、27.526±0.200°、28.132±0.200°、29.630±0.200°、32.150±0.200°、32.961±0.200°和33.645±0.200°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.240±0.100°、8.262±0.100°、9.189±0.100°、10.841±0.100°、12.861±0.100°、13.269±0.100°、14.135±0.100°、14.651±0.100°、15.907±0.100°、16.303±0.100°、16.770±0.100°、17.788±0.100°、18.099±0.100°、19.053±0.100°、21.659±0.100°、21.912±0.100°、22.410±0.100°、22.829±0.100°、24.408±0.100°、25.218±0.100°、26.009±0.100°、27.230±0.100°、27.526±0.100°、28.132±0.100°、29.630±0.100°、32.150±0.100°、32.961±0.100°和33.645±0.100°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.240°、8.262°、9.189°、10.841°、12.861°、13.269°、14.135°、14.651°、15.907°、16.303°、16.770°、17.788°、18.099°、19.053°、21.659°、21.912°、22.410°、22.829°、24.408°、25.218°、26.009°、27.230°、27.526°、28.132°、29.630°、32.150°、32.961°和33.645°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.788°±0.200°、18.099±0.200°、21.659±0.200°、和/或21.912±0.200°、和/或7.240±0.200°、和/或8.262±0.200°、和/或9.189±0.200°、和/或10.841±0.200°、和/或12.861±0.200°、和/或13.269±0.200°、和/或14.135±0.200°、和/或14.651±0.200°、和/或15.907±0.200°、和/或16.303±0.200°、和/或16.770±0.200°、和/或19.053±0.200°、和/或22.410±0.200°、和/或22.829±0.200°、和/或24.408±0.200°、和/或25.218±0.200°、和/或26.009±0.200°、和/或27.230±0.200°、和/或27.526±0.200°、和/或28.132±0.200°、和/或29.630±0.200°、和/或32.150±0.200°、和/或32.961±0.200°、和/或33.645±0.200°。
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.788°±0.100°、18.099±0.100°、21.659±0.100°、和/或21.912±0.100°、和/或7.240±0.100°、和/或8.262±0.100°、和/或9.189±0.100°、和/或10.841±0.100°、和/或12.861±0.100°、和/或13.269±0.100°、和/或14.135±0.100°、和/或14.651±0.100°、和/或15.907±0.100°、和/或16.303±0.100°、和/或16.770±0.100°、和/或19.053±0.100°、和/或22.410±0.100°、和/或22.829±0.100°、和/或24.408±0.100°、和/或25.218±0.100°、和/或26.009±0.100°、和/或27.230±0.100°、和/或27.526±0.100°、和/或28.132±0.100°、和/或29.630±0.100°、和/或32.150±0.100°、和/或32.961±0.100°、和/或33.645±0.100°。
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示。
表2式(I)化合物B晶型的XRPD图谱解析数据
本发明的一些方案中，上述B晶型，其差示扫描量热曲线在249.48±8℃处具有吸热峰的峰值。
本发明的一些方案中，上述B晶型，其差示扫描量热曲线在249.48±3℃处具有吸热峰的峰值。
本发明的一些方案中，上述B晶型，其DSC图谱基本如图6所示。
本发明还提供了式(I)化合物A晶型的制备方法，包括：
1)将式(I)化合物加入到醇类溶剂、乙酸乙酯、叔丁基甲醚、四氢呋喃、二氯甲烷中；
2)在15～100℃下搅拌1～168小时；
3)过滤，收集滤饼，滤饼置于30～45℃下真空干燥0.5～2小时，优选为35℃下真空干燥1小时；
其中，式(I)化合物为
本发明的一些方案中，上述醇类溶剂选自甲醇和乙醇。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型、上述式(I)化合物的B晶型或式(I)化合物A晶型的制备方法在制备治疗LSD1相关疾病的药物上的应用。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型或上述式(I)化合物A晶型的制备方法在制备治疗LSD1相关疾病的药物上的应用。
本发明还提供了一种药物组合物，其含有治疗有效量的上述式(I)化合物、上述式(I)化合物的A晶型、上述式(I)化合物的B晶型和药学上可接受的载体。
本发明还提供了一种药物组合物，其含有治疗有效量的上述式(I)化合物或上述式(I)化合物的A 晶型和药学上可接受的载体。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型、上述式(I)化合物的B晶型或上述药物组合物在制备心肌肌球蛋白抑制剂药物中的应用。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型或上述药物组合物在制备心肌肌球蛋白抑制剂药物中的应用。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型、上述式(I)化合物的B晶型或上述药物组合物在制备治疗心衰和肥厚型心肌疾病中的应用。
本发明还提供了上述式(I)化合物、上述式(I)化合物的A晶型或上述药物组合物在制备治疗心衰和肥厚型心肌疾病中的应用。
本发明还提供了一种在需要的受试者中治疗与心肌肌球蛋白抑制剂相关的疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的式(I)化合物、式(I)化合物的A晶型、式(I)化合物的B晶型或药物组合物。
本发明还提供了一种在需要的受试者中治疗与心肌肌球蛋白抑制剂相关的疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的式(I)化合物、式(I)化合物的A晶型或药物组合物。
本发明还提供了一种在需要的受试者中治疗心衰和肥厚型心肌疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的式(I)化合物、式(I)化合物的A晶型、式(I)化合物的B晶型或药物组合物。
本发明还提供了一种在需要的受试者中治疗心衰和肥厚型心肌疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的式(I)化合物、式(I)化合物的A晶型或药物组合物。
技术效果
本发明式(I)化合物的A晶型易于获得、物理稳定性和化学稳定性均较好，具有很高的工业应用价值和经济价值。本发明化合物对心肌肌球蛋白ATP酶有较好的抑制作用，且其具有优良的药代动力学性质。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
必须注意的是，除非上下文另有明确说明或与本文明显相悖，否则如本文和所附权利要求所用的本发明的内容(尤其随附权利要求书的内容)中使用的单数形式“一”、“一个”、“所述”及类似术语应解释为包括单数和复数两者。因此，例如，提及“所述化合物”包括提及一种或多种化合物；等等。
术语“无定形”或者“无定形形式”意在表示所讨论的物质、组分或产物，缺少特征性的晶体形状或结晶 结构，当例如通过XRPD(X-射线粉末衍射)测定时基本上不是晶体或者所讨论的物质、组分或产物，例如当使用偏振光显微镜观看时不是双折射的或者立方体的，或者X射线粉末衍射图不具尖峰。在某些实施方案中，包含物质的无定形形式的样品可基本上不含其它无定形形式和/或结晶形式。
本发明所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于10℃，或小于等于9℃，或小于等于8℃，或小于等于7℃，或小于等于6℃，或小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
除非另有规定，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用表示，则表示该化合物的(Z)型异构体或(E)型异构体或两种异构体的混合物。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：φ/ω扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：TEA代表三乙胺；DIEA代表N,N-二异丙基乙胺；PE代表石油醚；EtOAc代表乙酸乙酯；EA代表乙酸乙酯；THF代表四氢呋喃；MeOH代表甲醇；MTBE代表甲基叔丁基醚；DCM代表二氯甲烷；EtOH代表乙醇；iPrOH代表异丙醇；Boc2O代表二碳酸二叔丁酯；L-selectride代表三仲丁基硼氢化锂；TCFH代表N,N,N,N-四甲基氯甲脒六氟磷酸盐；FA代表甲酸；TFA代表三氟乙酸；ACN代表乙腈；TLC代表薄层色谱；HPLC代表高效液相色谱；LCMS代表液质联用色谱；DMSO代表二甲亚砜； DMF代表N,N-二甲基甲酰胺；LDA代表二异丙基氨基锂；DMAC代表N,N-二甲基乙酰胺；PEG-400代表聚乙二醇400；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；DMSO-d6代表氘代二甲亚砜；CDCl3代表氘代氯仿；BID代表每天两次；QD代表每天一次；PO口服给药；IV表示静脉注射给药。
化合物经手工或者软件命名，市售化合物采用供应商目录名称。
本发明仪器及分析方法
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法一，A晶型测试测试参数见表3。
表3 XRPD测试参数
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法二，由布鲁克仪器的D2Phaser型采集获得，测试参数见表4。
表4 XRPD测试参数
本发明差热分析(Differential Scanning Calorimeter,DSC)方法一，测试参数见表5。
表5 DSC测试参数
本发明差热分析(Differential Scanning Calorimeter,DSC)方法二，测试参数见表6。
表6 DSC测试参数
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法一，测试参数见表7。
表7 TGA测试参数
附图说明
图1：式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图；
图2：式(I)化合物A晶型的DSC谱图；
图3：式(I)化合物A晶型的TGA谱图；
图4：式(I)化合物的单晶X射线衍射(SC-XRD)立体结构椭球图；
图5：式(I)化合物B晶型的Cu-Kα辐射的XRPD谱图；
图6：式(I)化合物B晶型的DSC谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1
合成路线：
步骤A:在20℃下，向1-1(5g,32.02mmol,4.07mL,1eq)的THF(50mL)的溶液中加入1-2(4.66g,38.43mmol,1.2eq)和钛酸四乙酯(21.92g,96.07mmol,19.92mL,3eq)，反应液在60℃下搅拌16小时，向反应液中加入乙酸乙酯(100mL)，冷却到0℃后缓慢加入水(20mL)，搅拌0.5小时，过滤，滤液用饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤后浓缩得到化合物1-3。
步骤B:在氮气保护-78℃下，向1-3(9g,34.71mmol,1eq)的THF(100mL)的溶液缓慢滴加L-selectride(1M,41.65mL,1.2eq)，反应液在-78℃下搅拌2小时后缓慢加入到饱和氯化铵水溶液(100mL)中，用EA萃取(100mL×2)，合并的有机相用饱和食盐水洗涤(100mL×3)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1-3:1)得到化合物1-4。
步骤C:在20℃下，向1-4(6.6g)的MeOH(50mL)溶液中加入HCl/MeOH(200mmol.50mL,7.92eq)，反应液搅拌16小时后浓缩得到化合物1-5的盐酸盐。
步骤D:在20℃下，向1-5的盐酸盐(1g)的EtOH(10mL)溶液中加入1-6(1.51g,7.74mmol,1.5eq,HCl)和DIEA(4.00g,30.96mmol,5.40mL,6eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物1-7.
步骤E:在氮气保护-20℃下，向1-7(1.54g,8.08mmol,1eq)的DCM(15mL)溶液中加入TEA(2.45g,24.24mmol,3.37mL,3eq)，然后加入1-8(1.39g,5.14mmol,6.37e-1eq)的DCM(15mL)溶液，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(30mL)稀释，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1-5:1)得到化合物1-9.
步骤F:在氮气保护下，向1-9(0.648g,1.53mmol,1eq)的MeOH(7.6mL)溶液中加入甲醇钠(1M,6.43ml,1eq)，反应液在20℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH到5左右，然后加入EA(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物1-10。
步骤G:向1-10(348mg,919.74μmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,4mL,17.40eq)，反应液在50℃下搅拌16小时，向反应液中加入EA(30mL)，然后加入1M氢氧化钠水溶液调节pH到8左右，分液后有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(10mL)并搅拌20分钟，过滤，滤饼高真空干燥后得到式(I)化合物，经过XPRD测试，得到的式(I)化合物即为式(I)化合物的A晶型。1H NMR(DMSO-d6,400MHz):δppm 9.60-9.47(m,1H),7.34-7.26(m,2H),7.25-7.16(m,1H),6.96(br d,J＝6.0Hz,1H),4.82-4.71(m,1H),4.44-4.34(m,1H),1.93-1.81(m,4H),1.70(br s,4H),1.48(br d,J＝6.4Hz,3H)；LCMS(ESI)m/z:321.2(M+1)。
实施例2式(I)化合物A晶型的制备
将式(I)化合物(80mg,249.74μmol)加入到乙醇(3mL)中,在80℃下搅拌16小时。冷却到室温后过滤,固体真空干燥。得到化合物式(I)化合物的A晶型。1H NMR(DMSO-d6,400MHz):δppm 9.60-9.47(m,1H),7.34-7.26(m,2H),7.25-7.16(m,1H),6.96(br d,J＝6.0Hz,1H),4.82-4.71(m,1H),4.44-4.34(m,1H),1.93-1.81(m,4H),1.70(br s,4H),1.48(br d,J＝6.4Hz,3H)；LCMS(ESI)m/z:321.2(M+1)。式(I)化合物A晶型的XRPD,DSC和TGA均使用相应的方法一测试，其检测结果图谱依次如图1、2、3所示。
将上述溶剂乙醇替换为甲醇、二氯甲烷、乙酸乙酯、四氢呋喃，在室温或加热温度下均得到式(I)化合物的A晶型。实验结果如表8所示。
表8不同溶剂搅拌下得到的晶型实验

实施例3式(I)化合物B晶型的制备
取约60mg A晶型用TGA从室温(20-25℃)以10℃/分钟的速率加热至250℃后再自然降温(降温过程未控制其速率)降至室温，得到化合物式(I)化合物的B晶型。1H NMR(DMSO-d6,400MHz):δppm9.57(s,1H),7.32-7.27(m,2H),7.22-7.15(m,1H),6.96(br d,J＝6.4Hz,1H),4.78-4.72(m,1H),4.38(s,1H),1.86-1.82(m,4H),1.70-1.67(m,4H),1.47(br d,J＝6.8Hz,3H)。式(I)化合物B晶型的XRPD和DSC均使用相应的方法二测试，其检测结果图谱依次如图5和6所示。
实施例4：式(I)化合物的单晶X-射线衍射检测分析
1.仪器参数和数据收集
生产厂家：布鲁克公司；
仪器型号：Bruker D8 VENTURE；
X-射线光源：采用高强度微聚焦旋转阳极光源；
Cu转靶：
功率：2.5kW；
管电压：50kV；
管电流：50mA；
测角仪：四轴(Kappa，ω，2θ，φ)测角仪；
探测器：大面积photon II探测器，探测器有效面积14cm×10cm；
探测器到样品的距离：d＝45mm。
2.晶体培养
称取14.3mg样品加入MeOH(2mL)，样品不溶，然后滴入DMSO(1mL)，搅拌至全部溶解，将样品溶解置于4mL半密封样品瓶中，在室温下缓慢挥发。7天后得到无色块状晶体。送测单晶测试。
3.晶体数据列表
表9式(I)化合物的单晶结构数据

4.结论
单晶数据显示，单晶为式(I)化合物。式(I)化合物的单晶X射线衍射(SC-XRD)立体结构椭球图见附图4。式(I)化合物的单晶结构数据和参数见表9。
生物测试数据：
实验例1：心肌肌球蛋白ATP酶活性的抑制效应实验
实验试剂：
心肌原肌球蛋白/肌钙蛋白复合物(Cytoskeleton,Cat.#TT05)
心肌肌球蛋白S1(Cytoskeleton,Cat.#MYS03)
心肌肌动蛋白(Cytoskeleton,Cat.#AD99-A)
ATP酶测定生化试剂盒(Cytoskeleton,Cat.#BK051)
实验步骤：
1)准备化合物
a)在Echo中用DMSO对化合物进行4倍稀释，8个浓度梯度，并分别转移200nL化合物到96孔板(Corning-3696)中。
b)1000rpm离心15秒，封板待用。
2)准备F-肌动蛋白
a)配置缓冲液5mM Pipes-KOH pH 7.0,500μM ATP,500μM二硫苏糖醇，并加入2.5mL缓冲液溶解1mg F-肌动蛋白，蛋白浓度为0.4mg/mL。
b)室温放置10分钟以充分溶解蛋白。
c)加入2.0mM MgCl2和2.0mM EGTA，室温放置20分钟以形成蛋白聚合物。
3)准备细肌丝
a)加入200μL冰水溶解1mg心肌原肌球蛋白/肌钙蛋白复合物，蛋白浓度为5mg/mL。
b)加入1000μL步骤1中准备的F-肌动蛋白，混匀。
c)室温放置20分钟。
d)87K xg 4℃离心1.5小时。
e)配置PM12缓冲液12mM Pipes-KOH,pH 7.0,2mM MgCl2，并加入1200μL缓冲液重悬蛋白。
4)准备反应溶液，并开始实验
a)加入250μL冰的PM12缓冲液到250μg S1肌球蛋白中，蛋白浓度为1mg/mL。
b)按照下面的顺序，依次加入试剂混合，以得到反应混合液：
400μL的PM12，
400μL的5x MSEG(来自ATP酶测定生化试剂盒)，
1200μL的肌动蛋白/心肌原肌球蛋白/肌钙蛋白复合物，
40μL的肌球蛋白S1，
40μL的100x PNP(来自ATP酶测定生化试剂盒)，
10.4μL的100mM ATP。
c)加入10μL 440μM CaCl2溶液到96孔板中，放置到37℃培养箱预热。
d)加入100μL反应混合液到96孔板中，1000rpm离心10秒。
e)在SpectraMax 340PC上连续读数10分钟，间隔30秒，仪器温度37℃，波长360nm。
数据分析：
用Prism分析数据，实验结果见表10。
表10本发明化合物对心肌肌球蛋白ATP酶活性的抑制效应IC50值测试结果
结论：本发明化合物具有较好的心肌肌球蛋白ATP酶抑制活性。
实验例2：大鼠体内药代动力学评价
实验目的：
检测本发明化合物在大鼠体内的药代动力学参数
实验方案：
1)实验药品：本发明化合物；
2)实验动物：4只7-9周龄的雄性SD大鼠，随机分为2组，每组2只；
3)药物配制：称取适量药物，溶于DMAC：PEG-400：30％2-HP-β-CD＝5:25:70的混合溶剂中，配置成0.2mg/mL；
实验操作：
第1组动物通过尾静脉单次注射给予剂量为0.2mg/kg、浓度为0.2mg/mL的药物，第2组动物通过灌胃给予剂量为1mg/kg、浓度为0.2mg/mL的化合物。动物于给药后0.0833(仅尾静脉注射组)、0.25、0.5、1、2、4、6、8和24小时采集血浆样品。
数据分析：
使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的药代动力学测试结果见表11。
表11本发明化合物的药代动力学测试结果
--表示不存在
结论：本发明化合物具有良好的大鼠体内药代动力学性质。

Claims (15)

  1. 式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：18.283±0.200°、19.662±0.200°和22.420±0.200°；
  2. 根据权利要求1所述的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°和28.056±0.200°。
  3. 根据权利要求2所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°和30.256±0.200°。
  4. 根据权利要求3所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143±0.200°、16.522±0.200°、17.053±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、23.909±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°、30.256±0.200°和33.761±0.200°。
  5. 根据权利要求1所述的A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的5、6、7或8个特征衍射峰：11.143±0.200°、18.283±0.200°、19.662±0.200°、22.420±0.200°、26.259±0.200°、27.261±0.200°、28.056±0.200°和30.256±0.200°。
  6. 根据权利要求5所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.143°、13.260°、14.860°、16.163°、16.522°、17.053°、17.537°、18.283°、19.662°、22.420°、23.568°、23.909°、26.259°、26.726°、27.261°、28.056°、29.008°、30.256°、31.219°、31.646°、32.037°、32.438°、32.807°、33.761°、34.534°、35.404°、36.856°、37.813°和39.456°。
  7. 根据权利要求1所述的A晶型，其XRPD图谱基本如图1所示。
  8. 根据权利要求1～7任意一项所述的A晶型，其差示扫描量热(DSC)曲线在249.53±3℃和306.12±3℃处具有吸热峰的峰值。
  9. 根据权利要求1所述的A晶型，其DSC图谱基本如图2所示。
  10. 根据权利要求1～7任意一项所述的A晶型，其热重分析(TGA)曲线在200±3℃时失重达0.075％，在250±3℃时失重达0.164％。
  11. 根据权利要求1所述的A晶型，其TGA图谱基本如图3所示。
  12. 权利要求1所述式(I)化合物A晶型的制备方法，包括：
    1)将式(I)化合物加入到醇类溶剂、乙酸乙酯、叔丁基甲醚、四氢呋喃、二氯甲烷中；
    2)在15～100℃下搅拌1～168小时；
    3)过滤，收集滤饼，滤饼置于30～45℃下真空干燥0.5～2小时，优选为35℃下真空干燥1小时；
    其中，式(I)化合物为
  13. 一种药物组合物，其含有治疗有效量的根据权利要求1～11任意一项所述的式(I)化合物或式(I)化合物的A晶型和药学上可接受的载体。
  14. 根据权利要求1～11任意一项所述的式(I)化合物或式(I)化合物的A晶型或根据权利要求13所述的药物组合物在制备心肌肌球蛋白抑制剂药物中的应用根据权利要求13所述的药物组合物在制备心肌肌球蛋白抑制剂药物中的应用。
  15. 根据权利要求1～11任意一项所述的式(I)化合物或式(I)化合物的A晶型或根据权利要求13所述的药物组合物在制备治疗心衰和肥厚型心肌疾病中的应用。
PCT/CN2023/072433 2022-01-27 2023-01-16 7-氮杂螺[4,5]癸烷-6,10-二酮类化合物的晶型及其制备方法 WO2023143205A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109928959A (zh) * 2017-12-18 2019-06-25 中国科学院上海生命科学研究院 抗心肌肥厚的药物、制备方法和用途
CN111116492A (zh) * 2019-01-25 2020-05-08 青岛吉澳医药科技有限公司 氘代苯甲氨嘧啶二酮衍生物及其用途
US20210253563A1 (en) * 2018-06-26 2021-08-19 Cytokinetics, Inc. Cardiac sarcomere inhibitors
WO2022179611A1 (zh) * 2021-02-25 2022-09-01 南京明德新药研发有限公司 取代的吡啶-2,4-二酮类衍生物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109928959A (zh) * 2017-12-18 2019-06-25 中国科学院上海生命科学研究院 抗心肌肥厚的药物、制备方法和用途
US20210253563A1 (en) * 2018-06-26 2021-08-19 Cytokinetics, Inc. Cardiac sarcomere inhibitors
CN111116492A (zh) * 2019-01-25 2020-05-08 青岛吉澳医药科技有限公司 氘代苯甲氨嘧啶二酮衍生物及其用途
WO2022179611A1 (zh) * 2021-02-25 2022-09-01 南京明德新药研发有限公司 取代的吡啶-2,4-二酮类衍生物

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