CN115583952B - Polycrystal of phosphodiesterase 5 inhibitor, preparation method and application thereof - Google Patents

Polycrystal of phosphodiesterase 5 inhibitor, preparation method and application thereof Download PDF

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CN115583952B
CN115583952B CN202211213940.XA CN202211213940A CN115583952B CN 115583952 B CN115583952 B CN 115583952B CN 202211213940 A CN202211213940 A CN 202211213940A CN 115583952 B CN115583952 B CN 115583952B
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formula
compound
phosphodiesterase
inhibitor
salt
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CN115583952A (en
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王靖林
于瑞梅
穆振强
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Amicogen China Biopharm Co Ltd
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Jinan Meiruwei Biotechnology Co ltd
Shandong Lukang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention provides a polycrystal of a type 5 phosphodiesterase inhibitor, a preparation method and application thereof. The polycrystal of the phosphodiesterase type 5 inhibitor is hydrochloride of the compound of the formula I,the hydrochloride salt of the compound of formula I has diffraction characteristic peaks at the following 2θ angles, measured using Cu-ka radiation: 6.089 + -0.2 °, 7.189 + -0.2 °, 8.711 + -0.2 °, 9.191 + -0.2 °, 12.284 + -0.2 °, 23.954 + -0.2 °. Compared with the compound of the formula I and other known polymorphs, the polycrystal of the type 5 phosphodiesterase inhibitor has better solubility, quicker onset of action, longer half-life and better bioavailability.

Description

Polycrystal of phosphodiesterase 5 inhibitor, preparation method and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a polycrystal of a type 5 phosphodiesterase inhibitor, a preparation method and application thereof.
Background
Erectile dysfunction (Erectile dysfunction; ED for short) refers to the inability to achieve and/or maintain a sufficient erection to achieve satisfactory sexual life. Based on statistics that about 1.5 million men currently suffer from different degrees of ED symptoms worldwide, it is expected that the number of suffering from the disease will double in 2025. Phosphodiesterase type 5 (PDE 5) inhibitors are the most mature ED therapeutic drugs currently being studied. There are five classes of drugs approved for sale today, sildenafil (Sildenafil), tadalafil (Tadanafil), vardenafil (Vardenafil), udenafil (Udenafil) and Mi Luona fil (Mirodenafil), respectively. The compounds have strong effect of selectively inhibiting phosphodiesterase, and have attracted wide attention and become a new research hotspot. Numerous structural modifications have been made to these compounds in an attempt to increase their activity and selectivity towards phosphodiesterase 5.
Sildenafil analogs are the hot spot of current research in order to find the best drugs for treating male erectile dysfunction with higher activity, better selectivity, better tolerance, better effect and less side effects. The sildenafil analog 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfanyl) ] phenyl-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3d ] pyrimidine-7-thione (compound of formula I) is a phosphodiesterase inhibitor of formula 5.
The inventors studied it earlier and found that the mesylate salt crystal form exists, however, the inventors found that the sildenafil analog and the known mesylate salt thereof have poor solubility, and in particular, the sildenafil analog has a solubility in water of < 0.01mg/mL, belongs to a poorly soluble compound, and the bioavailability is also to be improved. Solubility is one of the most important properties in drug discovery, and compounds with low solubility can have many negative effects, including: low solubility limits drug absorption and reduces oral bioavailability; the solubility is low, and intravenous injection preparation can not be made; the development of the pharmaceutical preparation is difficult; the prepared preparation needs frequent high-dose administration, and burden of patients is increased.
The crystal forms are different solid states formed by different crystal lattice space arrangements of compound molecules or atoms, and the stability, bioavailability and other aspects of different crystal forms of the same medicine can be obviously different, so that the curative effect of the medicine is affected, and therefore, the research on the crystal forms of the medicine is an important component for carrying out basic research on medicine substances.
Disclosure of Invention
It is well known in the pharmaceutical arts that salt forms of a compound, as well as polymorphic forms of the salt, can affect, for example, the solubility, rate of dispersion, bioavailability, chemical and physical stability of the compound, and the safety and efficacy of a Drug product made based on the compound (see, e.g., knapman, k. Modern Drug discovery, 2000:53).
Thus, the identification of salt forms of phosphodiesterase type 5 inhibitors (sildenafil analogs) with optimal physical and chemical properties would be advantageous for the development of such compounds as pharmaceuticals. Particularly useful physical and chemical properties include: easy and reproducible preparation, crystallinity, water solubility, stability to visible and ultraviolet light, stability under accelerated stability conditions of temperature and humidity, better pharmacokinetic results and safety.
The sildenafil analog 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfanyl) ] phenyl-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3d ] pyrimidine-7-thione (free base form, formula I) and its mesylate salt are described in chinese patent CN201710361203.7 and WO2018209809A1 as inhibitors of phosphodiesterase type 5, and methods of synthesis of this free base form are described in chinese patent No. cn201510553662. X, the contents of which are incorporated herein by reference in their entirety. The inventors have found in further crystal form studies that not all acids are able to form an effective salt form with the free base form, which is subject to the nature of the free base itself and the choice of method, nor is the salt form formed equally useful.
For example, in some embodiments of the present application, at least 12 acids are used to form salts with the compound of formula I, respectively, wherein, although most of the acids can produce better solids upon solvent screening, in further scale-up, different crystallization modes such as suspension, volatilization, antisolvent methods, etc. are used and XRPD characterization of the resulting solids is performed, and as a result, most of the resulting crystals are consistent with the free base, salt formation is difficult or the resulting salts are extremely unstable, such as succinic acid, adipic acid, L-malic acid, benzoic acid, fumaric acid, etc.
For example, in some embodiments of the present invention, salt forms with better crystallinity and solid state are prepared, however, these salt forms have poor stability and are prone to seeding phenomena such as maleate and the like.
Furthermore, the free base form is poorly water soluble (solubility < 0.01 mg/mL) and insoluble in ethanol, methanol, acetonitrile and acetone at room temperature, and the mesylate polymorph disclosed in CN201710361203.7 has improved solubility in water and ethanol compared to its free base form which is already slightly soluble in water and ethanol, but its solubility in other solvents remains to be improved.
In addition, due to solubility and sensitivity to pH, the existing preparation method of mesylate polymorphs is cumbersome, the choice of solvent is single, and temperature and pH need to be controlled multiple times and strictly, and the preparation method comprises: 200g of absolute ethanol and 100g of the free base form (compound of formula I) are introduced into a clean and dry reaction flask, and after stirring uniformly, 200g of 5% NaOH are slowly introduced. After the addition, the compound of formula I is completely dissolved with stirring. After the solid is completely dissolved, filtering at the temperature below 10 ℃ (the condition must be met below 10 ℃), adding a mixed solution of 20g of methanesulfonic acid and 80g of absolute ethyl alcohol into the filtrate to adjust the pH value to 7-8 (taking care of cooling by ice water), re-precipitating the solid material, and stirring and crystallizing for 2 hours. Filtering, adding solid material into 320g absolute ethanol, heating to 30-35deg.C, regulating pH with methanesulfonic acid (about 22 g), gradually dissolving and raising temperature, dissolving solid material completely, maintaining pH of solution at 3-4 to 3 (no more than 60deg.C), stirring for 10min, measuring pH at 3-4 to 3, refluxing at 80deg.C for 1 hr, and finishing refluxing. Cooling to 70 deg.c, and filtering. The filtrate is naturally cooled to room temperature, and then cooled to below 15 ℃ by ice water. Standing for crystallization for 2h, suction filtering, and drying the solid material at 80-90 ℃ to obtain the mesylate of the compound shown in the formula A. Adding methanesulfonic acid salt of the compound shown in the formula A into 3 times of ethanol, heating to 50-60 ℃, regulating the pH value to 3-4 to 3 by methanesulfonic acid, heating to 70-75 ℃, completely dissolving solid materials, hot press-filtering, cooling filtrate to below 20 ℃, standing for crystallization for 10 hours, centrifuging, and drying the solid materials. Obtain the mesylate salt polycrystal of the compound shown in the fine formula A.
In the invention, the invention provides a series of compounds with improved water solubility, wider solvent selection range, simpler preparation method, easy repeated operation and faster onset of action (T) max Shortened), has a longer half-life (T) 1/2 ) The salt forms of the compound of the formula I have better bioavailability, and have better crystallinity and solid characters.
Specifically, the technical scheme of the invention is as follows:
in a first aspect of the invention, the present invention provides a novel polymorph of a phosphodiesterase inhibitor form 5, said novel polymorph being its hydrochloride, mesylate, sulfate, L-tartrate and citrate salts.
Hydrochloride polymorphs of a compound of formula I
The hydrochloride salt of the compound of formula I has diffraction characteristic peaks at the following 2θ angles, measured using Cu-ka radiation: 6.089 + -0.2 °, 7.189 + -0.2 °, 8.711 + -0.2 °, 9.191 + -0.2 °, 12.284 + -0.2 °, 23.954 + -0.2 °.
Further, the hydrochloride salt of the compound of formula I also has diffraction characteristic peaks at the following 2θ angles, measured using Cu-ka radiation: 5.848 + -0.2 °, 6.468 + -0.2 °, 7.471 + -0.2 °, 18.635 + -0.2 °, 21.566 + -0.2 °, 24.999 + -0.2 °;
further, the hydrochloride salt of the compound of formula I also has diffraction characteristic peaks at the following 2θ angles, measured using Cu-ka radiation: 17.460 + -0.2 °, 21.308 + -0.2 °, 24.534 + -0.2 °, 11.749 + -0.2 °;
And, further, the XRPD pattern of the hydrochloride salt of the compound of formula I is shown in figure 6.
In an embodiment of the invention, the physical properties of the hydrochloride salt of the compound of formula I are measured. Wherein the melting point of the hydrochloride of the compound of the formula I is 213+/-2 ℃, and the TGA decomposition temperature is not lower than 220 ℃; further, the TGA profile of the hydrochloride salt of the compound of formula I is shown in fig. 7; the hydrochloride of the compound of formula I has a DSC spectrum with an exothermic peak at 200-230 ℃, and the DSC spectrum is shown in figure 8.
Further, the raman spectrum of the hydrochloride salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 2957.45, 2939.40, 1607.29, 1580.59, 1544.24, 1521.63, 1434.57, 1404.00, 1311.28, 1291.99, 1259.99, 1196.45, 1154.33, 1110.30, 938.37, 795.80, 678.39, 661.61, 615.49, 569.36, 509.56, 441.46, 405.82, 334.54, 159.91; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The raman spectrum of the hydrochloride salt of the compound of formula I is shown in figure 9.
Further, the infrared spectrum of the hydrochloride salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3409.90, 3267.48, 2973.95, 2958.91, 2929.86, 2873.75, 2669.34, 2645.29, 2584.90, 2509.02, 2452.32, 1621.05, 1605.33, 1572.26, 1542.44, 1512.78, 1499.16, 1468.16, 1435.39, 1414.54, 1390.48, 1326.32, 1310.98, 1283.89, 1263.28, 1239.13, 1194.79, 1151.55, 1105.83, 1081.99, 1057.88, 1023.00, 974.17, 913.07, 886.88, 814.80, 798.94, 672.35, 643.17, 612.11, 578.08, 535.66, 506.10, 476.04, 442.23; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the Compounds of formula IThe infrared spectrum of the hydrochloride salt of (2) is shown in FIG. 10.
Mesylate polymorphs of a compound of formula I
In order to distinguish it from existing mesylate polymorphs, when the mesylate polymorph of the compound of formula I according to the present invention occurs simultaneously with existing mesylate polymorphs, the mesylate polymorph of the compound of formula I according to the present invention is referred to as the mesylate polymorph of the compound of formula I or the mesylate salt of the compound of formula I, and the existing mesylate salt is collectively referred to as the existing mesylate salt or mesylate salt I.
The X-ray powder diffraction pattern of the mesylate salt of the compound of formula I, measured using Cu-ka radiation, has diffraction signature peaks at the following 2θ angles: 5.340 + -0.2 °, 10.701 + -0.2 °, 16.795 + -0.2 °, 20.746 + -0.2 °, 26.982 + -0.2 °;
further, the X-ray powder diffraction pattern of the mesylate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 10.321 + -0.2 °, 19.363 + -0.2 °, 23.629 + -0.2 °, 24.056 + -0.2 °, 25.114 + -0.2 °, 26.380 + -0.2 °;
further, the X-ray powder diffraction pattern of the mesylate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 8.367 + -0.2 °, 15.198 + -0.2 °, 15.577 + -0.2 °, 16.238 + -0.2 °, 17.498 + -0.2 °, 25.304+ -0.2 °, 29.75+ -0.2 °, 31.336 + -0.2 °, 31.692 + -0.2 °;
And, further, an X-ray powder diffraction pattern of the mesylate salt of the compound of formula I, as measured using Cu-ka radiation, is shown in fig. 16.
In an embodiment of the invention, the physical properties of the hydrochloride salt of the compound of formula I are measured. Wherein the mesylate of the compound of formula I has a melting point of 186+ -2deg.C and a TGA decomposition temperature of no less than 250deg.C, and the TGA spectrum of the mesylate of the compound of formula I is shown in figure 17; the DSC spectrum of the mesylate of the compound of formula I has an exothermic peak at 100-137.5℃and an exothermic peak at 187-200℃as shown in FIG. 18.
Further toThe raman spectrum of the mesylate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 2943.93, 2928.71, 1606.11, 1580.39, 1542.35, 1515.18, 1420.38, 1405.55, 1313.60, 1291.71, 1264.68, 1251.66, 1189.53, 1156.92, 1111.27, 1041.70, 930.83, 917.78, 887.35, 791.69, 776.47, 722.12, 682.99, 606.90, 599.08, 509.08, 435.16, 405.90, 348.20, 330.81, 237.33, 224.28, 174.28, 113.41; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The raman spectrum of the mesylate salt of the compound of formula I is shown in figure 19.
Further, the infrared spectrum of the mesylate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3454.98, 3257.19, 3006.01, 2977.98, 2957.20, 2929.86, 2869.74, 2717.43, 2624.36, 2496.99, 1654.63, 1570.14, 1544.57, 1517.88, 1497.96, 1469.16, 1428.13, 1392.48, 1308.84, 1287.03, 1265.46, 1241.35, 1208.93, 1194.85, 1157.52, 1111.64, 1079.95, 1058.27, 1036.16, 1023.42, 977.11, 937.34, 917.07, 886.92, 822.90, 814.78, 782.96, 775.26, 721.80, 688.67, 644.65, 630.38, 562.18, 535.89507.60, 443.35; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The infrared spectrum of the mesylate salt of the compound of formula I is shown in figure 20.
Sulphate polymorphs of a compound of formula I
The X-ray powder diffraction pattern of the sulfate of formula I has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 5.769 + -0.2 °, 8.715 + -0.2 °, 11.665 + -0.2 °, 14.751 + -0.2 °, 17.415 + -0.2 °, 22.974+ -0.2 °; further, the X-ray powder diffraction pattern of the sulfate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 8.196 + -0.2 °, 10.000+ -0.2 °, 12.691 + -0.2 °, 20.688 + -0.2 °; further, the X-ray powder diffraction pattern of the sulfate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 12.245 + -0.2 °, 20.166 + -0.2 °, 23.573 + -0.2 °, 31.770 + -0.2 °, 32.641 + -0.2 °; and, further, the X-ray powder diffraction pattern of the sulfate salt of the compound of formula I measured using Cu-ka radiation is shown in fig. 12.
In an embodiment of the invention, the physical properties of the sulfate salt of the compound of formula I are measured. Wherein the melting point of the sulfate of the compound of formula I is 186 ℃ + -2 ℃, the TGA decomposition temperature is not lower than 240 ℃, the DSC spectrum of the sulfate of the compound of formula I has an exothermic peak at 75-125 ℃ and 200-240 ℃ respectively, the TGA spectrum is shown in figure 13, and the DSC spectrum of the sulfate of the compound of formula I is shown in figure 14.
Further, the raman spectrum of the sulfate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 2934.55, 1607.78, 1578.68, 1543.67, 1520.13, 1435.55, 1403.20, 1312.24, 1291.07, 1260.11, 1194.85, 1152.97, 1107.66, 973.88, 932.88, 919.93, 889.72, 788.31, 673.94, 665.31, 613.53, 440.9, 406.38, 339.49, 233.75, 220.81, 148.11; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The raman spectrum of the sulphate salt of the compound of formula I is shown in figure 20.
Further, the infrared spectrum of the sulfate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3414.75, 3265.93, 2976.59, 2687.42, 1621.05, 1605.52, 1572.24, 1542.58, 1519.17, 1500.61, 1467.50, 1434.36, 1414.06, 1388.47, 1366.42, 1328.32, 1310.84, 1291.85, 1280.20, 1264.47, 1254.10, 1239.16, 1214.04, 1196.72, 1149.57, 1112.26, 1079.70, 1058.06, 1030.98, 1025.56, 1015.00, 973.39, 923.31, 909.90, 895.24, 883.21, 814.68, 799.62, 770.93, 673.14, 643.33, 617.59, 578.46, 538.35, 508.27, 476.19, 442.40; wave number error of + -2 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The infrared spectrum of the sulfate salt of the compound of formula I is shown in figure 21.
Polymorphic forms of L-tartrate salt of the compound of formula I
The X-ray powder diffraction pattern of the L-tartrate salt of the compound of formula I, measured using Cu-ka radiation, has diffraction signature peaks at the following 2θ angles: 7.651 + -0.2 °, 10.158 + -0.2 °, 14.610 + -0.2 °, 15.391 + -0.2 °, 24.313 + -0.2 °, 25.599 + -0.2 °; further, the X-ray powder diffraction pattern of the L-tartrate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 9.510 + -0.2 °, 13.890 + -0.2 °, 14.288 + -0.2 °, 18.179 + -0.2 °, 18.520 + -0.2 °, 22.130 + -0.2 °; and, further, an X-ray powder diffraction pattern of the L-tartrate salt of the compound of formula I, as measured using Cu-ka radiation, is shown in fig. 22.
In an embodiment of the present invention, the physical properties of the L-tartrate salt of the compound of formula I are measured. Wherein the L-tartrate salt of the compound of formula I has a TGA decomposition temperature of not less than 180deg.C and a TGA spectrum as shown in figure 23; the DSC spectrum of L-tartrate of the compound of formula I has an exothermic peak at 100-150deg.C, which is a water loss peak, and the DSC spectrum is shown in figure 24.
Further, the Raman spectrum of the L-tartrate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 2935.77, 1604.29, 1577.13, 1543.18, 1521.46, 1466.81, 1434.50, 1407.54, 1311.56, 1266.15, 1198.91, 1152.30, 1104.90, 1031.66, 1003.66, 932.57, 921.80, 889.48, 803.32, 790.39, 667.60, 611.59, 568.51, 516.81, 490.19, 447.88, 376.79, 310.01, 236.76, 215.09; wave number error of + -2 cm -1 。
Further, the infrared spectrum of the L-tartrate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3434.5, 3320.42, 3258.75, 2977.96, 2958.24, 2929.86, 2870.14, 2708.25, 1704.80, 1603.82, 1572.23, 1542.62, 1518.73, 1497.9, 1464.32, 1410.47, 1332.33, 1303.14, 1262.30, 1212.95, 1194.78, 1136.55, 1112.73, 1078.01, 1022.32, 1007.52, 974.75, 935.34, 919.30, 905.53, 886.85, 852.56, 813.03, 790.10, 679.34, 644.68, 618.95, 575.65, 485.09; wave number error of + -2 cm -1 。
Citrate polymorphs of a compound of formula I
The X-ray powder diffraction pattern of the citrate salt of formula I, measured using Cu-ka radiation, has diffraction characteristic peaks at the following 2θ angles: 6.538 + -0.2 °, 17.835 + -0.2 °, 23.011 + -0.2 °, 23.953 + -0.2 °, 24.153 + -0.2 °, 26.600 + -0.2 °; further, the X-ray powder diffraction pattern of the citrate salt of the compound of formula I, measured using Cu-ka radiation, also has diffraction signature peaks at the following 2θ angles: 7.573 + -0.2 °, 23.253 + -0.2 °, 25.078 + -0.2 °, 27.385 + -0.2 °;
Further, the X-ray powder diffraction pattern of the citrate salt of the compound of formula I also has diffraction signature peaks at the following 2θ angles, measured using Cu-ka radiation: 12.407 + -0.2 °, 13.143 + -0.2 °, 14.151 + -0.2 °, 15.171 + -0.2 °, 15.673 + -0.2 °, 16.013 + -0.2 °, 27.020 + -0.2 °, 28.566 + -0.2 °; and, further, an X-ray powder diffraction pattern of the citrate salt of the compound of formula I, as measured using Cu-ka radiation, is shown in fig. 26.
In an embodiment of the invention, the physical properties of the citrate salt of the compound of formula I are measured. Wherein the citrate salt of the compound of formula I has a TGA decomposition temperature of not less than 150 ℃ and a TGA profile as shown in figure 27; the DSC spectrum of citrate of the compound of formula I has exothermic peaks at 125-165 ℃ respectively, and the DSC spectrum is shown in figure 28.
Further, the raman spectrum of the citrate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3010.79, 2934.85, 1606.20, 1578.13, 1542.70, 1519.30, 1497.08, 1444.74, 1408.9, 1348.56, 1314.16, 1269.08, 1252.76, 1198.07, 1149.53, 1112.69, 1030.35, 930.68, 911.18, 813.68, 792.01, 724.84, 672.84644.67, 614.33, 542.83, 510.33, 437.82, 408.49, 345.65317.48, 211.31, 172.31, 145.89; wave number error of + -2 cm -1 。
Further, the infrared spectrum of the citrate salt of the compound of formula I comprises the following wavenumbers (cm -1 ) One or more of the peaks of (a): 3419.60, 3261.69, 2960.26, 2925.85, 2865.73, 1719.14, 1605.30, 1571.68, 1542.62, 1496.35, 1442.94, 1396.52, 1362.41, 1342.36, 1331.21, 1285.50, 1262.73, 1248.12, 1194.61, 1154.56, 1108.53, 1081.40, 1029.01, 978.28, 928.50, 918.11, 886.24712.76, 764.97, 723.29, 667.26, 640.41, 608.03, 578.45, 536.65, 505.89, 445.22; wave number error of + -2 cm -1 。
In a third aspect of the present invention, there is provided a process for preparing a polymorph of a phosphodiesterase type 5 inhibitor as described in the first and second aspects above, the process comprising: adding a compound of the formula I into a solvent, continuously stirring at 40-80 ℃, slowly adding acid liquor at 40-80 ℃, suspending at 40-80 ℃, cooling to room temperature, and standing; filtering the precipitated solid, washing, volatilizing at room temperature or rotary evaporating, and recrystallizing.
In an embodiment of the invention, the acid solution is hydrochloric acid, methanesulfonic acid, sulfuric acid, L-tartaric acid or citric acid;
in an embodiment of the invention, the solvent is selected from one or more of methanol, water, acetonitrile, acetone, tetrahydrofuran, preferably acetonitrile, tetrahydrofuran or acetone/water.
In some embodiments of the invention, the method comprises: adding the compound shown in the formula I into a solvent, continuously stirring at 60 ℃, slowly adding 1-2 times of equivalent, preferably equivalent or 1.2 times of equivalent acid solution at 60 ℃, suspending at 60 ℃ for 0.5-1 hour, cooling to room temperature, standing for 12-16 hours, preferably 14 hours, filtering the precipitated solid, washing with acetonitrile, and volatilizing at room temperature to obtain the polycrystal of the type 5 phosphodiesterase inhibitor. The polymorphs mean in particular the hydrochloride and sulfate salts.
In some embodiments of the invention, the method comprises: adding the compound of the formula I into a solvent, continuously stirring at 60 ℃, slowly adding 1-2 times of equivalent, preferably equivalent or 1.2 times of equivalent acid solution at 60 ℃, suspending at 60 ℃ for 0.5-1 hour, cooling to room temperature, standing for 12-16 hours, preferably 14 hours, performing rotary evaporation and drying, recrystallizing at 40-60 ℃, preferably 50 ℃, filtering and drying to obtain the polycrystal of the type 5 phosphodiesterase inhibitor. The polymorphs are inter alia the nail sulfonates, L-tartrates and citrates. In an embodiment of the present invention, the solvent used in the recrystallization is selected from acetonitrile, acetone, ethyl acetate, and methanol.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a hydrochloride polymorph of a phosphodiesterase type 5 inhibitor as described in the first aspect above and/or a mesylate polymorph of a phosphodiesterase type 5 inhibitor as described in the second aspect above.
In a fourth aspect of the present invention, there is provided the use of a polymorph of a phosphodiesterase type 5 inhibitor as defined in the first aspect above or a pharmaceutical composition as defined in the third aspect above for the preparation of a medicament for preventing or treating male erectile dysfunction.
And, in a fifth aspect of the present invention, there is provided the use of a polymorph of a phosphodiesterase type 5 inhibitor as set forth in the first aspect above or a pharmaceutical composition as set forth in the third aspect above for the preparation of a medicament for preventing or treating a disease associated with phosphodiesterase type 5 comprising: female sexual dysfunction, benign prostatic hyperplasia, bladder obstruction, incontinence, angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral circulatory system diseases, asthma, bronchitis, alzheimer's disease, and acute respiratory failure.
In a sixth aspect of the invention, there is provided a method of preventing or treating male erectile dysfunction comprising administering to a subject a therapeutically effective amount of a polymorph of a phosphodiesterase type 5 inhibitor as defined in the first aspect above or a pharmaceutical composition as defined in the third aspect above. "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment. By "therapeutically effective amount" is meant an amount of an active compound or pharmaceutical agent, including a compound of the present invention, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other medical staff, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
Compared with the prior art, the technical scheme of the application has the following advantages:
compared with the compound shown in the formula I or a known crystal form thereof, the polycrystal of the phosphodiesterase type 5 inhibitor has improved water solubility, improved solubility and stability in other organic solvents, shorter peak time of drug concentration and longer half-life period, and has quicker onset of action, longer action time and better bioavailability. Specifically, regarding solubility, the compound of formula I belongs to a poorly water-soluble compound (solubility less than 0.01 mg/mL), and is known to be hardly soluble in most organic solvents such as methanol, ethanol, acetonitrile and acetone at room temperature, in addition to being well soluble in tetrahydrofuran, the presently known mesylate I has improved water solubility, but its solubility is still poor, and is known to be slightly soluble in ethanol. The novel salt of the compound of the formula I generally has improved water solubility, and the solubility of the novel salt of the compound of the formula I at 25 ℃ is not lower than 0.1mg/mL, and particularly, the solubility of the hydrochloride and the mesylate of the compound of the formula I to water can reach 1.7mg/mL and 2.7mg/mL. And the new salt of the compound in the formula I can be better dissolved in tetrahydrofuran and tetrahydrofuran/water, and simultaneously can be better dissolved in acetone/water, most of the new salt can be dissolved in methanol/water and acetonitrile/water, especially the hydrochloride and the mesylate of the compound in the formula I can be better dissolved in methanol, acetone and acetonitrile, so that the selectivity of dissolving the usable solvent is increased.
Furthermore, the novel salt forms provided by the present invention act more rapidly than the compound of formula I or the known mesylate salt I, wherein the hydrochloride salt of the compound of formula I, the mesylate salt of the compound of formula I has an average T max The maximum plasma concentration can be reached more rapidly than 0.75 and 0.375 hours, respectively, and the average T of the compound of formula I max For 6.17 hours (3-8 hours), the average T of the known mesylate I max 7 hours (6-8 hours); the present invention provides novel salt forms having a longer half-life wherein the hydrochloride salt of the compound of formula I, the average T of the mesylate salt of the compound of formula I 1/2 Respectively is2.66 hours and 2.82 hours, and can exert more durable action, and the average T of the compound of the formula I 1/2 Average T of known mesylate I at 1.98 hours max 1.84 hours.
Other description
In the present invention, the term "crystal form" is not only understood as "crystal type" or "crystal structure"; in the present context, a "crystal form" is understood more as a "substance having a specific crystal structure" or a "crystal of a specific crystal type". In the present invention, the "crystal form" is confirmed by various data of the present invention described above, such as an X-ray powder diffraction pattern and the like. Those skilled in the art will appreciate that experimental errors therein depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is known to those skilled in the art that, for example, X-ray powder diffraction patterns generally vary with the conditions of the instrument. In addition, experimental errors in peak angles are typically 5% or less, and errors in these angles should also be taken into account, typically allowing for errors of + -0.2 deg.. In addition, due to the influence of experimental factors such as the sample height, an overall shift in peak angle is caused, and generally a certain shift is allowed. Thus, it will be appreciated by those skilled in the art that any crystalline form having a pattern identical or similar to the characteristic peaks in the pattern of the present invention is within the scope of the present invention.
The methods of thermogravimetric analysis (TGA), differential scanning calorimetric analysis (DSC), X-ray powder diffraction analysis (XRPD), hygroscopicity analysis (DVS), raman spectroscopy (Raman), infrared spectroscopy (IR) described in the present invention are performed as follows.
TGA method: instrument model: netzsch TGA 209F3, temperature range: scanning rate at 30-400 deg.c: 10 ℃/min, purge gas: 25ml/min, shielding gas: 15mL/min. DSC method: instrument model: TA DSC Q2000, temperature range: 20-300 ℃, scanning rate: 10 ℃/min, nitrogen flow rate: 20mL/min. XRPD method: instrument model: bruker D8 advance, target: cu kα (40 kv,40 ma), sample-to-detector distance: 30cm, scan range: 3 ° -40 ° (2 theta value), scanning step size: 0.05-0.5s. DVS method: instrument model: SMS DVS advantage, 0-95% RH), temperature: 25 ℃. IR (IR)The model of the method instrument is as follows: nicolet-Magna FT-IR 750, scan range: 4000to 350cm-1, resolution: 4cm -1 . The Raman method comprises the following steps: instrument model: thermo Scientific DXR, laser wavelength: 780nm, scan range: 730 to 50cm -1 Resolution: 2cm -1 。
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiments of the application and together with the description serve to explain the application and do not constitute an undue limitation to the application. Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein: the free base and API in the figures represent compounds of formula I.
FIG. 1 is a polarized photograph of a compound of formula I.
FIG. 2 is an X-ray powder diffraction (XRPD) pattern of a compound of formula I.
Figure 3 thermogravimetric analysis (TGA) profile of the compound of formula I.
FIG. 4 is a differential scanning calorimeter analysis (DSC) of a compound of formula I.
Fig. 5 is a polarized photograph of the hydrochloride salt of the compound of formula I.
FIG. 6 is an X-ray powder diffraction (XRPD) pattern of the hydrochloride salt of the compound of formula I.
Fig. 7 is a thermogravimetric analysis (TGA) profile of the hydrochloride salt of the compound of formula I.
FIG. 8 is a differential scanning calorimeter analysis (DSC) of the hydrochloride salt of the compound of formula I.
Fig. 9 Raman spectrum (Raman) plot of the hydrochloride salt of the compound of formula I.
FIG. 10 is an Infrared (IR) spectrum of the hydrochloride salt of the compound of formula I.
FIG. 11 is a polarized photograph of a sulfate salt of the compound of formula I.
FIG. 12 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt of the compound of formula I.
Figure 13 thermogravimetric analysis (TGA) profile of the sulfate salt of the compound of formula I.
Figure 14 is a Differential Scanning Calorimetric (DSC) plot of the sulfate salt of the compound of formula I.
Fig. 15 is a polarized photograph of the mesylate salt of the compound of formula I.
FIG. 16 is an X-ray powder diffraction (XRPD) pattern of the mesylate salt of the compound of formula I.
Figure 17 thermogravimetric analysis (TGA) of the mesylate salt of the compound of formula I.
FIG. 18 is a Differential Scanning Calorimetric (DSC) diagram of the mesylate salt of the compound of formula I.
Fig. 19 Raman spectrum (Raman) plot of the mesylate salt of the compound of formula I.
FIG. 20 is an infrared spectrum (IR) diagram of the mesylate salt of the compound of formula I.
FIG. 21 is a polarized photograph of the L-tartrate salt of the compound of formula I.
FIG. 22 is an X-ray powder diffraction (XRPD) pattern of the L-tartrate salt of the compound of formula I.
FIG. 23 thermogravimetric analysis (TGA) of the L-tartrate salt of the compound of formula I.
FIG. 24 is a Differential Scanning Calorimetric (DSC) diagram of the L-tartrate salt of the compound of formula I.
Fig. 25 is a polarized photograph of the citrate salt of the compound of formula I.
FIG. 26 is an X-ray powder diffraction (XRPD) pattern of the citrate salt of a compound of formula I.
Figure 27 shows thermogravimetric analysis (TGA) of citrate of the compound of formula I.
Figure 28 is a differential scanning calorimeter analysis (DSC) of citrate of a compound of formula I.
FIG. 29 is a graph comparing X-ray powder diffraction (XRPD) of a compound of formula I with its respective salt.
Figure 30 is a graph comparing thermogravimetric analysis (TGA) of a compound of formula I with its respective salts.
FIG. 31 is a differential scanning calorimeter analysis (DSC) comparison of a compound of formula I with its respective salt.
Fig. 32 is a graph of Mean time to drug profile (mean±sd, n=4) after single oral administration of compound of formula I hydrochloride and compound of formula I mesylate to male SD rats.
FIG. 33 is a graph of plasma concentration versus time (A) for male SD rats after single oral administration of 9mg/kg of the compound of formula I hydrochloride; plasma concentration versus time profile (B) for male SD rats after single oral administration of 9mg/kg of the mesylate salt of the compound of formula I.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, materials and reagents used in the present invention may be obtained by conventional means or by a purchasing platform. And, unless otherwise indicated, are used in a manner familiar to those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The compounds of formula I described herein and used in the examples of the present invention (i.e., sildenafil analogs, 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfocarbonyl)]Phenyl-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3d]Pyrimidine-7-thiones, e.g., buddha, huang Yiguan, mo Wenjuan Synthesis Process study of a sildenafil analog [ J ]Chinese current medicine, 2014,21 (5): 15-17, or as described in Chinese patent CN104650093A, the contents of which are incorporated herein by reference in their entirety. The polarized photographs, X-ray powder diffraction (XRPD) patterns, thermogravimetric analysis (TGA) patterns, and Differential Scanning Calorimetry (DSC) patterns of the compounds of formula I are shown in fig. 1-4. In a specific embodiment of the invention, the compounds of formula I, also referred to as the free base, have the following properties: no crystal type and columnar crystal. The crystal form melting point is T onset No seeding behavior before melting at 224 ℃, onset of decomposition at about 260 ℃. Within the range of 0-95% relative humidity, the crystalline form does not transform.
Preparation example 1 hydrochloride salt of the Compound of formula I
470mg of the compound of formula I was accurately weighed into a eggplant-shaped bottle, 40mL of acetonitrile solvent was added and stirred continuously at 60℃and then 1.2-fold equivalent of hydrochloric acid solution (about 100. Mu.L of concentrated hydrochloric acid solution was diluted with 10mL of acetonitrile) was slowly added at 60 ℃. The reaction phase was suspended at 60℃for 1 hourAfter that, the mixture was cooled to room temperature and allowed to stand for 14 hours. The precipitated solid was filtered and washed 3 times with a small amount of acetonitrile. The solid obtained was then evaporated at room temperature to give yellow needle-like crystals. In the infrared spectrogram, the characteristic peak of salification is obvious at 3300-3500cm < -1 >. The stoichiometric ratio of the salt was determined to be 1:1 by HPLC measurement. The yellow needle-like crystal is hydrochloride of the compound in the formula I, which is called hydrochloride for short. The polarized light photo, XRPD pattern, TGA pattern, DSC pattern, raman pattern and IR pattern are shown in figures 5-10 respectively. The hydrochloride is in the form of needle-like crystal, and has a melting point T onset =213 ℃, decomposition starts at about 220 ℃. The crystal forms are not transformed in the range of 0-95% relative humidity. Wherein the hydrochloride XRPD data information is as follows:
preparation example 2 sulphates of the Compound of formula I
470mg of the compound of formula I are accurately weighed into a eggplant-shaped bottle, 40mL of a mixed solvent of acetone and water (10%, i.e., V/V=9:1) is added, and stirring is continued at 60 ℃, and then 1.2 times equivalent of sulfuric acid solution (34. Mu.L of concentrated sulfuric acid is diluted with 10mL of acetone and water (9:1)) is slowly added at 60 ℃. The reaction phase was suspended at 60℃for 1 hour, cooled to room temperature and allowed to stand for 14 hours. The precipitated solid was filtered and washed 3 times with a small amount of acetonitrile. The solid obtained was then evaporated at room temperature to give a yellow solid (hydrate, columnar crystals). In infrared spectrogram, 3300-3500cm -1 Has obvious characteristic peak of salification and is at 1100cm -1 There is a stretching vibration of sulfate ions. The stoichiometric ratio of the salt was determined to be 2:1 by HPLC measurement (formula I: sulfuric acid). The yellow solid is the sulfate of the compound of the formula I, which is called sulfate for short. Its polarized, XRPD pattern, TGA pattern, DSC pattern are shown in figures 11-14, respectively. The sulfate is in the form of hydrate, column A crystalline body, which is dehydrated and transformed at 100 ℃, and the salt has a melting point of T onset =186 ℃, decomposition starts at about 240 ℃. The crystal forms are not transformed in the range of 0-95% relative humidity.
The XRPD data information for the sulfate salts are shown below:
preparation example 3 mesylate salt of the Compound of formula I
470mg of the compound of formula I was accurately weighed into a eggplant-shaped bottle, 40mL of tetrahydrofuran solvent was added and stirred constantly at 60℃and then an equivalent amount of methanesulfonic acid solution (65. Mu.L of methanesulfonic acid was dissolved in 10mL of tetrahydrofuran) was slowly added at 60 ℃. The reaction phase was suspended at 60℃for 1 hour, cooled to room temperature and allowed to stand for 14 hours. The reaction phase was rapidly evaporated on a rotary evaporator, the sample after spin-evaporation drying was dissolved in a small amount of acetonitrile at 50 ℃, filtered, the filtrate was cooled to room temperature and slowly precipitated, and a yellow solid (columnar crystals) was obtained after filtration and drying. In infrared spectrogram, 3300-3500cm -1 Has obvious characteristic peak of salification and is at 1200cm -1 The left and right sides are provided with telescopic vibration of sulfonate ions. The stoichiometric ratio of the salt was determined to be 1:1 by HPLC measurement. The yellow solid (columnar crystals) obtained is the mesylate of the compound of formula I, abbreviated as mesylate, whose polarograms, XRPD patterns, TGA patterns, DSC patterns, raman patterns, IR patterns are shown in fig. 15-20, respectively. Methanesulfonate salt is a columnar crystal having a melting point of 186 ℃ and starts to decompose at about 250 ℃. The crystal forms are not transformed in the range of 0-95% relative humidity. Wherein the XRPD data information for the mesylate salt is shown below:
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Preparation example 4L-tartrate salt of the Compound of formula I
470mg of the compound of formula I was accurately weighed into a eggplant-shaped bottle, 40mL of tetrahydrofuran solvent was added and stirred constantly at 60℃and then an equivalent amount of L-tartaric acid solution (65. Mu. L L-tartaric acid was dissolved in 10mL of tetrahydrofuran) was slowly added at 60 ℃. The reaction phase was suspended at 60℃for 1 hour, cooled to room temperature and allowed to stand for 14 hours. The reaction phase was rapidly evaporated to dryness on a rotary evaporator, and the dried sample was added with about 15mL of ethyl acetate solution, and was subjected to suspension equilibration for 24 hours at room temperature, and then filtered and dried to obtain yellow solid powder. 3300-3500cm in infrared spectrogram -1 Has obvious characteristic salt forming peak. The stoichiometric ratio of the salt was determined to be 1:1 by HPLC measurement. The yellow solid powder is L-tartrate of the compound of formula I, which is called L-tartrate for short. Its polarized, XRPD pattern, TGA pattern, DSC pattern are shown in figures 21-24, respectively. The L-tartrate salt was a yellow solid powder. The salt form starts to decompose at 180 ℃ to remove L-tartaric acid (i.e., decompose before melting) and thus has no stable melting point. The crystal forms are not transformed in the range of 0-95% relative humidity. Wherein the XRPD data information for L-tartrate is as follows:
PREPARATION EXAMPLE 6 citrate salt of the Compound of formula I
Accurately weighing 470mg of the compound of formula I in a eggplant-shaped bottle, adding 40mL of tetrahydrofuran solvent, stirring at 60deg.C, and thenAn equivalent amount of citric acid solution (65. Mu.L of citric acid dissolved in 10mL of tetrahydrofuran) was slowly added at 60 ℃. The reaction phase was suspended at 60℃for 1 hour, cooled to room temperature and allowed to stand for 14 hours. The reaction phase was rapidly evaporated on a rotary evaporator, the sample after spin-evaporation drying was dissolved in a small amount of methanol solution at 50 ℃, filtered, the filtrate was cooled to room temperature and slowly precipitated, and a yellow solid (bulk crystal) was obtained after filtration and drying. In infrared spectrogram, 3300-3500cm -1 There is a distinct characteristic peak of salt formation, as well as a red shift of the carbonyl peak of the carboxylic acid. The stoichiometric ratio of the salt was determined to be 2:1 by HPLC measurement (formula I: citric acid). The yellow solid (bulk crystal) obtained is the citrate of the compound of formula I, which is called citrate for short. Its polarized, XRPD pattern, TGA pattern, DSC pattern are shown in figures 25-28, respectively. Citrate is a bulk crystal. The salt form starts to decompose at 150 ℃ and directly removes citric acid (i.e. decomposes before melting) and therefore has no stable melting point. The crystal forms are not transformed in the range of 0-95% relative humidity. The XRPD data information for citrate is shown below:
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Example 1
1. Selection of a solvent:according to the solubility of the compound of the formula I, the compound of the formula I is insoluble in methanol, acetonitrile and acetone at room temperature and has better solubility in tetrahydrofuran, the following 8 solvents and combinations are selected, so that the solvents which are most suitable for forming various salt forms of the formula I are selected. The 8 solvents and combinations were respectively: methanol, acetone, acetonitrile, tetrahydrofuran, methanol/water (v/v=9:1),Acetone/water (v/v=9:1), acetonitrile/water (v/v=9:1), tetrahydrofuran/water (v/v=9:1). The results are shown in Table 1:
TABLE 1
Since the compounds of formula I are insoluble in methanol, acetonitrile and acetone at room temperature and have a good solubility in tetrahydrofuran, the solutions are initially cloudy in columns 1, 2, 3 and 5, 6, 7 of table 1 before the compounds of formula I are mixed with the acid, and clear in columns 4, 8 before the compounds of formula I are mixed with the acid. When the compound of formula I was mixed with each acid and heated to rest for 15 hours, the phenomenon thereof is shown in table 1. Wherein "∈" indicates that the cloudy solution became clear after adding the acid and heating for 15 hours. "-" means that the clear solution remains clear after the addition of acid and heating to rest for 15 hours. "o" means that the clear solution became cloudy after addition of acid and heating to rest for 15 hours. "×" indicates that the cloudy solution remained cloudy after the addition of acid and heat to rest for 15 hours.
2. Salt screening:the pKa of the compound of formula I is 5.68 and the following 12 acids are salified with the compound of formula I: hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, benzoic acid, succinic acid, adipic acid, p-toluenesulfonic acid.
All solutions of the compound of formula I and no solid precipitate were evaporated to dryness at room temperature in various reaction solutions (table 1), recrystallized with poor solid properties, and the obtained solid was observed. Acids (e.g., glassy solids or oils) with poor solid character after reaction with formula I are eliminated.
Results: the clear solution obtained by solvent screening was found to have a good solids for the most part after volatilizing at room temperature. Thus, a 100mg sample was prepared by amplifying a compound of formula I with 12 acids in tetrahydrofuran (since there is better dissolution in both tetrahydrofuran). The resulting solid is crystallized in various crystallization modes, such as suspension, volatilized, antisolvent, and XRPD characterization of the resulting solid is performed. As a result, it was found that XRPD of the solid obtained by crystallization of the compound of formula I with succinic acid, adipic acid, L-malic acid, benzoic acid and fumaric acid was consistent with the compound of formula I, and therefore the formation of salts of these five acids with the compound of formula I was difficult or unstable; the solid crystals obtained with the compound of formula I and p-toluene sulfonic acid are poorly reproducible, so these six acids are excluded.
(2) The salt form (i.e. hydrochloride, sulfate, mesylate, maleate, L-tartrate and citrate) with good solid property, which is obtained by separating out and volatilizing the solid and reacts with the compound of the formula I, is amplified by 100mg again, and has good salifying property, and the formed salt has good crystallinity and solid state.
3. Solubility of the salt forms at different pH
(1) An aqueous solution of pH 2.0 (glycine-hydrochloric acid buffer), pH 4.6 (disodium hydrogen phosphate-citric acid buffer) and pH 6.8 (disodium hydrogen phosphate-citric acid buffer) was prepared. (2) The excessive compound of formula I, hydrochloride, sulfate, methanesulfonate, maleate, L-tartrate and citrate solids prepared in preparation examples 1-6 are respectively mixed and stirred with 1.0mL of the buffer solution and deionized water to prepare saturated solution, the excessive solid exists in the solution, and the solution is stirred at room temperature for 24 hours, wherein each experiment is 2 parts. (3) The suspension in (2) was centrifuged and the supernatant was compared to determine the concentration of the free base (i.e. the compound of formula I) in various media by HPLC. The solubility results are shown in table 2.
Table 2 (at 25 ℃ C.)
As a result, the solubility of the compound of formula I and the various salts in deionized water was found to vary significantly, but the solubility differences were small in the ph=2.0, ph=4.6 and ph=6.8 buffers. The six salts are significantly better soluble in water than the compound of formula I, with the highest solubility of the mesylate salt, followed by the hydrochloride salt. The solubility of each salt in water is in the order: methanesulfonate > hydrochloride > maleate > L-tartrate > citrate > sulfate > free base. In the buffer at ph=2.0, neither the salts nor the compound of formula I have high solubility. And after the experiment was completed, all five salts were converted to hydrochloride salts, except for sulfate. The hydrochloride is illustrated to be a dominant crystalline form that is more stable in a more acidic environment.
4. Physical stability
The compound of formula I, hydrochloride, sulfate, mesylate, maleate, L-tartrate and citrate prepared in preparation examples 1-6 are placed for 10 days at the temperature of 40 ℃ with the humidity of 75%, and then XRPD is characterized, so that the maleate has a crystal transformation phenomenon, and other salts are relatively stable.
EXAMPLE 2 pharmacokinetic testing
1. This example is intended to provide a single administration of the hydrochloride and mesylate salts of the compounds of formula I (derived from preparations 1 and 3) to SD rats by gavage (PO) and plasma was collected at 0.25, 0.5, 0.75, 1, 2, 4, 8 and 24 hours before and after administration. The concentration of the compound of formula I in SD rat plasma was quantitatively determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis method. Pharmacokinetic parameters were calculated by WinNonlin 6.4 software in a non-compartmental model.
2. Instrument: liquid chromatography tandem mass spectrometer (LCMSMS-025): the chromatograph is Shimadzu liquid chromatograph (Japan), and comprises LC-30AD binary pump, SIL-30AC autosampler, CTO-20A column incubator, CBM-20A system controller and CBM-20A degasser; the mass spectrometer was an AB SCIEX API6500 triple quadrupole mass spectrometer (canada) equipped with an electrospray ionization interface and an AB SCIEX analysis 1.6.3 data processing system. The lc tandem mass spectrometer and software have been authenticated according to the standard operating procedures of the wisdom chemistry.
Other instruments: micro-electronic balances (model: XP205/XP26, mettler-Toledo), electronic balances (model: PL2002, TBD), cryo-refrigerated centrifuges (model: fresio.017, thermo), isoflurane anesthetics (model: R510-11, deep-zhen Ruiwo), vortex mixers (model: KQ5200DA, IKA), vortex mixers (model: G560E, IKA), ultrasonic cleaners (model: KQ5200DA, shumei), ultrasonic cleaners (model: KQ5200DE, kunshan ultrasonic instruments Co., ltd.), 96-well inlet plate (Axygen), pipettors (1-10. Mu.l, 10-100. Mu.l, 20-200. Mu.l, 100-1000. Mu.l, eppendorf), milli-Q ultra-pure water systems (Elix 20, millipore), ultra-low temperature refrigerators (model: scientific for 900-905, 906, thermo), and the like.
3. Test animals: 8 SD rats, male, 169-196g,6-8 weeks purchased from Shanghai Laike Biotechnology Co., ltd., production license number SCXK (Shanghai) 2017-0012, certification number 20170012002474. Animals in the dosing group were fasted overnight prior to dosing, and fed was resumed 4 hours after dosing, with free water throughout the experiment.
4. Standard and internal standard and reagent
TABLE 3 Standard and internal Standard
Names of Compounds Compounds of formula I (Standard) Tolbutamide (internal standard)
Molecular weight 470 270.35
Lot number 180711 076K1277
Content or purity 99.6％ 100.2％
Source SHANGHAI ZHONGTUO PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Sigma of
Storage conditions Room temperature, protected from light Room temperature, protected from light
TABLE 4 reagents
5. Formulation of the administration preparation
Formulation of "0.5% MC in Water": accurately weighing 500ml of water, heating in a 70 ℃ water bath kettle, placing 400ml of water in a 500ml glass bottle, placing the glass bottle on a magnetic stirrer for stirring, accurately weighing 2.5g of methyl cellulose, adding the methyl cellulose into the bottle while stirring, stirring for 120 minutes, placing the glass bottle in a 4 ℃ refrigerator for one night, taking out the glass bottle containing MC aqueous solution, and fixing the volume to 500ml.
0.9mg/ml oral administration formulation of the hydrochloride salt of the compound of formula I formulated with "0.5% MC in water": 15.064ml"0.5%MC in water' was accurately measured into a clean glass bottle, placed on a magnetic stirrer and stirred, 14.61mg of the hydrochloride salt of the compound of formula I was added and stirred for a further 40 minutes.
0.9mg/ml of the mesylate salt of the compound of formula I: 13.771ml"0.5%MC in water' is accurately measured into a clean glass bottle, placed on a magnetic stirrer for stirring, 14.94mg of the mesylate of the compound of formula I is added and stirred for 30 minutes.
"0.5% MC in water" is a colorless transparent solution, and both formulations for administration are pale yellow uniform suspensions.
After formulation of the dosing formulation, appropriate amounts (1 part per layer) were accurately sampled from the upper, middle and lower layers of the suspension, respectively, and the actual concentration was measured daily using LC-UV.
6. Animal grouping and sampling time points
TABLE 5 grouping of test animals
TABLE 6 animal dosing and sampling
Remarks: * Fasted: the administration was fasted overnight until 4hr after administration.
7. Sample collection and storage
Collection of plasma samples: according to the predetermined time point, fixing the corresponding animal, taking about 150 μl of blood by cardiac puncture after tail vein puncture or isoflurane anesthesia, anticoagulating blood sample with K2EDTA, placing on wet ice, centrifuging the sample at 4deg.C for 5min with 2000g centrifugal force within 15min after sampling, and obtaining plasma. The plasma sample is frozen in dry ice and stored in a refrigerator at-70 ℃ for a long time until the sample is analyzed.
8. Plasma sample analysis
Pretreatment of plasma samples: a20.0. Mu.l SD rat plasma sample was taken, 200.0. Mu.l of working internal standard solution (tolbutamide: 10ng/ml; dexamethasone (not involved in quantification): 10ng/ml, formulated in acetonitrile) was added, vortexed for 2min and centrifuged at 13000rpm for 5min. 100.0 μl of supernatant was added to 100.0 μl of Milli-Q water sample and vortexed for 2min for sample LC-MS/MS analysis.
Chromatographic conditions: mobile phase a: milli-Q water/0.1% formic acid; mobile phase B: acetonitrile/0.1% formic acid;
elution mode: gradient, elution procedure is shown in the table below.
Time (min) Mobile phase B (%)
0.00 35
0.20 35
1.50 75
1.80 95
2.10 95
2.11 35
2.60 stop
Flow rate: 0.4000ml/min; sample injection volume: 2.0 μl; sample introduction temperature: 4 ℃; chromatographic column: poroshell 120, ec-C18,50 x 2.1mm,2.7 μm; column temperature: 45 ℃; run time: 2.6min; washing needles: acetonitrile/methanol/isopropanol/Milli-Q water, 25/25/25/25, (v/v/v/v), 0.02%DMSO,0.5%Formic Acid.
The mass spectrometry condition adopts an electrospray ion source (Turbo spray), and a multi-channel reaction monitoring (MRM) mode is selected for secondary mass spectrometry under a positive ion detection mode. The mass spectrum detection operating parameters and ion source parameters are shown in table 7.
TABLE 7 Mass Spectrometry detection conditions for CM1024 and tosylurea (internal standard)
Remarks: the compound of formula I simultaneously monitors 2 ion channels, and the result of the compound of formula I-01 is adopted in quantification.
The accompanying standard curve for sample detection and quality control sample results the accompanying standard curve for plasma sample detection and quality control sample accuracy results are shown in table 8.
TABLE 8 Standard curve for plasma sample determination of compounds of formula I
Plasma Samples Anal.Conc.(ng/ml) CalcμLated Conc.(ng/ml) Accuracy(％)
STD1-01 1.00 1.12 111.8
STD2-01 2.00 2.19 109.7
STD3-01 5.00 5.14 102.8
STD4-01 15.0 *51.1 NA
STD5-01 50.0 49.6 99.3
STD6-01 150 161 107.6
STD7-01 500 537 107.5
STD8-01 900 1012 112.4
STD9-01 1000 1141 114.1
STD1-02 1.00 0.892 89.2
STD2-02 2.00 1.86 93.1
STD3-02 5.00 4.45 88.9
STD4-02 15.0 13.4 29.5
STD5-02 50.0 47.8 95.5
STD6-02 150 149 99.1
STD7-02 500 453 90.7
STD8-02 900 848 94.2
STD9-02 1000 947 94.7
* : the calculated concentration is excluded from the calibration curve because it is not in the range of 85% -115% of the theoretical concentration.
TABLE 9 quality control samples for the plasma sample assay of the compounds of formula I
9. Pharmacokinetic analysis: based on the plasma drug concentration-time data and the actual dose per animal, the pharmacokinetic parameters of the compound of formula I in plasma were calculated in a non-compartmental model using WinNonlin software (usa), including the area under the drug-time curve AUC, the mean residence time MRT, the elimination half-life t 1/2 Peak concentration C max Peak time of sum T max Etc.
10. Test results
Actual concentration detection of the drug administration preparation: after the two groups of dosing formulations were formulated, the actual concentration was measured by LC-UV after the day of dilution and the deviation from the theoretical concentration was calculated. When the average deviation value is within + -15%, the related data calculation is calculated as the theoretical concentration. The deviation of the actual concentration from the theoretical concentration obtained by the detection is shown in Table 10.
TABLE 10 deviation of actual concentration from theoretical concentration for the formulations administered
11. Clinical observation: no obvious clinical abnormalities were observed.
12. Pharmacokinetic results
The average pharmacokinetic parameters of the compound of formula I in the plasma of each SD rat after oral administration of the hydrochloride salt of the compound of formula I and the mesylate salt of the compound of formula I are shown in table 11 and the average drug concentration versus time profile is shown in fig. 32. The plasma concentrations, pharmacokinetic parameters and drug-time profiles of the compounds of formula I for each SD rat are shown in tables 12-13, as well as fig. 33.
After single gastric administration of 9mg/kg of compound hydrochloride of formula I to male SD rats, the compound of formula I reached a maximum blood concentration of 0.750+ -0.842 hr, maximum blood concentration C max 83.0+ -51.1 ng/ml; mean residence time MRT INF 3.95+ -0.898 hr; area under the drug-time curve AUC of 0 to last measurable concentration corresponding to time point last 285±99.1hr ng/ml, respectively; area under drug-time curve AUC from 0 to infinity INF 320.+ -.102 hr ng/ml, respectively.
After single gastric administration of 9mg/kg of the mesylate salt of the compound of formula I to male SD rats, the compound of formula I reached a maximum blood level, maximum blood level C, of 0.375.+ -. 0.144hr max 72.4+/-26.5 ng/ml; mean residence time MRT INF 3.88+ -0.994 hr; area under the drug-time curve AUC of 0 to last measurable concentration corresponding to time point last 239±116hr ng/ml respectively; area under drug-time curve AUC from 0 to infinity INF 274.+ -. 142hr ng/ml, respectively.
Table 11. Average pharmacokinetic parameters after single oral administration of compound of formula I hydrochloric acid and compound of formula I mesylate in male SD rats (mean±sd, n=4)
PK Parameters PO-Compound hydrochloride of formula I PO-Compound mesylate of formula I
T max (hr) 0.750±0.842 0.375±0.144
C max (ng/ml) 83.0±51.1 72.4±26.5
T 1/2 (hr) 2.66±0.762 2.82±0.833
MRT INF (hr) 3.95±0.898 3.88±0.994
AUC last (hr*ng/ml) 285±99.1 239±116
AUC INF (hr*ng/ml) 320±102 274±142
TABLE 12 blood levels and pharmacokinetic parameters at various time points after single oral administration of 9mg/kg of the Compound hydrochloride of formula I to Male SD rats
BQL:Below the lower limit of quantification(1.00ng/ml)；NA:Not available.
TABLE 13 blood plasma levels and pharmacokinetic parameters at various time points after single oral administration of 9mg/kg of the mesylate salt of Compound of formula I in Male SD rats
BQL:Below the lower limit of quantification(1.00ng/ml)；NA:Not available.
The sulfate salt of preparation 2, the L-tartrate salt of preparation 5 and the citrate salt of preparation 6 were each tested according to the procedure of this example, with differences in the average pharmacokinetic parameters, although not as good as the results for the hydrochloride and mesylate salts, but with different degrees of improvement over the compound of formula I. In a word, the improvement effect of the hydrochloride, the mesylate and the sulfate of the compound shown in the formula I is most remarkable, and other salt forms are improved to a certain extent, so that the compound has better bioavailability.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (19)

  1. A polycrystal of a phosphodiesterase type 5 inhibitor is characterized in that the phosphodiesterase type 5 inhibitor is shown as a formula I, the polycrystal is hydrochloride of the compound of the formula I,
    The hydrochloride salt of the compound of formula I has diffraction characteristic peaks at the following 2θ angles, measured using Cu-ka radiation: 5.848 + -0.2 °, 6.089 + -0.2 °, 6.468 + -0.2 °, 7.189 + -0.2 °, 7.471 + -0.2 °, 8.711 + -0.2 °, 9.191 + -0.2 °, 11.749 + -0.2 °, 12.284 + -0.2 °, 17.460 + -0.2 °, 18.635 + -0.2 °, 21.308 + -0.2 °, 21.566 + -0.2 °, 23.954 + -0.2 °, 24.534 + -0.2 °, 24.999 + -0.2 °.
  2. 2. The polymorph of a phosphodiesterase type 5 inhibitor according to claim 1, characterized in that the XRPD pattern of the hydrochloride salt of the compound of formula I is shown in figure 6.
  3. 3. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the melting point of the hydrochloride salt of the compound of formula I is 213±2 ℃.
  4. 4. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the TGA decomposition temperature of the hydrochloride salt of the compound of formula I is not lower than 220 ℃.
  5. 5. The polymorph of a phosphodiesterase type 5 inhibitor according to claim 1, characterized in that the TGA profile of the hydrochloride salt of the compound of formula I is shown in figure 7.
  6. 6. The polymorph of a phosphodiesterase type 5 inhibitor according to claim 1, characterized in that the DSC profile of the hydrochloride salt of the compound of formula I has an exothermic peak at 200-230 ℃.
  7. 7. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the DSC profile of the hydrochloride salt of the compound of formula I is shown in figure 8.
  8. 8. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the raman spectrum of the hydrochloride salt of the compound of formula I comprises one or more of the following peaks in wave numbers: 2957.45, 2939.40, 1607.29, 1580.59, 1544.24, 1521.63, 1434.57, 1404.00, 1311.28, 1291.99, 1259.99, 1196.45, 1154.33, 1110.30. 938.37, 795.80, 678.39, 661.61, 615.49, 569.36, 509.56, 441.46, 405.82, 334.54, 159.91; wave number error of + -2 cm -1 。
  9. 9. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the raman spectrum of the hydrochloride salt of the compound of formula I is shown in figure 9.
  10. 10. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the infrared spectrum of the hydrochloride of the compound of formula I comprises one or more of the following peaks in wave numbers: 3409.90, 3267.48, 2973.95, 2958.91, 2929.86, 2873.75, 2669.34, 2645.29, 2584.90, 2509.02, 2452.32, 1621.05, 1605.33, 1572.26, 1542.44, 1512.78, 1499.16, 1468.16, 1435.39, 1414.54, 1390.48, 1326.32, 1310.98, 1283.89, 1263.28, 1239.13, 1194.79, 1151.55, 1105.83, 1081.99, 1057.88, 1023.00, 974.17, 913.07, 886.88, 814.80, 798.94, 672.35, 643.17, 612.11, 578.08, 535.66, 506.10, 476.04, 442.23; wave number error of + -2 cm -1 。
  11. 11. The polymorph of a phosphodiesterase inhibitor form 5 according to claim 1, characterized in that the infrared spectrum of the hydrochloride salt of the compound of formula I is shown in figure 10.
  12. 12. A method of forming a polymorph of a phosphodiesterase type 5 inhibitor according to any one of claims 1 to 11, comprising: adding a compound of the formula I into a solvent, continuously stirring at 40-80 ℃, slowly adding acid liquor at 40-80 ℃, suspending at 40-80 ℃, cooling to room temperature, and standing; filtering the precipitated solid, washing, volatilizing at room temperature or rotary evaporating, and recrystallizing to obtain the final product; the acid liquor is hydrochloric acid, and the solvent is one or more selected from water, acetonitrile, acetone and tetrahydrofuran.
  13. 13. The method according to claim 12, wherein the solvent is acetonitrile, tetrahydrofuran or acetone/water.
  14. 14. The method according to claim 12, characterized in that the method comprises: adding a compound shown in the formula I into a solvent, continuously stirring at 60 ℃, slowly adding 1-2 times equivalent acid liquor at 60 ℃, suspending at 60 ℃ for 0.5-1 hour, cooling to room temperature, standing for 12-16 hours, filtering precipitated solid, washing with acetonitrile, and volatilizing at room temperature to obtain a polycrystal of the type 5 phosphodiesterase inhibitor.
  15. 15. The method according to claim 12, characterized in that the method comprises: adding the compound shown in the formula I into a solvent, continuously stirring at 60 ℃, slowly adding an equivalent or 1.2 times of an equivalent acid solution at 60 ℃, suspending at 60 ℃ for 0.5-1 hour, cooling to room temperature, standing for 14 hours, performing rotary evaporation and drying, recrystallizing at 40-60 ℃, filtering and drying to obtain the polycrystal of the type 5 phosphodiesterase inhibitor.
  16. 16. The method according to claim 12, wherein the recrystallization solvent is selected from acetonitrile, acetone, ethyl acetate, or methanol.
  17. 17. A pharmaceutical composition comprising a polymorph of a phosphodiesterase type 5 inhibitor according to any one of claims 1 to 11.
  18. 18. Use of a polymorph of a phosphodiesterase type 5 inhibitor according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 17 for the preparation of a medicament for the prevention or treatment of male erectile dysfunction or for the prevention or treatment of a disease associated with phosphodiesterase type 5.
  19. 19. The use according to claim 18, wherein the disease associated with phosphodiesterase type 5 comprises: female sexual dysfunction, benign prostatic hyperplasia, bladder obstruction, incontinence, angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral circulatory system diseases, asthma, bronchitis, alzheimer's disease, and acute respiratory failure.
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