WO2019001551A1 - Crystalline form of free base of imidazo-isoindole derivative and preparation method therefor - Google Patents

Abstract

Provided are a crystalline form G of a free base of an imidazo-isoindole derivative and a preparation method therefor. The chemical structure of the compound is shown in formula (I), and the chemical name thereof is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a] isoindole-5-yl) piperidine-1-yl) phenyl)-1H-pyrazol-1-yl) ethanol. Provided are the application of the crystalline form G of the compound in a pharmaceutical composition and the pharmaceutical use of the crystalline form G and the composition in the preparation of a medicine for treating diseases with pathological characteristics of tryptophan metabolic pathway mediated by IDO (indoleamine-pyrrole-2,3-dioxygenase). The crystalline form G of the compound has good stability, and the crystallization solvent that is used has low toxicity and residue and may be used well in clinical treatment.

Description

Crystal form of imidazoisoindole derivative free base and preparation method thereof Technical field

The present invention relates to (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)benzene Form G of -1H-pyrazol-1-yl)ethanol and its preparation, its use in pharmaceutical compositions, and the G crystal form and composition have IDO-mediated tryptophan metabolism in preparation Use in diseases that pathologically characterized.

Background technique

Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The host's natural defense mechanisms (such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds. The alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan. Fast enzyme, which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein. IDO is closely related to interferon (IFN), interleukin (IL), tumor necrosis factor and other cytokines, and they can activate IDO under certain conditions. In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells; On the other hand, IDO catalyzes the main product produced by the metabolism of tryptophan. Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body. A large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.

Inhibitors of the disclosed selective inhibitors of IDO include WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834, and the like.

IDO inhibitors have good application prospects in the pharmaceutical industry as a drug. Patent application WO2016169421A1 (publication date 2016.10.27) discloses a novel high-efficiency and low-toxic selective IDO inhibitor compound with excellent effects and effects. In particular, it has excellent pharmacogen absorption activity and its chemical name is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindole-5-) The base)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol has the structure shown below:

The crystal structure as a pharmaceutically active ingredient often affects the chemical stability of the drug. The difference in the crystal form, preparation method and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystals. type. In general, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, agglomeration, and poor fluidity. These differences often lead to difficulties in production amplification. The stability of the existing crystal form needs to be improved. Therefore, it is necessary to improve the various properties of the compound. We need to study in depth to find new crystal forms with high purity and good chemical stability.

Summary of the invention

The technical problem to be solved by the present invention is to provide a free base of the imidazoisoindole derivative (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1] a crystal form of -a]isoindole-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol, which has good crystal form stability and chemical stability Sex, and the crystallization solvent used is low in toxicity and low in residue, and can be better applied to the clinic.

The technical solution of the present invention is as follows:

The present invention provides a G crystal form of the compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation, and the diffraction angle 2θ angle is 6.3. There are characteristic peaks at 7.2, 10.4, 11.0, 12.1, 14.6, 16.4, 18.0, 19.2, 19.8, 22.5, 24.2, 26.4 and 28.9, wherein the error range of the 2θ angle of each characteristic peak is ±0.2.

In one embodiment of the present invention, the present invention provides a G crystal form of a compound of the formula (I), characterized in that X-ray powder diffraction represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation. The spectrum has diffraction angles 2θ of 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90 and 30.16. There are characteristic peaks in which the error range of the 2θ angle of each characteristic peak is ±0.2.

In one embodiment of the present invention, the present invention provides a G crystal form of a compound of the formula (I), characterized in that X-ray powder diffraction represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation. The spectrum has a diffraction angle 2θ angle of 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90, 30.16, There are characteristic peaks at 31.42, 32.70, 37.13 and 40.15, wherein the error angle of the 2θ angle of each characteristic peak is ±0.2.

In one embodiment of the invention, the invention provides a crystalline form of G of the compound of formula (I), characterized by a melting point of from 210 ° C to 220 ° C, preferably from 212.1 ° C to 213.5 ° C, more preferably 213.24 ° C.

In one embodiment of the invention, the invention further provides a process for the preparation of the G crystalline form of the compound of formula (I), the process being selected from the group consisting of:

(1) Method 1, the compound of the formula (I) is dissolved in an appropriate amount of a solvent, volatilized, crystallized and washed, and dried to obtain a target G crystal form selected from ester solvents and ethers. a solvent, a nitrile, an alcohol solvent, the ester solvent is selected from ethyl acetate or isopropyl acetate, and the ether solvent is selected from the group consisting of tetrahydrofuran, propylene glycol methyl ether or 1,4-dioxane, the nitrile The solvent is selected from the group consisting of acetonitrile, and the alcohol solvent is selected from the group consisting of isopropanol, ethanol or methanol;

(2) Method 2, by dissolving the compound of the formula (I) in an appropriate amount of a good solvent, adding an anti-solvent, performing crystallization, filtering and crystallization, washing, and drying to obtain a target G crystal form, the good solvent It is selected from a halogenated hydrocarbon or ether solvent, the halogenated hydrocarbon solvent is selected from dichloromethane, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the anti-solvent is selected from aliphatic hydrocarbons. a solvent-like solvent, the aliphatic hydrocarbon solvent is selected from n-heptane; or the good solvent is selected from an ether solvent or an alcohol solvent, the ether solvent is selected from the group consisting of propylene glycol methyl ether, and the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol, the anti-solvent is selected from pure water;

(3) Method 3, the compound of the formula (I) is placed in an appropriate amount of a solvent, beaten, filtered and washed, and dried to obtain a target crystal form G, the organic solvent being selected from the group consisting of:

An ester solvent, an ether, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an alcohol, an aromatic hydrocarbon, a halogenated hydrocarbon solvent or a mixed solvent selected from the group consisting of ethyl acetate, isopropyl acetate or butyl acetate And an ether solvent selected from the group consisting of propylene glycol methyl ether, tetrahydrofuran or 1,4-dioxane, the alicyclic hydrocarbon solvent is selected from cyclohexane, and the aliphatic hydrocarbon solvent is selected from n-heptane. The aromatic hydrocarbon solvent is selected from cumene or xylene, the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol, and the halogenated hydrocarbon solvent is selected from dichloromethane, and the mixed solvent is selected from the group consisting of dichloromethane. a mixed solvent of an alcohol and an ether, a mixed solvent of two different alcohol solvents, or a mixed solvent of an alcohol solvent and water, and the ratio of the mixed solvent of the alcohol solvent to the ether is from 0.1:1 to 1:0.1. It is also possible to use methanol/methyl tert-butyl ether = 1:1, the ratio of the two different alcohol solvents is from 0.1:1 to 1:0.1, and methanol/isopropanol = 1:1, the alcohol The ratio of solvent to water mixed solvent is 0.1:1 to 1:0.1, and methanol/water = 1:1; the beating temperature is selected from room temperature to solvent boiling point temperature, and may also be 5 0 ° C, the room temperature is selected from 15-25 ° C, and can also be 25 ° C.

The invention further relates to a pharmaceutical composition of Form G of the compound of formula (I), characterized in that it comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention further relates to a G crystalline form pharmaceutical composition of a compound of formula (I), characterized in that it comprises one or more second therapeutically active agents selected from the group consisting of: an anti-inflammatory agent, a matrix Metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.

The invention further relates to the use of a pharmaceutical composition of Form G or Form G of the compound of formula (I) for the preparation of a medicament for the treatment of a pathological feature having an IDO-mediated tryptophan metabolism pathway selected from the group consisting of Cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder or AIDS; the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, Brain, skin, oral, prostate, bone, kidney, ovarian, bladder, liver, fallopian tube, ovarian, peritoneal, stage IV melanoma, glioma, glioblastoma , hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma or non-small cell lung cancer.

The G crystal form of the compound of the formula (I) obtained by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) was subjected to structural measurement, crystal form study, and solvent residue of the obtained crystal was carried out. The test.

The preparation method of the crystal form in the present invention includes crystallization, crystallization, a positive and negative solvent (good solvent-antisolvent) or beating.

The method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, crystallization of a volatile solvent, seed crystal induced crystallization, etc., and the cooling temperature is selected from 40 ° C or lower, and may also be -10 ° C to 40 ° C. It can also be stirred during the crystallization process.

The starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.

Detailed description of the invention

In the description and claims of the present application, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, unless otherwise indicated. However, for a better understanding of the present invention, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided by the present application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and explanations of the terms provided by the present application shall prevail.

The "beating" as used in the present invention refers to a method in which the solubility of a substance in a solvent is poor, but the solubility of the impurity in a solvent is good, and the beating and purifying can remove the color, change the crystal form or remove a small amount of impurities.

The term "halogenated" as used in the present invention means substituted by "halogen atom", and "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.

The "C _1-6 alkyl group" of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl. , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.

The "hydroxy group, cyano group or the like" as used in the present invention means a group such as -OH or -CN.

The "ester solvent" as used in the present invention means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to, acetic acid. Ethyl ester, isopropyl acetate or butyl acetate.

The "ether solvent" as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or , 4-dioxane.

The "aliphatic hydrocarbon solvent" as used in the present invention refers to a carbon having a basic property of an aliphatic compound and having carbon atoms in the molecule which are connected to each other in a chain, and the carbon atoms are 1-10. Hydrogen compounds such as saturated aliphatic hydrocarbons include alkane solvents, specific examples including, but not limited to, n-butane, n-pentane, n-hexane or n-heptane.

The "alicyclic hydrocarbon solvent" as used in the present invention refers to a hydrocarbon compound having a cyclic carbon skeleton and having similar properties to aliphatic hydrocarbons and having a number of ring atoms of 1-8, and specific examples include, but are not limited to, rings. Pentane or cyclohexane.

The "alcohol solvent" as used in the present invention means a group derived from one or more "hydroxyl groups" substituted with one or more hydrogen atoms on the "C _1-6 alkyl group", said "hydroxyl group" and "C" _1-6 alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, propanol or 2-propanol.

The "aromatic hydrocarbon solvent" as used in the present invention refers to a conjugated system having a closed ring in a molecule, a carbocyclic compound having a п electron number conforming to the Huckel rule and containing 6-8 ring carbon atoms, and a derivative thereof. General examples include, but are not limited to, cumene or xylene.

The "halogenated hydrocarbon solvent" as used in the present invention means a group derived by substituting one or more "halogen atoms" for one or more hydrogen atoms on a "C _1-6 alkyl group", said "halogen atom" And "C _1-6 alkyl" are as defined above, and specific examples include, but are not limited to, methyl chloride, dichloromethane, chloroform or carbon tetrachloride.

The "nitrile solvent" as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted "C _1-6 alkyl", said "cyano" and "C _1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

The "mixed solvent" as used in the present invention means a solvent obtained by mixing one or more different kinds of organic solvents in a certain ratio, or a solvent obtained by mixing an organic solvent and water in a certain ratio, and the certain ratio is 0.1. 1 to 1:0.1, preferably 1:1; the mixed solvent is preferably a mixed solvent of an alcohol and an ether, a mixed solvent of two different alcohol solvents, or a mixed solvent of an alcohol solvent and water; the alcohol The mixed solvent of the ether and the ether is preferably a mixed solvent of methanol and methyl tert-butyl ether, and the mixed solvent of the two different alcohol solvents is preferably a mixed solvent of methanol and isopropyl alcohol, and the alcohol solvent and water The mixed solvent is preferably a mixed solvent of methanol and water.

The "good solvent" as used in the present invention means a solvent having a strong solubility to a molecule (or a solute) and a small interaction with a molecule (or a solute).

The "anti-solvent" as used in the present invention means that the solubility to a molecule (or a solute) is low, poor or insoluble.

By using a good solvent in combination with an anti-solvent, the solubility of the crystal to be crystallized in the solvent is lowered. Since the anti-solvent combines well with it, the solubility of the molecule (or solute) is lowered, so that the molecule (or solute) is precipitated to form a solid phase. The solid is then filtered from the liquid phase, and the two solvents are separated to obtain the desired crystal.

The good solvent and the anti-solvent system are preferably a system in which a halogenated hydrocarbon, an ether solvent and an aliphatic hydrocarbon solvent are combined, or an ether solvent, an alcohol solvent and water, and a system 2; The solvent is selected from a halogenated hydrocarbon or ether solvent, the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the anti-solvent is selected from the group consisting of fat. a hydrocarbon solvent, the aliphatic hydrocarbon solvent is selected from n-heptane; the good solvent in the system 2 is selected from an ether solvent or an alcohol solvent, and the ether solvent is selected from the group consisting of propylene glycol methyl ether, and the alcohol solvent is selected. From ethanol, 2-propanol or methanol, the anti-solvent is selected from pure water;

The "X-ray powder diffraction pattern or XRPD" according to the present invention means that according to the Bragg formula 2d sin θ = nλ (where λ is the wavelength of the X-ray,

The order of diffraction n is any positive integer, generally taking the first-order diffraction peak, n=1), when the X-ray is incident on the crystal or part of the crystal sample with the sweep angle θ (the angle of incidence angle, also called the Bragg angle) When a certain atomic plane with d-plane plane spacing is used, the Bragg equation can be satisfied, and the X-ray powder diffraction pattern is measured.

The "differential scanning calorimetry or DSC" described in the present invention refers to measuring the temperature difference and the heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase change information of the sample.

The "2θ or 2θ angle" as used in the present invention means a diffraction angle, θ is a Bragg angle, and the unit is ° or degree, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, more preferably ±0.2.

The "plane spacing or interplanar spacing (d value)" according to the present invention means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points. The parallelepiped unit, which is divided into juxtapositions, is called the interplanar spacing. The spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice. The lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different;

Or ang.

The invention further relates to a pharmaceutical composition comprising a G crystalline form of a compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents. The pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms. For example, the G crystalline form or pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection, and concentrated injections). Solution), suppository, inhalant or spray.

Furthermore, the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field. When the injection is formulated, an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be formulated into a suppository or the like. For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray. In certain preferred embodiments, the G crystalline form of the invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the G crystalline form of the invention is present in a pharmaceutical composition or medicament in unit dosage form.

The G crystalline form of the compound of formula (I) of the invention may be administered alone or in combination with one or more second therapeutic agents. Accordingly, in certain preferred embodiments, the pharmaceutical composition further comprises one or more second therapeutic agents. In certain preferred embodiments, the second therapeutic agent is selected from the group consisting of an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressive agent, an anticancer agent, and an anti-disease A toxicant, a growth factor modulator, an immunomodulator or an anti-vascular hyperproliferative compound.

The components to be combined (for example, the G crystal form of the present invention and the second therapeutic agent) may be administered simultaneously or sequentially sequentially. For example, the second therapeutic agent can be administered prior to, concurrently with, or after administration of the G crystalline form of the invention or a stereoisomer thereof. Furthermore, the ingredients to be combined may also be administered in combination in the form of the same formulation or in separate separate formulations.

The crystalline form of G of the compounds of formula (I) of the present invention can be used for the preparation of a medicament for the treatment and/or prevention of IDO-mediated tryptophan metabolism. Accordingly, the present application also relates to the use of the G crystalline form of the compound of the formula (I) of the present invention for the preparation of a medicament for the treatment and/or prevention of IDO-mediated tryptophan metabolism in a subject. disease. Further, the present application relates to a method of inhibiting a disease associated with tryptophan metabolism mediated by IDO, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the formula (I) of the present invention Form G of the compound, or a pharmaceutical composition of the invention.

In certain preferred embodiments, the disease is a disease associated with tryptophan metabolism mediated by IDO, selected from the group consisting of: cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, Psychological disorder or AIDS; the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, Bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma, Myeloma or non-small cell lung cancer.

Advantageous effects of the invention

Compared with the prior art, the technical solution of the present invention has the following advantages:

(1) The G crystal form of the anhydrous compound represented by the formula (I) of the present invention does not contain or contains only a low content of residual solvent, and meets the limit requirement of the residual solvent of the pharmaceutical product according to the National Pharmacopoeia, and thus the crystal of the present invention can be It is preferably used as a pharmaceutically active ingredient.

(2) Studies have shown that the G crystal form of the compound of the formula (I) prepared by the invention has high purity, and the crystal form is unchanged under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good; HPLC The purity change is small and the chemical stability is high; the G crystal form of the anhydrous compound represented by the formula (I) obtained by the technical scheme of the present invention can meet the pharmaceutical requirements for production transportation and storage, and the production process is stable, reproducible and controllable, and can be adapted to Industrial production.

DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of the crystalline form of Compound G of formula (I).

Figure 2 is a DSC chart of the crystalline form of Compound G of formula (I).

Figure 3 is a first cycle map of DVS of the compound G crystal form of the formula (I).

Figure 4 is a second cycle view of DVS of the compound G crystal form of the formula (I).

Figure 5 is an X-ray powder diffraction pattern of the compound B crystal form of the formula (I).

Figure 6 is a DSC chart of the crystalline form of Compound B of formula (I).

Figure 7 is an XRPD pattern of the G crystal form for 0 days.

Fig. 8 is an XRPD pattern of the G crystal form after being allowed to stand at 40 ° C and a relative humidity of RH 75% for 15 days.

Figure 9 is an XRPD pattern of Form C for 0 days.

Figure 10 is an XRPD pattern of Form C after 15 days of standing at 40 ° C and relative humidity RH 75%.

Detailed ways

The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the scope and scope of the invention.

Test conditions for the instruments used in the test:

1. Differential Scanning Calorimeter (DSC)

Instrument model: Mettler Toledo DSC 3 ⁺ STAR ^e System

Purge gas: nitrogen

Heating rate: 10.0 ° C / min

Temperature range: 20-250

2. X-ray Powder Diffraction (XRPD)

(1) Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer

Ray: Monochrome Cu-Kα ray (λ=1.5406)

Scanning mode: θ/2θ, scanning range: 10-48°

Voltage: 40KV, current: 40mA

(2) Instrument model: Rigaku UltimalV X-ray powder diffractometer

Ray: Monochrome Cu-Kα ray (λ=1.5418)

Scanning mode: θ/2θ, scanning range: 3-45°

Voltage: 40KV, current: 40mA

3. Dynamic Vapour Sorption (DVS)

Instrument model: DVS advantage

Temperature: 25 ° C

Solvent: water

Humidity change: 0-95-0-95-0%RH, dm/dt=0.002

Comparative Example (Preparation method in Examples 40 and 41 in Patent Application WO2016169421A1 (Publication Date 2016.10.27))

(1) 6-Fluoro-5-(piperidin-4-yl)-5H-imidazo[5,1-a]isoindole ditrifluoroacetate (Compound 1g) (see patent application WO2016169421A1 (Publication Date) Preparation method in Example 1 in 2016.10.27)

first step

4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 1c

Lithium diisopropylamide (32.5 mL, 65.0 mmol) was added to tetrahydrofuran (50 mL), and pre-prepared 1-bromo-3-fluorobenzene 1a (8.75 g, 50.0 mmol, 25 mL) in tetrahydrofuran was added dropwise at -78 °C. Stir at -78 ° C for 1 hour. Further, a pre-formed solution of tert-butyl 4-formylpiperidine-1-carboxylate 1b (8.75 g, 50.0 mmol, 25 mL) in THF was added dropwise at -78 ° C, and stirred at -78 ° C for one hour. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc) 1c (16.3 g, yellow syrup solid, yield 84.0%).

MS m/z (LC-MS): 332.0 [M-56]

Second step

4-((2-Bromo-6-fluorophenyl)(p-toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 1d

Compound 1c (15 g, 38.63 mmol) was dissolved in tetrahydrofuran (350 mL) and sodium hydride (3.09 g, 77.26 mmol) A solution of pre-formed p-toluenesulfonyl chloride (8.10 g, 42.49 mmol, 250 mL) in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 30 minutes, stirred at reflux for 4 hours, and stirred at 70 ° C for 48 hours. After the reaction was completed, the mixture was cooled to 0 ° C, EtOAc (EtOAc) (EtOAc) Chromatography The residue obtained was purified using EtOAc (EtOAc:EtOAc)

MS m/z (LC-MS): 314.0/316.0 [M-56-TsO]

third step

4-((2-Bromo-6-fluorophenyl)(1H-imidazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester 1e

The imidazole (12.5 g, 184.3 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (7.40 g, 184.3 mmol) was added portionwise, and the mixture was stirred at room temperature for 1 hour, and the pre-formed compound 1d was added dropwise. (10.0 g, 18.43 mmol, 20 mL) of N,N-dimethylformamide was stirred at 100 ° C for 12 hours. After completion of the reaction, ethyl acetate (300 mL) was added, and the mixture was washed with saturated sodium chloride (150 mL×3). The resulting residue was purified by EtOAc (EtOAc m.

MS m/z (LC-MS): 438.4/40.1 [M+1]

the fourth step

4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylic acid tert-butyl ester 1f

Compound 1e (1.90 g, 4.33 mmol), N,N-dicyclohexylmethylamine (1.35 g, 6.93 mmol), triphenylphosphine (908 mg, 3.46 mmol) was added to N,N-dimethylformamide (10 mL), palladium acetate (390 mg, 1.74 mmol) was added under an argon atmosphere, and the mixture was stirred at 100 ° C for 4.5 hours. After completion of the reaction, the reaction mixture was evaporated.jjjjjjjjjjjjjjjjj %).

MS m/z (LC-MS): 358.1 [M+1]

the fifth step

6-Fluoro-5-(piperidin-4-yl)-5H-imidazo[5,1-a]isoindole ditrifluoroacetate 1 g

Compound 1f (1.30 g, 3.64 mmol) was dissolved in dichloromethane (5 mL). After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals

MS m/z (LC-MS): 258.3 [M+1]

(2) 4-(4-Bromophenyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole (Compound 40a) (see CN104755477A) (publication 2015.07.01) preparation method on page 44 of the manual)

(3) (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)benzene Base-1H-pyrazol-1-yl)ethanol (Compound 41)

first step

4-(4-Bromophenyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole 40a (14.8 g, 42 mmol), 6 -Fluoro-5-(piperidin-4-yl)-5H-imidazo[5,1-a]isoindole 17a (13.9 g, 42 mmol) was added to N,N-dimethylformamide (300 mL). Tri-tert-butylphosphine tetrafluoroborate (1.863 g, 64.5 mmol) and potassium phosphate (35 g, 168 mmol) were added and replaced three times with argon. Tris(dibenzylideneacetone)dipalladium (2.92 g, 3.19 mmol) was added, and the reaction mixture was heated to 110 ° C, and the reaction was stirred for 2 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness crystals crystals. 6.38 g, gray oil, yield: 29%).

Second step

The compound 40b (9 g, 17.1 mmol) was dissolved in methanol (100 mL), and concentrated hydrochloric acid (12M, 5.7 mL) was added, and the reaction mixture was warmed to 45 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and then the mixture was stirred and evaporated, and the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with eluent system (dichloromethane and methanol) Compound 40c (5.2 g, yellow solid, yield: 65%).

third step

Compound 40c (1.4 g, 3.16 mmol) was subjected to chiral preparation (separation conditions: chiral preparative column Superchiral S-AS (Chiralway), 2 cm ID x 25 cm Length, 5 μm; mobile phase: CO ₂ /MeOH/DEA=60/ 40/0.05 (v/v/v), flow rate: 50 mL/min, and the corresponding fractions were collected and concentrated under reduced pressure to give compound 40 (630 mg, yellow solid) and compound 41 (652 mg, yellow solid).

Example 1

50 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared by the method of Examples 40, 41 in the patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, followed by the addition of isopropyl acetate ( 50 to 100 μL), stirred at 25 ° C for 5 days, filtered, and then dried under vacuum at 25 ° C to give a white to pale yellow powder. The X-ray diffraction pattern of the crystalline sample is shown in Figure 1. The DSC spectrum is shown in Figure 2. There is a sharp melting endothermic peak near 213.24 ° C. This crystal form is defined as G crystal form, passing DVS (Figures 3 and 4). The G crystal form of the anhydrous compound represented by the formula (I) is determined by the detection, and the characteristic peak positions thereof are as follows:

Table 1, G crystal characteristic peak

Example 2

20 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared by the method of Examples 40, 41 in the patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, and dichloromethane (1.5 mL) was added. ), stirring at room temperature, stirring or heating at 50 ° C, stirring and dissolving, adding an anti-solvent n-heptane to produce a precipitate, stirring and crystallization, filtering, and drying to obtain a solid. The crystal sample was subjected to XRPD to detect diffraction angles 2θ at 6.31, 7.30, 8.96, 10.32, 10.95, 12.15, 14.70, 15.15, 16.42, 17.20, 17.82, 19.10, 19.79, 21.18, 21.66, 22.53, 24.22, 26.51, 27.24, 28.83, There are characteristic peaks near 29.10, 31.44, 32.07, 37.06 and 40.41, and the product is determined to be a G crystal form.

Example 3

20 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared by the method of Examples 40, 41 in the patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, and then tetrahydrofuran (1.5 mL) was added. The mixture was stirred or dissolved at room temperature, stirred and heated at 50 ° C to dissolve, and slowly volatilized at room temperature to obtain a solid. The crystal sample was subjected to XRPD to detect diffraction angles 2θ at 6.30, 7.27, 8.92), 10.26, 10.92, 12.10, 14.67, 15.10, 16.40, 17.14, 17.80, 19.06, 19.66, 21.18, 21.54, 22.84, 24.21, 26.27, 27.21, 28.85. There are characteristic peaks near 29.98, 31.40, 32.12 and 39.97, and the product is determined to be a G crystal form.

Example 4

20 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared according to patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, and methyl tert-butyl ether was added: methanol (volume ratio 1:1) 50-100 μL) mixed solvent, stirred at 50 ° C for 5 days, filtered, and dried under vacuum at 25 ° C to give a white to pale yellow powder. The crystal sample was subjected to XRPD to detect diffraction angles 2θ at 6.38, 7.34, 8.97, 10.31, 10.97, 12.17, 14.75, 15.16, 16.23, 17.15, 17.83, 19.14, 19.68, 21.46), 21.62, 22.53, 24.25, 26.32, 27.28, 28.83. There are characteristic peaks near 30.05, 31.48, 32.16 and 40.02, and the product is determined to be a G crystal form.

Example 5

50 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared according to patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, added with acetonitrile (50-100 μL), stirred at 25 ° C for 5 days, filtered It was then dried under vacuum at 25 ° C to give a white to pale yellow powder. The X-ray diffraction pattern of the crystal sample is shown in Fig. 5. The DSC spectrum is shown in Fig. 6. There is a sharp melting endothermic peak near 210.54 °C. This crystal form is defined as B crystal form, and the characteristic peak positions are shown in the following table. :

Table 2, B crystal characteristic peak

Example 6

20 mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl) -1H-pyrazol-1-yl)ethanol (prepared according to patent application WO2016169421A1 (publication date 2016.10.27)) was added to the reaction flask, and dichloromethane (1.5 mL) was added thereto, and dissolved or heated at 25 ° C with stirring. The mixture was dissolved by stirring at 50 ° C, and slowly volatilized under room temperature to obtain a solid. The solid sample was subjected to XRPD to detect diffraction angles 2θ at 6.02, 6.31, 7.55, 8.85, 9.80, 11.14, 12.16, 14.57, 16.02, 16.60, 17.92, 18.33, 19.15, 19.79, 21.34, 21.62, 22.36, 24.28, 25.53, 26.41, There are characteristic peaks near 27.39, 28.90 and 31.61, and the product is determined to be Form B.

Example 7

Weigh 20 mg of the G crystal form obtained in Example 3, place it in a reaction flask, add propylene glycol methyl ether (1 mL), raise the temperature to 80 ° C, keep it for 10 minutes, then lower it to 20 ° C, discard the supernatant, and precipitate the precipitate at 25 After vacuum drying at ° C, the weight was 12.76 mg, and the yield was 63.8%. The precipitates were examined by XRPD for diffraction angles 2θ at 6.31, 7.30, 8.96, 10.32, 10.95, 12.15, 14.70, 15.15, 16.42, 17.20, 17.82, 19.10, 19.79, 21.18, 21.66, 22.53, 24.22, 26.51, 27.24, 28.83, 29.10. There are characteristic peaks near 31.44, 32.07, 37.06 and 40.41, and the product is determined to be a G crystal form.

Example 8

10 mg of the crystalline form G obtained in Example 3 and the crystalline form B obtained in Example 6 were weighed, mixed, and placed in a reaction flask, and an appropriate amount of n-heptane was added thereto, and beaten at 25 ° C for 5 days, and another 20 mg of the crystalline form G and Form B was placed in a reaction flask and beaten under the above conditions. After the completion of the beating, the sample was taken out to measure the X-ray diffraction pattern. The results showed that all of the three vials were obtained in the G crystal form, indicating that under this condition, the B crystal form was converted into the G crystal form, and the G crystal form was a more stable crystal form.

Experimental program

Exemplary experimental protocols for the crystalline shaped products of the present invention are provided below to demonstrate the advantageous or beneficial technical effects of the crystalline shaped products of the present invention. However, it should be understood that the following experimental schemes are merely illustrative of the present invention and are not intended to limit the scope of the invention. A person skilled in the art can make appropriate modifications or changes to the technical solutions of the present invention without departing from the spirit and scope of the present invention.

Experimental example 1

(1) The G crystal form obtained in Example 2 and the sample of the B crystal form product prepared in the patent application WO2016169421A1 (publication date 2016.10.27) were placed in an open position, and the stability of the sample under illumination (4500 Lux) was examined. . The sampling time was 5 days and 10 days, and the HPLC and XPRD results are shown in Table 1.

Test result 1:

Comparison of light stability between the G and B crystal samples of the compounds shown in Table 1 and formula (I)

(2) The G and B crystal product samples were placed in an open and closed position to investigate the stability of the samples under different temperature and humidity conditions, including 40 ° C - 75% RH, 60 ° C - 75% RH, 80 ° C. The sampling time was 7 days and 14 days, and the HPLC and XRPD results are shown in Table 2.

Test result 2:

Table 2 Comparison of temperature and humidity stability of G and B crystal samples of the compound represented by formula (I)

Test Conclusions:

From the stability investigation results of Tables 1 and 2, it was revealed that the G-form and the B-form of the compound represented by the formula (I) were exposed to light, and the X-form of the G crystal form and the B crystal form showed no change in the crystal form, but G. The purity of the crystal form is higher than that of the B crystal form, so the chemical stability of the G crystal form is better than that of the B crystal form under illumination conditions. Under the conditions of high temperature and high humidity, the XRPD of the G crystal form and the B crystal form show no change in the crystal form. The chemical purity changes are small.

Experimental example 2

The G crystal form was placed in an open state with a solid prepared by the method of Examples 40 and 41 in the patent application WO2016169421A1 (publication date 2016.10.27) (the solid was determined to be C crystal form by XRPD detection), and 40 ° C was observed. Stability under humidity RH 75%. The sampling time was 15 days, and the XRPD test results are shown in the attached drawings.

test results:

Figure 7 is an XRPD diagram of the G crystal type 0 day;

Figure 8 is an XRPD pattern of G crystal form placed at 40 ° C and relative humidity RH 75% for 15 days;

Figure 9 of the accompanying drawings is an XRPD pattern of a C crystal type 0 day;

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 10 is an XRPD pattern of a C crystal form placed at 40 ° C and a relative humidity of RH 75% for 15 days.

Test Conclusions:

The stability investigation results of Figure 7, Figure 8, Figure 9, and Figure 10 of the specification show that the G crystal form of the compound of the formula (I) is placed at 40 ° C and the relative humidity RH 75%, and the XRPD peak type is basically No change, G crystal form is stable; C crystal form is changed at 40 ° C, relative humidity RH 75%, XRPD peak shape changes, some peak characteristics disappear, crystallinity decreases; thus, at 40 ° C The physical stability of the G crystal form is better than that of the C crystal form under the condition that the relative humidity RH75% is placed.

Claims (8)

1. The G crystal form of the compound of the formula (I) is characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation, and the diffraction angle 2θ angle is 6.3, 7.2, 10.4, 11.0. , 12.1, 14.6, 16.4, 18.0, 19.2, 19.8, 22.5, 24.2, 26.4 and 28.9 have characteristic peaks, wherein the error range of each characteristic peak 2θ angle is ±0.2,

   
2. The crystal form of G according to claim 1, wherein an X-ray powder diffraction pattern represented by an angle of diffraction angle 2θ is obtained using Cu-Kα radiation, and the diffraction angle 2θ angle is 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90 and 30.16 have characteristic peaks, wherein the error range of the 2θ angle of each characteristic peak is ±0.2.
3. The G crystal form according to claim 2, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle is obtained using Cu-Kα radiation, and the diffraction angle 2θ angle is 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90, 30.16, 31.42, 32.70, 37.13 and 40.15 with characteristic peaks, wherein each The characteristic peak 2θ angle has an error range of ±0.2.
4. A crystalline form of G according to any one of claims 1 to 3, which has a melting point of from 210 ° C to 215 ° C, preferably from 210.3 ° C to 213.5 ° C, more preferably 210.54 ° C or 213.24 ° C.
5. A process for the preparation of the G crystalline form of the compound of formula (I) according to claim 1, wherein the process is selected from the group consisting of:

   (1) Method 1, the compound of the formula (I) is dissolved in an appropriate amount of solvent, crystallized, filtered and washed, and dried to obtain a target G crystal form selected from ester solvents and ethers. , a nitrile, an alcohol solvent, the ester solvent is selected from ethyl acetate or isopropyl acetate, and the ether solvent is selected from the group consisting of tetrahydrofuran, propylene glycol methyl ether or 1,4-dioxane, the nitrile The solvent is selected from the group consisting of acetonitrile, and the alcohol solvent is selected from the group consisting of isopropanol, ethanol or methanol;

   (2) Method 2, by dissolving the compound of the formula (I) in an appropriate amount of a good solvent, adding an anti-solvent, performing crystallization, filtering and crystallization, washing, and drying to obtain a target G crystal form, the good solvent It is selected from a halogenated hydrocarbon or ether solvent, the halogenated hydrocarbon solvent is selected from dichloromethane, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the anti-solvent is selected from aliphatic hydrocarbons. a solvent-like solvent, the aliphatic hydrocarbon solvent is selected from n-heptane; or the good solvent is selected from an ether solvent or an alcohol solvent, the ether solvent is selected from the group consisting of propylene glycol methyl ether, and the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol, the anti-solvent is selected from pure water;

   (3) Method 3, the compound of the formula (I) is placed in an appropriate amount of a solvent, beaten, filtered and washed, and dried to obtain a target crystal form G, the organic solvent being selected from the group consisting of:

   An ester solvent, an ether, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an alcohol, an aromatic hydrocarbon, a halogenated hydrocarbon solvent or a mixed solvent selected from the group consisting of ethyl acetate, isopropyl acetate or butyl acetate And an ether solvent selected from the group consisting of propylene glycol methyl ether, tetrahydrofuran or 1,4-dioxane, the alicyclic hydrocarbon solvent is selected from cyclohexane, and the aliphatic hydrocarbon solvent is selected from n-heptane. The aromatic hydrocarbon solvent is selected from cumene or xylene, the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol, and the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane.

   The mixed solvent is selected from a mixed solvent of an alcohol and an ether, a mixed solvent of two different alcohol solvents, or a mixed solvent of an alcohol solvent and water.
6. A pharmaceutical composition comprising the crystalline form of G according to any one of claims 1 to 4, characterized in that it comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
7. A pharmaceutical composition comprising the G crystalline form of any one of claims 1 to 4 or the pharmaceutical composition of claim 6, comprising one or more second therapeutically active agents, said second therapeutic activity The agent is selected from the group consisting of an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anticancer agent, an antiviral agent, a growth factor modulator, an immunomodulator, or an anti-hyperkine Proliferating compounds.
8. The G crystal form of the compound of the formula (I) according to any one of claims 1 to 4, the pharmaceutical composition according to claim 6 or the pharmaceutical composition according to claim 7 having an IDO-mediated color in the preparation of the treatment Use of a disease characterized by pathological characteristics of a metabolic pathway selected from the group consisting of cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder or AIDS; said cancer is selected from the group consisting of breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma or non-small cell lung cancer.

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