CN108884099A - A kind of crystal form of free alkali and preparation method thereof of imidazo isoindoles derivative - Google Patents
A kind of crystal form of free alkali and preparation method thereof of imidazo isoindoles derivative Download PDFInfo
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Abstract
The present invention relates to a kind of crystal forms of free alkali and preparation method thereof of imidazo isoindoles derivative.Specifically, B, C, D, E, F crystal form, chemical name is (S) -2- (4- the present invention relates to the A of compound shown in formula (I)（4- (4- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) ethyl alcohol.The invention further relates to be used to prepare A, B, C, D, the preparation method of E, F crystal form, in the application of pharmaceutical composition and A, B, C, D, E, F crystal form and pharmaceutical composition are preparing the purposes in disease of the treatment with the IDO tryptophan metabolic pathway pathological characteristics mediated, the A, B of formula (I) compound obtained by the present invention, C, D, E, F crystal form has good stability, and recrystallisation solvent low toxicity and low residue used, can be preferably applied to clinical treatment.
Description
The present invention relates to the A, B of (S) -2- (4- (4- (4- (fluoro- 5H- imidazo [5, the 1-a] iso-indoles -5- base of 6-) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) ethyl alcohol, C, D, E, F crystal form and preparation method thereof, it is in the application of pharmaceutical composition and the A, B, C, the purposes of D, E, F crystal form, its pharmaceutical composition in the disease for the tryptophan metabolic pathway pathological characteristics that there is IDO to mediate for preparation treatment.
Tumor biotherapy is the new treatment that treatment and prevention of tumour is carried out using modern biotechnology and its Related product, because of it safely, effectively, the features such as adverse reaction is low, as the 4th kind of mode of the oncotherapy after operation, radiotherapy, chemotherapy, antitumor effect is obtained by transferring the natural immunology defense (such as the tumor immune escape mechanism for inhibiting IDO to mediate) of host or giving the very strong substance of naturally-produced targeting.
Indoles amine-pyrroles -2,3- dioxygenase (Indoleamine-pyrrole-2,3-dioxygenase, it IDO) is a kind of iron content ferroheme monomeric protein, it is made of 403 amino acid residues, the α-helixstructure domain folded including two, big structure domain include catalytic pocket, and with IDO can occur for substrate the effects of hydrophobic in catalytic pocket.IDO is the enzyme for being catalyzed tryptophan transfer and turning to formylkynurenine, people and other mammals (rabbit, mouse) are widely distributed in the tissue in addition to liver, it is the rate-limiting enzyme that tryptophan catabolism can be uniquely catalyzed other than liver, and tryptophan is amino acid necessary to cell maintains activation and is proliferated, and constitutes the indispensable important component of protein.IDO and the cytokine profiles such as interferon (interferon, IFN), interleukins (interleukin, IL), tumor necrosis factor are in close relations, they can activate IDO under certain condition.And there are the horizontal very sensitive point of adjustment of a tryptophan in the cell cycle of T- cell, on the one hand, IDO makes local tryptophan depletion, causes T- cells arrest in the G1 interim phase, to inhibit the proliferation of T cell；On the other hand, the primary product cynruin that IDO is catalyzed that tryptophan metabolism generates causes Cellular Oxidation agent and antioxidant to change and induces T- Apoptosis by Mediated by Free Radicals, this is the intrinsic immunosuppression mechanism for being present in body.At present a large number of studies show that IDO higher expression in leukaemia cell, keeps local T cell proliferation suppressed, the immune response for inhibiting T- cell-mediated makes the transduction of T- cell activation signal be obstructed, thus the attack of mediate tumor cell escape immune system.It has been found that most of mankind's tumor groups express IDO with becoming second nature.Therefore, IDO is the target of the cancer immunotherapy of a tool potentiality.
The inhibitor patent application of disclosed selective depression IDO includes WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834 etc..
IDO inhibitor has a good application prospect as drug in pharmaceuticals industry, the applicant is in patent application PCT/CN2016/079054 (WO2016169421A1, publication date 2016-10-27) provide a kind of structure novel high-efficiency low-toxicity selective IDO inhibitor compound, has the effect of excellent and effect, in especially excellent medicine generation, absorbs activity, entitled (the S) -2- of its chemistry (4- (4- (4- (fluoro- 5H- imidazo [5, the 1-a] iso-indoles -5- base of 6-) piperidines
- 1- base) phenyl) -1H- pyrazol-1-yl) ethyl alcohol, structure is as follows
Crystalline structure as medicinal active ingredient often influences the chemical stability of the drug, and the difference of crystal form, preparation method and condition of storage is likely to result in the variation of the crystalline structure of compound, sometimes can also be along with the crystal form for generating other forms.In general, unbodied drug products do not have well-regulated crystalline structure, and often poor with other defects, such as product stability, crystallization is thinner, and it is more difficult to filter, and easily agglomerate, poor fluidity etc., these differences often lead to difficulty when production is amplified.The stability of existing crystal form is to be improved.Therefore, it is necessary for improving each side's surface properties of compound, it would be desirable to which it is higher and have the stable novel crystal forms of good chemical that crystal form purity is found in further investigation.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of free alkali (S) -2- of imidazo isoindoles derivative (4- (4- (4- (fluoro- 5H- imidazos [5 of 6-, 1-a] iso-indoles -5- base) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) and ethyl alcohol A, B, C, D, E, F crystal form, the crystallization has good stability of crystal form and chemical stability, and recrystallisation solvent low toxicity and low residue used, can be preferably applied for clinic.
Technical scheme is as follows:
The present invention provides a kind of A crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 6.3,7.7,9.0,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.4,19.5,19.7,20.9,21.2,21.5,21.7,22.1, there is characteristic peak at 24.3,25.6 and 28.9, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of A crystal form of compound shown in formula (I), it is characterised in that: the A crystal form is 6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5,32.2,32.5,34.6, there is characteristic peak at 36.1,37.3 and 39.0, the error range of 2 θ is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound A crystal form shown in formula (I) comprising:
Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target A crystal form can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferably methanol；Be beaten temperature be selected from 30 DEG C~solvent boiling point temperature, preferably 50 DEG C.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of B crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 6.2,7.6,8.7,10.0 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.121.5,22.3,24.3,25.3,26.4, there is characteristic peak at 27.3,28.9 and 31.7, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of B crystal form of compound shown in formula (I), it is characterised in that: the B crystal form is 6.2,6.7,7.6,8.7,10., 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3, there is characteristic peak at 26.4,27.3,28.9 and 31.7, the error range of 2 θ is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound B crystal form shown in formula (I) comprising:
Compound shown in formula (I) is dissolved in solvent, crystallization by method one, and target B crystal form can be obtained after filtering, drying, and the solvent is selected from halogenated hydrocarbon solvent, preferably methylene chloride；
Compound shown in formula (I) is added in organic solvent, is beaten by method two, and filtering for crystallizing is simultaneously washed, and target B crystal form can be obtained after dry, the organic solvent is selected from:
Nitrile, esters, halogenated hydrocarbon, ethers, alcohols, nitroparaffin hydro carbons, alcohols and water mixed solvent, the nitrile solvents are selected from acetonitrile, the esters solvent is selected from ethyl acetate, the halogenated hydrocarbon solvent is selected from methylene chloride, the ether solvent is selected from tetrahydrofuran, and the alcohols solvent is selected from normal propyl alcohol, and the nitroparaffin hydrocarbon solvent is selected from nitromethane, the mixed solvent of the alcohols and water is selected from the mixed solvent of isopropanol and water, -95% isopropanol of preferably 5% water；The mashing temperature be selected from room temperature~solvent boiling point temperature, preferably 50 DEG C, preferred 15-25 DEG C of the room temperature, more preferable 25 DEG C.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of C crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, obtains the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4, there is characteristic peak at 27.3 and 28.3, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of C crystal form of compound shown in formula (I), it is characterised in that: the C crystal form is 4.1,6.0,6.3,6.5,7.6,8.4,8.7), 9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8 there is characteristic peak at 30.0 and 31.6, the error range of 2 θ is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound C crystal form shown in formula (I) comprising:
Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target C crystal form can be obtained after dry, and the organic solvent is ketones solvent, and the ketones solvent is selected from acetone；The mashing temperature be selected from room temperature~solvent boiling point temperature, preferably 50 DEG C, preferred 15-25 DEG C of the room temperature, more preferable 25 DEG C.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of form D of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, obtains the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7, there is characteristic peak at 27.6 and 29.2, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of form D of compound shown in formula (I), it is characterised in that: the form D is 15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6, there is characteristic peak at 29.2,30.4 and 31.9, the error range of 2 θ is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound form D shown in formula (I) comprising:
Compound shown in formula (I) is set and is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target form D can be obtained after dry, and the organic solvent is selected from aromatic hydrocarbon solvent, preferably cumene or dimethylbenzene；The mashing temperature be selected from 30 DEG C~solvent boiling point temperature, preferably 50 DEG C.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of crystal form E of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 18.2,18.7,19.2,20.1,21.7,22.8, there is characteristic peak at 24.6,26.7,27.7 and 29.2, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound crystal form E shown in formula (I) comprising:
Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and the crystal form E of target can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferred alcohol；The mashing temperature be selected from 30 DEG C~solvent boiling point temperature, preferably 50 DEG C.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of F crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 18.7,19.5,20.2,21.5,22.0,22.6,24.4,25.6, there is characteristic peak at 26.6,27.6,29.2 and 32.0, the error range of 2 θ is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of preparation method of compound F crystal form shown in formula (I) comprising:
Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target F crystal form can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferably 2- propyl alcohol；The mashing temperature be selected from 30 DEG C~solvent boiling point temperature, preferably 50 DEG C.
The invention further relates to a kind of pharmaceutical composition, the A crystal form of described pharmaceutical composition compound shown in formula (I), B crystal form, C crystal form, form D, crystal form E, F crystal form and pharmaceutically acceptable carrier, diluent or excipient are formed.
The invention further relates to the A crystal form of compound shown in formula (I), B crystal form, C crystal form, form D, crystal form E, the pharmaceutical compositions of F crystal form, it is characterized in that, described pharmaceutical composition also includes one or more second therapeutically active agents, and second therapeutically active agent is selected from: anti-inflammatory agent, Matrix Metalloproteinase Inhibitors, lipoxidase inhibitor, cytokine antagonist, immunosuppressor, anticancer agent, antivirotic, growth factor regulator, immunomodulator or anti-angiogenic anti-hyperproliferative compound.
The invention further relates to a kind of methods for preparing aforementioned pharmaceutical compositions, it is characterized in that, the step of being mixed the method includes the A crystal form of the compound as shown in formula (I), B crystal form, C crystal form, form D, crystal form E, F crystal form with pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the A crystal forms of compound shown in formula (I), B crystal form, C crystal form, form D, crystal form E, F crystal form or A, B, C, D, E, purposes of the pharmaceutical composition of F crystal form in the disease for the tryptophan metabolic pathway pathological characteristics that there is IDO to mediate for preparation treatment, the disease is selected from cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS, the cancer is selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, incidence is swollen Tumor, leukaemia, lymthoma, myeloma or non-small cell lung cancer.
By X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric analyzer (TGA) or Dynamic Water adsorption instrument (DVS) etc. to the A of compound shown in acquired formula (I), B, C, D, E, F crystal form carry out structure determination, crystal form research etc..
The method of crystallization of the present invention has room temperature crystallization, cooling crystallization, solvent flashing crystallization, is added crystal seed induction crystallization etc., and the temperature of the cooling is selected from 40 DEG C hereinafter, it is preferred that -10 DEG C to 40 DEG C, can also stir in the Crystallization Process.
Detailed description of the invention
Starting material used in crystal form preparation method of the present invention can be compound shown in any form of formula (I), and concrete form includes but is not limited to: amorphous, any crystal form etc..
In the description and claims of this application, unless otherwise stated, Science and Technology noun used herein has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, the definition and explanation of part relational language is provided below.In addition, with the definition of term provided herein and being construed to quasi- when the definition of term provided herein and explanation and the inconsistent normally understood meaning of those skilled in the art.
" mashing " of the present invention refers to that dissolubility is poor in a solvent using substance, but the impurity method that the good characteristic of dissolubility is purified in a solvent, and mashing purification can be with discoloration, change crystal form or a small amount of impurity of removal.
It is of the present invention it is " halogenated " refer to by " halogen atom " replace, " halogen atom " refers to fluorine atom, chlorine atom, bromine atom, iodine atom etc..
" hydroxyl, cyano, nitro etc. " of the present invention refers to-OH ,-CN ,-NO2Equal groups.
" C of the present invention1-6The alkyl containing 1-6 carbon atom of alkyl " expression linear chain or branched chain, specific example includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2- methyl butyl, neopentyl, 1- ethyl propyl, n-hexyl, isohesyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3, 3- dimethylbutyl, 2, 2- dimethylbutyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2, 3- dimethylbutyl, 2- ethyl-butyl, 1, 2- dimethyl propyl etc..
" esters solvent " of the present invention refers to the conjugate for the lower alcohol that the rudimentary organic acid that carbon atom quantity is 1 to 4 and carbon atom quantity are 1 to 6, and specific example includes but is not limited to: ethyl acetate, acetic acid
Isopropyl ester or butyl acetate.
" ether solvent " of the present invention refers to the chain compound or cyclic compound that containing ehter bond-O- and carbon atom number is 1 to 10, and specific example includes but is not limited to: propylene glycol monomethyl ether, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane.
" alcohols solvent " of the present invention refers to one or more " hydroxyl " substitution " C1-6Group derived from one or more hydrogen atoms on alkyl ", " hydroxyl " and " C1-6As defined hereinabove, specific example includes but is not limited to alkyl ": methanol, ethyl alcohol, normal propyl alcohol or 2- propyl alcohol.
" aromatic hydrocarbon solvent " of the present invention refers to the conjugated system in molecule with closed hoop, and п electron number meets the carbocyclic compound of Huckel's rule and its general name of derivative, specific example include but is not limited to: cumene or dimethylbenzene.
" halogenated hydrocarbon solvent " of the present invention refers to one or more " halogen atom " substitution " C1-6Group derived from one or more hydrogen atoms on alkyl ", " halogen atom " and " C1-6As defined hereinabove, specific example includes but is not limited to alkyl ": chloromethanes, methylene chloride, chloroform or carbon tetrachloride.
" nitrile solvents " of the present invention refer to one or more " cyano " substitution " C1-6Group derived from one or more hydrogen atoms on alkyl ", " cyano " and " C1-6As defined hereinabove, specific example includes but is not limited to alkyl ": acetonitrile or propionitrile.
" nitroparaffin hydrocarbon solvent " of the present invention refers to one or more " nitro " substitution " C1-6Group derived from one or more hydrogen atoms on alkyl ", " nitro " and " C1-6As defined hereinabove, specific example includes but is not limited to alkyl ": nitromethane.
" mixed solvent " of the present invention refers to the solvent that one or more different types of organic solvents mix according to a certain percentage, or the solvent that organic solvent and water mix according to a certain percentage, the certain proportion is 0.05:1~1:0.05, preferably 19:1；The mixed solvent is preferably the mixed solvent of alcohols solvent and water；The mixed solvent of the alcohols solvent and water is preferably the mixed solvent of isopropanol and water, and the alcohols solvent is as hereinbefore defined.
" X-ray powder diffraction collection or XRPD " of the present invention refer to according to bragg's formula 2d sin θ=n λ (in formula, λ be X-ray wavelength,The series n of diffraction is any positive integer, generally take first-order diffraction peak, n=1), when X-ray is with the sweep angle θ (complementary angle of incidence angle, also known as Bragg angle) when being incident on a certain atomic plane with d lattice plane spacing of crystal or partial crystals sample, it is just able to satisfy Bragg equation, to measure this group of X-ray powder diffraction figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers in sample heating or thermostatic process, temperature difference, differential heat flow between measurement sample and reference substance, to characterize all physical changes related with fuel factor and chemical change, the transformation information of sample is obtained.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree.
" interplanar distance or interplanar distance (d value) " of the present invention refers to that space lattice selects the unit vector a of the two neighboring lattice point of connection of 3 irrelevancy rows, b, c, dot matrix is divided into juxtaposed parallelepiped unit, referred to as interplanar distance by them.Space lattice is divided according to determining parallelepiped unit line, is obtained a set of
Rectilinear grid, referred to as space lattice or lattice.Dot matrix and lattice are respectively the different crystal faces with the periodicity of the Points And lines of geometry reflection crystal structure, and interplanar distance (the distance between parallel crystal face of i.e. adjacent two) is different；Unit isOr angstrom.
The invention further relates to, the A including formula (I) compound represented, B, C, D, E, F crystal form, and the pharmaceutical composition of optional one or more pharmaceutical carriers and/or diluent.Pharmaceutically acceptable any dosage form can be made in described pharmaceutical composition.For example, A of the invention, B, C, D, E, F crystal form or pharmaceutical preparation can be formulated as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection, injection sterile powder and concentrated solution for injection), suppository, inhalant or spray.
In addition, described pharmaceutical composition of the invention can also be with any suitable administration mode, such as the modes such as oral, parenteral, rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for when being administered orally, described pharmaceutical composition to can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation also may include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the pharmaceutical preparation can be made into injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, the conventional method in existing pharmaceutical field is can be used to be produced in described pharmaceutical composition.When preparing injection, additives can be added without in the pharmaceutical preparation, suitable additives can also be added according to the property of drug.When being used for rectally, the pharmaceutical preparation can be made into suppository etc..When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred aspects, A of the invention, B, C, D, E, F crystal form is to treat and/or prevention effective dose is present in pharmaceutical composition or drug.In certain preferred aspects, A of the invention, B, C, D, E, F crystal form are present in pharmaceutical composition or drug in the form of unit dose.
The A of formula (I) compound of the present invention, B, C, D, E, F crystal form can be administered alone, or are used in combination with one or more second therapeutic agents.Therefore, in certain preferred aspects, the pharmaceutical composition also contains one or more second therapeutic agents.In certain preferred aspects, the second therapeutic agent is selected from: anti-inflammatory agent, Matrix Metalloproteinase Inhibitors, lipoxidase inhibitor, cytokine antagonist, immunosuppressor, anticancer agent, antivirotic, growth factor regulator, immunomodulator or anti-angiogenic anti-hyperproliferative compound.
Each ingredient (for example, A of the invention, B, C, D, E, F crystal form and second therapeutic agent) to be combined can be administered simultaneously or successively sequentially separate medication.For example, A, B, C of the present invention can apply, D, E, prior to, concurrently with, or after F crystal form or its stereoisomer, application second therapeutic agent.In addition, each ingredient to be combined can also be administered in combination by same dosage form or in the form of separated different preparations.
The A of formula (I) compound of the present invention, B, C, D, E, F crystal form can be used for preparing treatment and/or prevention by the purposes in the disease of the IDO tryptophan metabolism mediated.Therefore, the application further relates to, the A of formula (I) compound of the present invention, B, C, D, E, and F crystal form is used to prepare the purposes of drug, and the drug is used for the relevant disease of tryptophan metabolism for treating and/or preventing to be mediated in subject by IDO.In addition, the application further relates to, a method of inhibiting the relevant disease of tryptophan metabolism mediated by IDO comprising the A of the formula (I) compound of the present invention for the treatment of and/or prevention effective dose is applied to subject with this need, B, C, D, E, F crystal form or pharmaceutical composition of the invention.
In certain preferred aspects, the disease is the related disease of tryptophan metabolism mediated by IDO, is selected from: cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape or AIDS；The cancer is selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma or non-small cell lung cancer.
Advantageous effect of the invention
Compared with prior art, technical solution of the present invention has the advantage that
(1) compound A shown in formula of the invention (I), B, C, D, E, F crystal form does not contain or only containing the residual solvent of lower content, meets the limitation requirement in relation to medical product residual solvent as defined in National Pharmacopeia, thus crystallization of the invention can be used preferably as medicating active ingredients.
(2) research has shown that, the A of compound shown in formula (I) of the present invention, B, C, D, E, F crystal form purity is higher, under conditions of illumination, high temperature, high humidity crystal form do not change, stability of crystal form it is good；The variation of HPLC purity is small, chemical stability is high；Compound A, B, C, D, E, F crystal form shown in the formula (I) that technical solution of the present invention obtains can satisfy the medicinal requirements of production and transport storage, and stable processing technique repeats controllably, can adapt in industrialized production.
Fig. 1 is the XRPD map of compound A crystal form shown in formula (I)；
Fig. 2 is the XRPD map of compound B crystal form shown in formula (I)；
Fig. 3 is the XRPD map of compound C crystal form shown in formula (I)；
Fig. 4 is the XRPD map of compound form D shown in formula (I)；
Fig. 5 is the XRPD map of compound crystal form E shown in formula (I)；
Fig. 6 is the XRPD map of compound F crystal form shown in formula (I)；
Fig. 7 is the DSC map of compound A crystal form shown in formula (I)；
Fig. 8 is the DSC map of compound B crystal form shown in formula (I)；
Fig. 9 is the DSC map of compound C crystal form shown in formula (I)；
Figure 10 is the DSC map of compound form D shown in formula (I)；
Figure 11 is the DSC map of compound crystal form E shown in formula (I)；
Figure 12 is the DSC map of compound F crystal form shown in formula (I)；
Figure 13 is that the DVS of compound B crystal form shown in formula (I) recycles map for the first time；
Figure 14 is that the DVS of compound B crystal form shown in formula (I) recycles map for the second time；
Figure 15 is 0 day XRPD of B crystal form figure；
Figure 16 is the XRPD figure after B crystal form is placed 15 days under the conditions of 40 DEG C, relative humidity RH75%；
Figure 17 is 0 day XRPD of C crystal form figure；
Figure 18 is the XRPD figure after C crystal form is placed 15 days under the conditions of 40 DEG C, relative humidity RH75%.
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is only used to illustrate the technical scheme of the present invention, and non-limiting the spirit and scope of the invention.
Test the test condition of instrument:
1, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model: Mettler Toledo DSC 3+STARe System
Purge gass: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 20-250
2, X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
(1) instrument model: Bruker D8Discover A25X- ray powder diffractometer
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 10-48 °
Voltage: 40KV, electric current: 40mA
(2) instrument model: Rigaku UltimalV X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha ray (λ=1.5418)
Scanning mode: the θ of θ/2, scanning range: 3-45 °
Voltage: 40KV, electric current: 40mA
3, Dynamic Water adsorption instrument (Dynamic Vapour Sorption, DVS)
Instrument model: DVS advantage
Temperature: 25 DEG C
Solvent: water
Humidity variation: 0-95-0-95-0%RH, dm/dt=0.002
Comparative example, (S) -2- (4- (4- (4- (fluoro- 5H- imidazo [5 of 6-, 1-a] iso-indoles -5- base) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) and ethyl alcohol (preparation of compound shown in formula (I) can refer to the preparation method in the embodiment 40,41 in patent application PCT/CN2016/079054 (WO2016169421A1 (publication date 2016-10-27))) preparation
(1) two trifluoroacetate (compound 1g) of the fluoro- 5- of 6- (piperidin-4-yl) -5H- imidazo [5,1-a] iso-indoles (referring to the preparation method in the embodiment 1 in patent application PCT/CN2016/079054 (WO2016169421A1 (publication date 2016-10-27)))
The first step
4- ((the bromo- 6- fluorobenzene of 2-) (hydroxyl) methyl) piperidines -1- t-butyl formate 1c
By lithium diisopropylamine (32.5mL, it 65.0mmol) is added in tetrahydrofuran (50mL), prefabricated bromo- 3- fluorobenzene 1a (8.75g, the 50.0mmol of 1- is added dropwise in -78 DEG C, tetrahydrofuran solution 25mL) stirs 1 hour in -78 DEG C.The tetrahydrofuran solution of prefabricated 4- formyl piperidine -1- t-butyl formate 1b (8.75g, 50.0mmol, 25mL) is added dropwise then at -78 DEG C, is stirred 1 hour in -78 DEG C.After reaction, in -78 DEG C of dropwise addition methanol (25mL) quenching reactions, reaction solution is concentrated under reduced pressure, gained residue is purified with eluant, eluent system (n-hexane and ethyl acetate) with silica gel column chromatography, obtain compound 1c (16.3g, yellow syrup solid, yield 84.0%).
MS m/z(LC-MS):332.0[M-56]
Second step
4- ((the bromo- 6- fluorophenyl of 2-) (p-toluenesulfonyl oxygroup) methyl) piperidines -1- t-butyl formate 1d
Compound 1c (15g, 38.63mmol) is dissolved in tetrahydrofuran (350mL), is added portionwise sodium hydride (3.09g, 77.26mmol), stirring to no gas is released.The tetrahydrofuran solution of prefabricated paratoluensulfonyl chloride (8.10g, 42.49mmol, 250mL) is added dropwise, stirs 30 minutes, return stirring 4 hours, is stirred 48 hours in 70 DEG C at room temperature.After reaction, it is cooled to 0 DEG C, water (50mL) quenching reaction is added dropwise, is added saturated sodium chloride solution (50mL), liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, gained residue is purified with eluant, eluent system (n-hexane and ethyl acetate) with silica gel column chromatography, obtain compound 1d (6.6g, faint yellow sticky solid, yield: 31.80%).
MS m/z(LC-MS):314.0/316.0[M-56-TsO]
Third step
4- ((the bromo- 6- fluorobenzene of 2-) (1H- imidazoles -1- base) methyl) piperidines -1- t-butyl formate 1e
By imidazoles (12.5g, 184.3mmol) it is dissolved in N, in dinethylformamide (50mL), sodium hydride (7.40g, 184.3mmol) is added portionwise, it is stirred at room temperature 1 hour, the N of prefabricated compound 1d (10.0g, 18.43mmol, 20mL) is added dropwise, dinethylformamide solution stirs 12 hours in 100 DEG C.After reaction, ethyl acetate (300mL) is added, is washed (150mL × 3) with saturated sodium chloride solution, organic phase is dry with anhydrous sodium sulfate
Dry, filtering, filtrate decompression concentration purifies gained residue with silica gel column chromatography with eluant, eluent system (methylene chloride and methanol), obtains compound 1e (1.90g, viscous brown solid, yield: 23.5%).
MS m/z(LC-MS):438.1/440.1[M+1]
4th step
4- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) piperidines -1- t-butyl formate 1f
By compound 1e (1.90g, 4.33mmol), N, N- dicyclohexylmethylamine (1.35g, 6.93mmol), triphenyl phosphorus (908mg, 3.46mmol) is added in n,N-Dimethylformamide solution (10mL), under argon atmospher, it is added palladium acetate (390mg, 1.74mmol), is stirred 4.5 hours in 100 DEG C.After reaction, reaction solution is concentrated under reduced pressure, gained residue is purified with eluant, eluent system (n-hexane and ethyl acetate) with silica gel column chromatography, obtains compound 1f (1.30g, clear yellow viscous solid, yield: 83.8%).
MS m/z(LC-MS):358.1[M+1]
5th step
Two trifluoroacetate 1g of 6- fluoro- 5- (piperidin-4-yl) -5H- imidazo [5,1-a] iso-indoles
Compound 1f (1.30g, 3.64mmol) is dissolved in methylene chloride (5mL), is added dropwise trifluoroacetic acid (5mL), is stirred 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, is obtained crude Compound 1g (1.77g, viscous brown solid), product directly carries out next step reaction without further purification.
MS m/z(LC-MS):258.3[M+1]
(2) 4- (4- bromophenyl) -1- (2- ((tetrahydro -2H- pyrans -2- base) oxygroup) ethyl) -1H- pyrazoles (compound 40a) (referring to the preparation method in CN104755477A (publication date 2015.07.01) specification page 44)
(3) (S) -2- (4- (4- (4- (fluoro- 5H- imidazo [5 of 6-, 1-a] iso-indoles -5- base) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) ethyl alcohol (compound 41, PCT/CN2016/079054 (preparation method in WO2016169421A1 (publication date 2016-10-27) embodiment 40,41)
The first step
By 4- (4- bromophenyl) -1- (2- ((tetrahydro -2H- pyrans -2- base) oxygroup) ethyl) -1H- pyrazoles 40a (14.8g, 42mmol), 6- fluoro- 5- (piperidin-4-yl) -5H- imidazo [5,1-a] iso-indoles 17a (13.9g, N 42mmol) is added, in dinethylformamide (300mL), tetrafluoro boric acid tri-tert-butylphosphine (1.863g is added, 64.5mmol) and potassium phosphate (35g, 168mmol), argon gas is replaced three times.It is added tris(dibenzylideneacetone) dipalladium (2.92g, 3.19mmol), argon gas displacement is primary, and reaction solution is warming up to 110 DEG C, is stirred to react 2 hours.After reaction, reaction solution is filtered, filtrate decompression concentration removes N, dinethylformamide purifies gained residue with silica gel column chromatography with eluant, eluent system (methylene chloride and methanol), obtains compound 40b (6.38g, grey grease, yield: 29%).
Second step
Compound 40b (9g, 17.1mmol) is dissolved in methanol (100mL), is added concentrated hydrochloric acid (12M, 5.7mL), reaction solution rises to 45 DEG C, is stirred to react 1 hour.After reaction, reaction solution is cooled to room temperature, it is 8 that saturated sodium carbonate tune reaction solution pH, which is added, filtering, filtrate decompression concentration purifies gained residue with silica gel column chromatography with eluant, eluent system (methylene chloride and methanol), obtains compound 40c (5.2g, yellow solid, yield: 65%).
Third step
Prepared by compound 40c (1.4g, 3.16mmol) progress chirality (separation condition: chiral preparatory column Superchiral S-AS (Chiralway), 2cm I.D. × 25cm Length, 5 μm；Mobile phase: CO2/ MeOH/DEA=60/40/0.05 (v/v/v), flow velocity: 50mL/min), its respective components is collected, is concentrated under reduced pressure, compound 40 (630mg, yellow solid) and compound 41 (652mg, yellow solid) are obtained, wherein compound 41 is measured as crystal form through XRPD, the crystal form is 4.1,6.0,6.3,6.5,7.6,8.4,8.7), 9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3 , have characteristic peak at 28.3,28.8,30.0 and 31.6, which is C crystal form.
Embodiment 1
Crude compound shown in 50mg formula (I) is added in reaction flask, is added methanol (50-100 μ L), 50 DEG C of constant temperature are stirred 5 days, are filtered, vacuum drying, obtain white to pale yellow powder.The XRPD map of the crystallized sample is shown in that Fig. 1, DSC map are shown in Fig. 7, and for endothermic peak near 217.9 DEG C, initial fusion temperature is 216.8 DEG C, this crystal form is defined as A crystal form, characteristic peak positions are as shown in table 1 below:
Table 1, A crystal form characteristic peak
Embodiment 2
Crude compound shown in 50mg formula (I) is added in reaction flask, is added acetonitrile (50-100 μ L), 25 DEG C of constant temperature are stirred 5 days, filtering, then 25 DEG C of vacuum drying, obtain white to pale yellow powder.The XRPD of the crystallized sample is shown in that Fig. 2, DSC spectrogram are shown in Fig. 8, and endothermic peak is near 210.5 DEG C, initial fusion temperature is 210.3 DEG C, this crystal form is defined as B crystal form, which may determine that without the crystallization water by the DVS map of Figure 13 and Figure 14, characteristic peak positions are as shown in table 2 below:
Table 2, B crystal form characteristic peak
The B crystal form sample obtained in 50 DEG C of ethyl acetate solvents is through 2 θ of XRPD detection of diffracted angle in 6.27,7.61,8.67,9.88,10.20,11.01,11.40,11.93,12.44,14.49,15.40,16.31,16.88,17.61,18.35,18.78,19.19,19.71,20.77,21.40,22.38,24.26,25.39,26.09,27.36,28.84 with 31.73 at have characteristic peak.
The B crystal form sample obtained in 50 DEG C of tetrahydrofuran solvents is through 2 θ of XRPD detection of diffracted angle in 6.27,7.62,8.68,9.88,10.18,11.18,11.95,12.15,14.46,15.16,16.34,17.58,18.33,18.75,19.13,19.83,20.78,21.42,22.33,24.25,25.14,26.51,27.38,28.86 with 31.66 at have characteristic peak.
Embodiment 3
Crude compound shown in 50mg formula (I) is added in reaction flask, is added acetone (1.5mL), is warming up to 80 DEG C, heat preservation after ten minutes, then is down to 20 DEG C, filters, dry solid.The crystallized sample is through 2 θ of XRPD detection of diffracted angle 6.27,7.60,8.67,9.88,10.20,11.01,11.40,11.92,12.45,14.49,15.40,16.31,16.88,17.61,18.35,18.78,19.19,19.71,20.77,21.40,22.38,25.40, there is characteristic peak at 26.10,27.38,28.85 and 31.72, determines that product is B crystal form.
Embodiment 4
Crude compound shown in 50mg formula (I) is added in reaction flask, it is added acetone (50-100 μ L), 25 DEG C of constant temperature are stirred 5 days, filtering, then 25 DEG C of vacuum drying, white is obtained to pale yellow powder, the XRPD of the crystallized sample is shown in that Fig. 3, DSC spectrogram are shown in Fig. 9, endothermic peak is near 210.1 DEG C, initial fusion temperature is 209.5 DEG C, this crystal form is defined as C crystal form, characteristic peak positions are as shown in table 3 below:
Table 3, C crystal form characteristic peak
The C crystal form sample obtained in 25 DEG C of acetone solvents is through 2 θ of XRPD detection of diffracted angle in 5.99,6.24,7.53,8.30,8.95,9.94,10.64,12.00,12.42,15.92,16.56,17.81,18.17,18.71,19.30,19.76,20.48,21.26,21.54,22.04,22.47,24.17,25.00,26.29,26.61,27.32,28.74 with 31.47 at have characteristic peak.
Embodiment 5
Crude compound shown in 50mg formula (I) is added in reaction flask, is added cumene (50-100 μ L), 50 DEG C of constant temperature are stirred 5 days, are filtered, vacuum drying, obtain white to pale yellow powder.The XRPD of the crystallized sample is shown in that Fig. 4, DSC map are shown in Figure 10, and for endothermic peak near 212.9 DEG C, initial fusion temperature is 211.1 DEG C, this crystal form is defined as form D, characteristic peak positions are as shown in table 4 below:
Table 4, form D characteristic peak
Embodiment 6
Crude compound shown in 50mg formula (I) is added in reaction flask, is added ethyl alcohol (50-100 μ L), 50 DEG C of constant temperature are stirred 5 days, are filtered, vacuum drying, obtain white to pale yellow powder.The XRPD of the solid sample is shown in that Fig. 5, DSC map are shown in Figure 11, and for endothermic peak near 211.5 DEG C, initial fusion temperature is 210.2 DEG C, this crystal form is defined as crystal form E, characteristic peak positions are as shown in table 5 below:
Table 5, crystal form E characteristic peak
Embodiment 7
Crude compound shown in 50mg formula (I) is added in reaction flask, is added 2- propyl alcohol (50-100 μ L), 50 DEG C of constant temperature are stirred 5 days, are filtered, vacuum drying, obtain white to pale yellow powder.The XRPD of the solid sample is shown in that Fig. 6, DSC map are shown in Figure 12, and for endothermic peak near 208.6 DEG C, initial fusion temperature is 206.9 DEG C, this crystal form is defined as F crystal form, characteristic peak positions are as shown in table 6 below:
Table 6, F crystal form characteristic peak
Experimental program
The exemplary tests scheme of crystalline product of the invention presented below, to show the favorable activity or advantageous effects of crystalline product of the present invention.It is understood that following testing programs are only the example to the content of present invention, rather than limiting the scope of the invention.Those skilled in the art can carry out modifications or changes appropriate to technical solution of the present invention, without departing from the spirit and scope of the invention under the introduction of this specification.
The study on the stability of experimental example 1, B crystal form and C crystal form
B crystal form and C crystal form sample opening are divided into placement, the stability of sample under the conditions of 40 DEG C of investigation, relative humidity RH75%, investigating sample time is 15 days.
Experimental result:
Figure of description Figure 15 is 0 day XRPD of B crystal form figure；
Figure of description Figure 16 is the XRPD figure after B crystal form is placed 15 days under the conditions of 40 DEG C, relative humidity 75%；
Figure of description Figure 17 is 0 day XRPD of C crystal form figure；
Figure of description Figure 18 is the XRPD figure after C crystal form is placed 15 days under the conditions of 40 DEG C, relative humidity 75%.
Experiment conclusion:
As the study on the stability of Figure of description Figure 15, Figure 16, Figure 17, Figure 18 the result shows that the B crystal form of compound shown in formula (I) is under conditions of 40 DEG C, relative humidity RH75% are placed, XRPD peak type does not change substantially, stable crystal form；Under conditions of 40 DEG C, relative humidity RH75% are placed, XRPD peak type is changed C crystal form, and part peak type feature disappears, and crystallinity reduces；It can be seen that the physical stability of B crystal form is better than C crystal form under conditions of 40 DEG C of RH75% are placed.
Claims (20)
- The A crystal form of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 6.3,7.7,9.0,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.4,19.5,19.7,20.9,21.2,21.5,21.7,22.1, there is characteristic peak at 24.3,25.6 and 28.9, the error range of 2 θ is ± 0.2
- A crystal form as described in claim 1, it is characterised in that: the A crystal form is 6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5, there is characteristic peak at 32.2,32.5,34.6,36.1,37.3 and 39.0, the error range of 2 θ is ± 0.2.
- The preparation method of the described in any item A crystal forms of claim 1-2, which is characterized in that the method are as follows:Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target A crystal form can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferably methanol.
- The B crystal form of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 6.2,7.6,8.7,10.0 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1 21.5,22.3,24.3,25.3,26.4, there is characteristic peak at 27.3,28.9 and 31.7, the error range of 2 θ is ± 0.2
- B crystal form as claimed in claim 4, it is characterised in that: the B crystal form is 6.2,6.7,7.6,8.7,10., 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3, there is characteristic peak at 26.4,27.3,28.9 and 31.7, the error range of 2 θ is ± 0.2.
- The preparation method of the described in any item B crystal forms of claim 4-5, is selected from:Compound shown in formula (I) is dissolved in solvent, crystallization by method one, filtering, and target B crystal form can be obtained after dry, and the solvent is selected from halogenated hydrocarbon solvent, preferably methylene chloride；Compound shown in formula (I) is added in organic solvent, is beaten by method two, and filtering for crystallizing is simultaneously washed, and target B crystal form can be obtained after dry, the organic solvent is selected from:Nitrile, esters, halogenated hydrocarbon, ethers, alcohols, nitroparaffin hydro carbons or alcohols and water mixed solvent, the nitrile solvents are selected from acetonitrile, the esters solvent is selected from ethyl acetate, the halogenated hydrocarbon solvent is selected from methylene chloride, the ether solvent is selected from tetrahydrofuran, the alcohols solvent is selected from normal propyl alcohol, and the nitroparaffin hydrocarbon solvent is selected from nitromethane, and the mixed solvent of the alcohols and water is selected from the mixed solvent of isopropanol and water.
- The C crystal form of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, 6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2, there is characteristic peak at 25.6,26.4,27.3 and 28.3, the error range of 2 θ is ± 0.2
- C crystal form as claimed in claim 7, it is characterised in that: the C crystal form is 4.1,6.0,6.3,6.5,7.6,8.4,8.7), 9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0, there is characteristic peak at 27.3,28.3,28.8,30.0 and 31.6, the error range of 2 θ is ± 0.2.
- The preparation method of the described in any item C crystal forms of claim 7-8, which is characterized in that the method are as follows:Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target C crystal form can be obtained after dry, and the organic solvent is ketones solvent, preferably acetone.
- The form D of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7, there is characteristic peak at 27.6 and 29.2, the error range of 2 θ is ± 0.2
- Form D as claimed in claim 10, it is characterised in that: the form D is 15.1,16.6,17.6,18.2,19.5,20.1 20.4,21.6,21.9,22.1,24.6, form D characteristic peak described in 26.7,27.6,29.2,30.4 and 31.9, the error range of 2 θ are ± 0.2.
- The preparation method of the described in any item form Ds of claim 10-11, which is characterized in that the method are as follows:Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target form D can be obtained after dry, and the organic solvent is selected from aromatic hydrocarbon solvent, preferably cumene or dimethylbenzene.
- The crystal form E of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 18.2,18.7,19.2,20.1,21.7,22.8,24.6,26.7, there is characteristic peak at 27.7 and 29.2, the error range of 2 θ is ± 0.2
- The preparation method of crystal form E described in claim 13, which is characterized in that the method are as follows:Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and the crystal form E of target can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferred alcohol.
- The F crystal form of compound shown in a kind of formula (I), it is characterised in that: radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 18.7,19.5,20.2,21.5,22.0,22.6,24.4,25.6,26.6,27.6, there is characteristic peak at 29.2 and 32.0, the error range of 2 θ is ± 0.2
- The preparation method of F crystal form described in claim 15, which is characterized in that the method are as follows:Compound shown in formula (I) is added in organic solvent, is beaten, filtering for crystallizing is simultaneously washed, and target F crystal form can be obtained after dry, and the organic solvent is selected from alcohols solvent, preferably 2- propyl alcohol.
- A kind of pharmaceutical composition, F crystal form and pharmaceutically acceptable carrier, diluent or excipient described in crystal form E, claim 15 described in form D, claim 13 described in any one of C crystal form, claim 10-11 described in any one of described pharmaceutical composition B crystal form, claim 7-8 described in any one of A crystal form of any of claims 1-2, claim 4-5 form.
- Pharmaceutical composition as claimed in claim 17, it is characterized in that, described pharmaceutical composition also includes one or more second therapeutically active agents, and second therapeutically active agent is selected from: anti-inflammatory agent, Matrix Metalloproteinase Inhibitors, lipoxidase inhibitor, cytokine antagonist, immunosuppressor, anticancer agent, antivirotic, growth factor regulator, immunomodulator or anti-angiogenic anti-hyperproliferative compound.
- A method of it prepares such as claim 17,18 described pharmaceutical compositions, it is characterized in that, the step of being mixed the method includes F crystal form described in crystal form E described in the C crystal form described in any one of B crystal form, claim 7-8 as described in any one of A crystal form of any of claims 1-2, claim 4-5, the form D described in any one of claim 10-11, claim 13, claim 15 with pharmaceutically acceptable carrier, diluent or excipient.
- Such as A crystal form of any of claims 1-2, B crystal form described in any one of claim 4-5, C crystal form described in any one of claim 7-8, form D described in any one of claim 10-11, crystal form E described in claim 13, F crystal form described in claim 15, purposes of the pharmaceutical composition described in any one of claim 17-18 in the disease for the tryptophan metabolic pathway pathological characteristics that there is IDO to mediate for preparation treatment, the disease is selected from cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS, the cancer is selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, ovary Cancer, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma or non-small cell lung cancer.
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| PCT/CN2017/107017 WO2018072742A1 (en) | 2016-10-21 | 2017-10-20 | Crystalline form of free base of imidazo isoindole derivative and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109983018A (en) * | 2017-06-30 | 2019-07-05 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of imidazo isoindoles derivative free alkali |
| CN109983020A (en) * | 2017-07-13 | 2019-07-05 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of imidazo isoindoles derivative |
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| CN110664812B (en) * | 2018-07-02 | 2023-04-07 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing imidazo isoindole derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103547579A (en) * | 2011-04-15 | 2014-01-29 | 新联基因公司 | Fused imidazole derivatives useful as ido inhibitors |
| CN105189466A (en) * | 2013-03-14 | 2015-12-23 | 新联基因公司 | Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization |
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103547579A (en) * | 2011-04-15 | 2014-01-29 | 新联基因公司 | Fused imidazole derivatives useful as ido inhibitors |
| CN105189466A (en) * | 2013-03-14 | 2015-12-23 | 新联基因公司 | Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization |
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109983018A (en) * | 2017-06-30 | 2019-07-05 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of imidazo isoindoles derivative free alkali |
| CN109983020A (en) * | 2017-07-13 | 2019-07-05 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of imidazo isoindoles derivative |
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| CN108884099B (en) | 2021-10-08 |
| TW201815793A (en) | 2018-05-01 |
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