WO2019076324A1 - Sel de l'inhibiteur de l'indoléamine-2,3-dioxygénase et son procédé de préparation - Google Patents

Sel de l'inhibiteur de l'indoléamine-2,3-dioxygénase et son procédé de préparation Download PDF

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WO2019076324A1
WO2019076324A1 PCT/CN2018/110682 CN2018110682W WO2019076324A1 WO 2019076324 A1 WO2019076324 A1 WO 2019076324A1 CN 2018110682 W CN2018110682 W CN 2018110682W WO 2019076324 A1 WO2019076324 A1 WO 2019076324A1
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compound
salt
group
formula
acid
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PCT/CN2018/110682
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王召印
胡新波
郭巍
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中国科学院上海有机化学研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and particularly relates to a guanamine-2,3-dioxygenase inhibitor salt and a preparation method thereof.
  • Indoleamine-2,3-dioxygenase (IDO) inhibitor is a tumor immunotherapy drug.
  • Patent application CN105481789A and CN disclose an IDO inhibitor comprising a sulfoximine and a 1,2,5-oxadiazole structure, the structure of which is shown in formula (I).
  • R 1 is C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 20 aryl, or 3-14 membered heteroaryl;
  • R 2 is H, C 6 -C 20 aryl, 3-14 membered heteroaryl, C 1 -C 12 alkyl or C 3 -C 12 cycloalkyl;
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl; or R 3 and R 4 together form a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom is sulfur, Oxygen, NH or NR h ;
  • Ar is a substituted or unsubstituted benzene ring, five- or six-membered heteroaryl group, said substitution means that one or more hydrogen atoms on Ar are substituted by halogen; n is an integer from 2 to 8;
  • R h is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 20 aryl, or 3-14 membered heteroaryl;
  • the salt is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, Amino, nitro, aldehyde, -CF 3 , -CN or -SF 5 .
  • the specific salt form of the drug may affect its solubility, absorbency, stability, crystallinity, and bioavailability, which may affect the clinical efficacy of the drug, drug dosage form selection, safety, production process, and packaging to some extent.
  • salts of the compounds of formula I, and salts of the compounds of formula I, as well as their polymorphs and amorphous forms have not yet been developed.
  • Another object of the present invention is to provide a process and application for the preparation of various salt forms of IDO inhibitors.
  • R 1 is C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 20 aryl, or 3-14 membered heteroaryl;
  • R 2 is H, C 6 -C 20 aryl, 3-14 membered heteroaryl, C 1 -C 12 alkyl or C 3 -C 12 cycloalkyl;
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl; or R 3 and R 4 together form a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom is sulfur, Oxygen, NH or NR h ;
  • Ar is a substituted or unsubstituted benzene ring, five- or six-membered heteroaryl group, and said substitution means that one or more hydrogen atoms on Ar are substituted by halogen;
  • n is an integer from 2 to 8;
  • R h is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 20 aryl, or 3-14 membered heteroaryl;
  • the salt is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, Amino, nitro, aldehyde, -CF 3 , -CN or -SF 5 .
  • the compound of formula I is selected from the group consisting of I-1, I-2 or I-3 as follows:
  • the compound of formula I is selected from the group consisting of
  • the salt is selected from the group consisting of:
  • the salt is an amorphous or crystalline.
  • the X-ray powder diffraction pattern of the amorphous material is substantially characterized by a graph selected from the group consisting of: Figure 1-2, Figure 2-2, Figure 4-2, Figure 5-2, Figure 10-2, or Figure 11-2.
  • the infrared spectrum of the amorphous material is substantially characterized by a graph selected from the group consisting of: Figure 1-1, Figure 2-1, Figure 4-1, Figure 5-1, Figure 10- 1. Or Figure 11-1.
  • the crystal form of the crystal is selected from the group consisting of Form 3, Form 6, Form 7, Form 8, Form 9, Form 12, Form 13 or Form 14.
  • the X-ray powder diffraction pattern of the Form N includes 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from the corresponding Table N-1, wherein N It is 3, 6, 7, 8, 9, 12, 13 or 14.
  • the X-ray powder diffraction pattern of the Form N further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from the corresponding Table N.
  • the X-ray powder diffraction pattern of Form N is substantially characterized as in Figure N-2, wherein N is 3, 6, 7, 8, 9, 12, 13, or 14.
  • the infrared spectrum of the crystalline form N is substantially characterized as in Figure N-1, wherein N is 3, 6, 12, 13, or 14.
  • the infrared spectrum of the salt is substantially characterized by a graph selected from the group consisting of: Figure 1-1, Figure 2-1, Figure 3-1, Figure 4-1, Figure 5-1, Figure 6-1, Figure 10-1, Figure 11-1, Figure 12-1, Figure 13-1, or Figure 14-1.
  • the X-ray powder diffraction pattern of Form 3 comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 3-1:
  • the X-ray powder diffraction pattern of Form 3 further comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 3.
  • the X-ray powder diffraction pattern of Form 3 is substantially as characterized by Figure 3-2.
  • the X-ray powder diffraction pattern of Form 6 comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from the following Table 6-1:
  • the X-ray powder diffraction pattern of Form 6 further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 6.
  • the X-ray powder diffraction pattern of Form 6 is substantially characterized as in Figure 6-2.
  • the X-ray powder diffraction pattern of Form 7 comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 7-1:
  • the X-ray powder diffraction pattern of Form 7 further comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from Table 7.
  • the X-ray powder diffraction pattern of Form 7 is substantially characterized as in Figure 7.
  • the X-ray powder diffraction pattern of Form 8 comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 8-1:
  • the X-ray powder diffraction pattern of Form 8 further comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 8.
  • the X-ray powder diffraction pattern of Form 8 is substantially characterized as in Figure 8.
  • the X-ray powder diffraction pattern of Form 9 comprises 3 or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 9-1:
  • the X-ray powder diffraction pattern of Form 9 further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 9.
  • the X-ray powder diffraction pattern of Form 9 is substantially characterized as in Figure 9.
  • the X-ray powder diffraction pattern of Form 12 comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 12-1:
  • the X-ray powder diffraction pattern of Form 12 further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 12.
  • the X-ray powder diffraction pattern of Form 12 is substantially as characterized by Figure 12-2.
  • the X-ray powder diffraction pattern of the crystalline form 13 comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from the following Table 13-1:
  • the X-ray powder diffraction pattern of the crystalline form 13 further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 13.
  • the X-ray powder diffraction pattern of Form 13 is substantially as characterized by Figure 13-2.
  • the X-ray powder diffraction pattern of Form 14 comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2 ° selected from the following Table 14-1:
  • the X-ray powder diffraction pattern of Form 14 further comprises three or more characteristic peaks having a value of 2 ⁇ ⁇ 0.2° selected from Table 14.
  • the X-ray powder diffraction pattern of Form 14 is substantially as characterized by Figure 14-2.
  • composition comprising:
  • the salt is a crystal or an amorphous substance, or an optical isomer thereof, or a solvate thereof.
  • the pharmaceutical composition further includes other anti-tumor drugs.
  • the other anti-tumor drug is an immunotherapeutic drug (such as a targeted therapeutic drug) or a chemotherapeutic drug for cancer.
  • the additional anti-tumor drug is selected from the group consisting of a PD-1 antibody, a CTLA-4 antibody, a PD-L1 antibody, a PD-L2 antibody, other chemotherapeutic drugs, or a combination thereof.
  • a salt according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for:
  • the guanamine-2,3-dioxygenase mediated disease is a disease characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.
  • the indoleamine-2,3-dioxygenase mediated diseases are cancer, neurodegenerative diseases, eye diseases, psychological disorders, depression, anxiety, Alzheimer's disease and/or Or autoimmune disease.
  • the cancer includes, but is not limited to, colon cancer, breast cancer, gastric cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple Myeloma, chronic myeloid leukemia, hematological tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the primary site of the tumor.
  • a process for the preparation of a salt according to the first aspect of the invention comprising the steps of: forming a salt of a compound of the formula I and an acid in an inert solvent or a compound of the formula I a salt, or a solvate thereof, is recrystallized in an inert solvent to give a salt according to the first aspect of the invention;
  • the acid is hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, phosphoric acid or sulfuric acid.
  • the compound of formula I is a compound of formula I-1, I-2, or I-3. In another preferred embodiment, the compound of formula I is compound A or B.
  • the inert solvent includes water, ethers, alcohols, ketones, nitriles, esters, cyclic ethers, aliphatic hydrocarbons, or a combination thereof.
  • the inert solvent is selected from the group consisting of diethyl ether, tert-butyl methyl ether, ethyl acetate, ethanol, acetonitrile, or a combination thereof.
  • the method comprises the steps of dissolving a compound of formula I in an inert solvent and mixing with the acid to provide a salt as described in the first aspect of the invention.
  • a method for preventing and/or treating a guanamine-2,3-dioxygenase-mediated disease comprising administering to a subject in need thereof (such as a patient) A step of the salt or the pharmaceutical composition of the second aspect of the invention.
  • the indoleamine-2,3-dioxygenase mediated disease is cancer, the method further comprising administering to the patient an additional anticancer agent (also known as an antitumor drug, The steps of the antitumor drug as described above).
  • an additional anticancer agent also known as an antitumor drug, The steps of the antitumor drug as described above.
  • Figure 1-1 shows the infrared spectrum of amorphous 1
  • Figure 1-2 shows the X-ray powder diffraction pattern of amorphous 1.
  • Figure 2-1 shows the infrared spectrum of amorphous 2
  • Figure 2-2 shows the X-ray powder diffraction pattern of amorphous 2.
  • Figure 3-1 shows the infrared spectrum of Form 3
  • Figure 3-2 shows the X-ray powder diffraction pattern of Form 3.
  • Figure 4-1 shows the infrared spectrum of amorphous 4
  • Figure 4-2 shows the X-ray powder diffraction pattern of amorphous 4.
  • Figure 5-1 shows the infrared spectrum of amorphous 5
  • Figure 5-2 shows the X-ray powder diffraction pattern of amorphous 5.
  • Figure 6-1 shows the infrared spectrum of Form 6
  • Figure 6-2 shows the X-ray powder diffraction pattern of Form 6.
  • Figure 7 shows an X-ray powder diffraction pattern of Form 7.
  • Figure 8 shows an X-ray powder diffraction pattern of Form 8.
  • Figure 9 shows an X-ray powder diffraction pattern of Form 9.
  • Figure 10-1 shows the infrared spectrum of amorphous 10
  • Figure 10-2 shows the X-ray powder diffraction pattern of amorphous 10.
  • Figure 11-1 shows the infrared spectrum of amorphous 11
  • Figure 11-2 shows the X-ray powder diffraction pattern of amorphous 11.
  • Figure 12-1 shows the infrared spectrum of Form 12
  • Figure 12-2 shows the X-ray powder diffraction pattern of Form 12.
  • Figure 13-1 shows the infrared spectrum of Form 13
  • Figure 13-2 shows the X-ray powder diffraction pattern of Form 13.
  • Figure 14-1 shows the infrared spectrum of Form 14;
  • Figure 14-2 shows the X-ray powder diffraction pattern of Form 14.
  • salts of the compounds of formula I and their various amorphous and polymorphic forms being structurally stable, Good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, good solubility, high purity and bioavailability, high efficiency inhibition of IDO enzymes, especially suitable for the development and production of high quality IDO enzymes Inhibitors are of great value for the formulation optimization and development of such IDO inhibitors.
  • the inventors completed the present invention.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • cycloalkyl refers to a ring having from 3 to 12 (preferably from 3 to 10) carbon atoms, having a monocyclic or polycyclic ring (including fused systems, bridged ring systems, and spiro ring systems). Alkyl group. In a fused ring system, one or more of the rings may be a cycloalkyl, heterocyclic, aryl or heteroaryl group as long as the attachment site is a ring through a cycloalkyl group. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or a fused ring (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and/or contain a hetero atom as long as the point of attachment is passed Atoms of aromatic heteroaryl groups.
  • the ring atom nitrogen and/or sulfur of the heteroaryl group is optionally oxidized to an N-oxide (N-O), a sulfinyl group or a sulfonyl group.
  • N-O N-oxide
  • Preferred heteroaryl groups include pyridinyl, pyrrolyl, indolyl, thienyl and furanyl.
  • heteroaryl refers to a 3-14 membered heteroaryl group, preferably a 5-12 membered heteroaryl group.
  • substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclic” as used herein refers to a heterocyclic group substituted by 1 to 5 (eg, 1 to 3) substituents.
  • the substituent is the same as the substituent defined by the substituted cycloalkyl group.
  • stereoisomer refers to a chiralally different compound of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • tautomer refers to an alternative form of a compound having a different proton position, such as an enol-ketone and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group.
  • Prodrug refers to any derivative of an embodiment compound that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples, or an active metabolite or residue thereof.
  • Particularly preferred derivatives and prodrugs are those which, when administered to a subject, increase the bioavailability of the compound of the example (eg, the compound administered orally is more readily absorbed into the blood) or the parent compound relative to the parent species
  • Derivatives and prodrugs to the bioregional compartment such as the brain or lymphatic system.
  • Prodrugs include the ester form of the compounds of the invention.
  • R 1 , R 2 , R 3 , R 4 and Ar are as described above.
  • Patent application CN105481789A describes an IDO inhibitor of the formula (I) containing a sulfoximine and a 1,2,5-oxadiazole structure, a process for its preparation and an activity test, the entire contents of which are incorporated herein by reference. .
  • the salt of the compound of formula I in the present invention is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate.
  • the compound of formula I is a compound of formula I-1, I-2, or I-3.
  • the compound of formula I is S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl) Sulfimide imine) propyl)amino)-1,2,5-oxadiazole-3-carboxamidine (Compound A).
  • the compound of formula I is R-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl) Sulfimide imine) propyl)amino)-1,2,5-oxadiazole-3-carboxamidine (Compound B).
  • Preferred salts of the invention include, but are not limited to, Compound A1, Compound A2, Compound A3, Compound A4, Compound A5, Compound A6, Compound Bl, Compound B2, Compound B3, Compound B4, or Compound B5.
  • the solid does not exist in an amorphous form or in a crystalline form.
  • the molecules are positioned within the three-dimensional lattice lattice.
  • polymorphism When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph”.
  • Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, flowability, and/or solid state stability.
  • the polymorphic form of the compound can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, and fluidity, etc., which are important factors influencing the drug-forming properties.
  • polymorph of the invention includes polymorphs of the salts of the compounds of formula I.
  • Preferred polymorphs of the invention include, but are not limited to, the polymorph 3 of the compound of formula A3 (ie, Form 3), and the polymorphs of Formula A6 6, 7, 8, 9 (ie Form 6) , 7, 8, 9), a compound of formula B3 polymorph 12 (ie, form 12), a compound of formula B4, polymorph 13 (ie, form 13) or a compound of formula B5, form 14 (ie, crystalline form) 14).
  • the amorphous substance of the salt of the compound of the formula I provided by the invention has the advantages of large solubility, easy absorption by the human body, high oral bioavailability and the like.
  • the amorphous form of the salt of the compound of formula I can be obtained by dissolving the salt of the compound of formula I in a suitable solvent, by freeze drying, spray drying, and the like.
  • Preferred amorphous forms of the invention include, but are not limited to, the compound amorphous form of formula A1, the amorphous form of compound of formula A2, the amorphous form of compound of formula A4, the amorphous form of formula A5, the compound of formula B1 Amorph 10 or compound B of formula B2 is amorphous 11.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One way is to dissolve the compound of interest in a solvent and then add an appropriate volume of anti-solvent in a controlled manner to bring the system just below the level of saturation.
  • seed crystals of the desired form can be added (and the integrity of the seed crystals are maintained), and the crystallization is completed by cooling the system.
  • the "active ingredient” as used herein means a compound of the formula I according to the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof.
  • the "active ingredient" of the present invention refers to a salt of a compound of formula I, including polymorphs and amorphous forms thereof.
  • the "active ingredient” and pharmaceutical compositions described herein are useful as IDO inhibitors.
  • a medicament for the preparation and prevention or/or treatment of a tumor is prepared.
  • a medicament for the preparation of a disease preventing and/or treating IDO mediated diseases is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose" is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • the compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of cancer.
  • the use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents and anticancer agents is also effective, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in "Cancer Principles and Practice of Oncology", VT Devita and S. Hellman (editor), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Press .
  • One of ordinary skill in the art will be able to discern effective combinations of agents based on the particular nature of the drug and the cancer involved.
  • anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinol receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, iseswagen Alkenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers, and reagents that interfere with cell cycle checkpoints, CTLA4 antibodies , PD-1 antibody, PD-L1 antibody, and the like.
  • the compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.
  • the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the accepted modes of administration of agents having similar effects.
  • the actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. .
  • the drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.
  • the therapeutically effective dose can generally be the total daily dose administered to the patient in a single or divided dose, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about daily. 30 mg / kg body weight.
  • a Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance.
  • the compounds of the preferred embodiments can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous). Or subcutaneous).
  • the preferred mode of administration is oral, and a convenient daily dose can be adjusted depending on the degree of bitterness.
  • the compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions.
  • Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).
  • Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Preferred liquid carriers, particularly carriers for injectable solutions include water, saline, aqueous dextrose and ethylene glycol.
  • Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • pharmaceutically acceptable salt refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group.
  • Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sul
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid.
  • the base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • the salt of the compound of the formula I of the present invention (including an amorphous form and a polymorph) is structurally stable, has good photostability, thermal stability, non-hygroscopicity and pharmacokinetic properties, and has good solubility and purity. Significantly improved bioavailability, highly effective inhibition of IDO enzymes, especially suitable for the development and production of high quality IDO enzyme inhibitors.
  • the preparation method of the salt of the compound of the formula I of the invention is simple, rapid, mild, simple and easy to operate, low in cost, stable in process, good in reproducibility and high in yield. Suitable for industrial scale production.
  • the salt of the compound of the formula I of the present invention has various pharmacological activities such as antitumor, neurodegenerative diseases (Alzheimer's disease), anti-inflammatory and the like.
  • Normal temperature or room temperature means 4 ° C to 30 ° C, preferably 15 to 25 ° C.
  • the X-ray powder diffraction pattern of the present invention was collected on a PANalytical X'Pert Powder X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • the XRD diffraction pattern of the obtained amorphous material 1 is basically as shown in Fig. 1-2, and the diffraction angle data is basically as shown in Table 1 below.
  • the XRD diffraction pattern of the obtained Form 3 is basically as shown in Fig. 3-2, and the diffraction angle data is basically as shown in Table 3 below.
  • the XRD diffraction pattern of the obtained Form 8 is basically as shown in Fig. 8, and the diffraction angle data is basically as shown in Table 8 below.
  • the NMR data is as follows:
  • the XRD diffraction pattern of the obtained Form 9 is basically as shown in Fig. 9, and the diffraction angle data is basically as shown in Table 9 below.
  • the XRD diffraction pattern of the obtained amorphous material 10 is basically as shown in Fig. 10-2, and the diffraction angle data is basically shown in Table 10 below.
  • Example 12 was obtained by the same procedure as in Example 5 using Compound B as a starting material. Melting point: 133.1-135.0 °C. The infrared spectrum is basically as shown in Figure 12-1.
  • the XRD diffraction pattern of the obtained Form 12 is basically as shown in Fig. 12-2, and the diffraction angle data is basically as shown in Table 12 below.
  • the XRD diffraction pattern of the obtained crystal form 13 is basically as shown in Fig. 13-2, and the diffraction angle data is basically as shown in Table 13 below.
  • the XRD diffraction pattern of the obtained Form 14 is basically as shown in Fig. 14-2, and the diffraction angle data is basically as shown in Table 14 below.
  • mice Male, weighing 18-22 g, were intragastrically administered with the compound A-p-TsOH salt (Form 6, Example 6), as shown in Table 5 below:
  • the rats were orally administered with 0.5% HPMC as a suspension, fasted for 12 hours before the test, and free to drink water. Uniformly eaten 2 hours after administration.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12 and 24 h after administration;
  • test compound (1-2 mg) was placed in two 1.5 mL glass vials, and 1 mL of PBS buffer solution of different pH was added. The sample was then placed on an Eppendorf Thermomixer comfort plate shaker. Shake for 24 hours at 1100 rpm. Then, 0.2 mL of the filtrate was taken out, and the filtrate was diluted 1000 times with methanol. The sample was quantitatively analyzed by the above LC/MS method, and the average concentration of the compound A in the two samples was calculated by the dilution factor.

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Abstract

La présente invention concerne un sel de l'inhibiteur de l'indoléamine-2,3-dioxygénase et un procédé de préparation de celui-ci. En particulier, l'invention concerne un sel d'un composé de formule I et une variété de substances amorphes et de polymorphes de celui-ci, les définitions de chaque groupe étant telles que décrites dans la description. Le sel a une structure stable, une bonne stabilité à la lumière, une thermostabilité, des propriétés non hygroscopiques et pharmacocinétiques, et une bonne solubilité, une pureté et une biodisponibilité significativement améliorées, et est particulièrement approprié pour le développement et la production d'un inhibiteur de l'enzyme IDO avec une qualité élevée.
PCT/CN2018/110682 2017-10-18 2018-10-17 Sel de l'inhibiteur de l'indoléamine-2,3-dioxygénase et son procédé de préparation WO2019076324A1 (fr)

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US20080146624A1 (en) * 2006-09-19 2008-06-19 Incyte Corporation Amidines as modulators of indoleamine 2,3-dioxygenase
CN105646389B (zh) * 2016-01-28 2019-06-28 中国科学院上海有机化学研究所 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途
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WO2017101884A1 (fr) * 2015-12-15 2017-06-22 江苏豪森药业集团有限公司 Inhibiteur de l'indolamine 2,3-dioxygénase et procédé pour sa préparation et utilisation correspondante
CN107176933A (zh) * 2016-03-09 2017-09-19 中国科学院上海有机化学研究所 一种含氮烷基化和芳基化亚砜亚胺的吲哚胺-2,3-双加氧酶抑制剂
CN107304191A (zh) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 吲哚胺2,3‑双加氧酶抑制剂及其制备方法与应用
WO2018072697A1 (fr) * 2016-10-17 2018-04-26 上海医药集团股份有限公司 Composé contenant un cycle d'oxadiazole, son procédé de préparation, et intermédiaire, composite et application associée
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