JP2016216446A - Polymorphic form of pyrrolidine-2,5-dione derivative, pharmaceutical composition and method of use as ido1 inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a crystal polymorphism of 3-(5-fluoro-1H-indole-3-yl)pyrrolidine-2,5-dione as an indole amine 2,3-dioxygenase 1 (IDO1) inhibitor having improved effectiveness in treatment and/or prevention of cancer or endometriosis.SOLUTION: There is provided a crystal form of 3-(5-fluoro-1H-indole-3-yl)pyrrolidine-2,5-dione having a powder X-ray diffraction pattern including characteristic peaks in two or more of about 6.7 degree 2θ, about 14.2 degree 2θ, about 15.0 degree 2θ, about 16.4 degree 2θ or about 24.4 degree 2θ.SELECTED DRAWING: None

Description

  The present invention relates to a crystalline form of a pyrrolidine-2,5-dione derivative.

  Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step of L-tryptophan (Trp) catabolism along the kynurenine pathway leading to the production of N-formylkynurenine It is a monomer-containing heme enzyme. 95% of Trp is metabolized by this kynurenine pathway. The kynurenine pathway (KYN) initiates the production of neuroactive and immunoregulatory metabolites collectively known as kynurenine and provides a precursor that supplements dietary niacin for NAD + and NADP + biosynthesis .

  IDO1 expressed by antigen presenting cells (APCs) such as dendritic cells (plasmacytoid DCs in tumor draining lymph nodes) contributes to T cell proliferation and survival by locally depleting tryptophan and increasing kynurenine. It can greatly affect and activate regulatory T cells, thereby attenuating the pro-inflammatory response. Thus, IDO1 can provide “immune privilege” to tissues affected by chronic inflammation, transplantation, and cancer, such as infections and allergic diseases. Since such an immunotolerogenic response can be expected to operate in a variety of physiopathological conditions, tryptophan metabolism and kynurenine production by IDO1 may be a very important interface between the immune and nervous systems. is there. IDO1 expression is up-regulated by pro-inflammatory cytokines and can be detected in various tissues such as placenta, spleen, thymus, lung, gastrointestinal tract, and central nervous system (Munn et al., Trends Immunol, 2013, 34). 137-43).

  IDO1 is a promising new therapeutic agent for treating cancer and other diseases characterized by reduced local Trp levels and / or imbalances in the levels of cytotoxic metabolites produced by the kynurenine pathway It has emerged as a molecular target (discussed in Munn et al., Trends Immunol, 2013, 34, 137-43). Indeed, inhibition of IDO1 activity as a therapeutic strategy has been tested in preclinical models of many diseases using the tryptophan analog L-1-methyltryptophan (L-1MT), the most widely used IDO1 inhibitor. Has been. Treatment with L-1MT alone or in combination with other drugs includes arthritis, ischemia reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV) / simian immunodeficiency virus (SIV) infection, airway inflammation, And in animal models of cancer, disease severity was reduced (Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274; Holmgard et al., J Exp Med, 2013, 210, 7, 1389-1402). For cancer, IDO1 induction has been observed in vivo during the rejection of allogeneic tumors, suggesting that this enzyme may play a role in the tumor rejection process (Uyttenhove et al., Nat Med, 2003). 9, 10, 1269 to 1274; Holmgard et al., J Exp Med, 2013, 210, 7, 1389 to 1402). Cervical cancer cells (or HeLa cells) co-cultured with peripheral blood lymphocytes (PBL) acquire an immunoinhibitory phenotype by up-regulation of IDO1 activity. The decrease in PBL proliferation after treatment with interleukin 2 (IL2) was thought to occur as a result of tumor cells releasing IDO1 in response to gamma interferon (IFN) -g (γ) secretion by PBL. Therefore, IDO1 activity in tumor cells can serve to attenuate the anti-tumor response, a process in which IFNγ plays a central role. Another evidence of a tumor immune resistance mechanism based on tryptophan degradation by IDO1 is that most human tumors constitutively express IDO1 and that its rejection is prevented by expression of IDO1 by immunogenic mouse tumor cells (Munn et al., Front Biosci, 2012, 4, 734-45; Godin-Ethier et al., Clin Cancer Res 2011, 17, 6985-6991; Johnson et al., Immunol Invest 2012, 41, 6-7, 765-797). This effect is accompanied by a lack of accumulation of specific T cells at the tumor site, and can be partially reversed without significant toxicity by systemic treatment of mice with IDO1 inhibitors (Holmagard et al., J Exp Med, 2013, 210, 7, 1389 to 1402).

  IDO1 expression has been demonstrated in a wide range of cancer patients by immunohistochemistry. Changes in the ratio of IDO1 mRNA, protein, or tryptophan to kynurenine in the blood, especially in malignant melanoma, acute myeloid leukemia, pancreas, colorectal, prostate, cervix, brain, endometrium, and ovarian cancer It has been detected in patients. In some malignant lesions, the presence of IDO1 is an independent predictor of worse clinical outcome (discussed in Munn et al., Front Biosci, 2012, 4, 734-45).

  Although the potential potential of IDO1 inhibitors as pharmaceuticals has attracted considerable interest, the original inhibitors were identified by modification of Trp rather than by the discovery of molecules with novel structural skeletons. . In the early 2000s, the best IDO1 inhibitors were dominated primarily by competitive Trp derivatives (such as L-1-MT) and non-competitive carbolines, which have affinity in the micromolar range. Showed sex. Since 2006, several potent nanomolar IDO1 inhibitors with a novel structural framework have been discovered by high-throughput screening, computational screening, or natural product isolation and optimization of the core pharmacophore of its structure . Many of these IDO1 inhibitors have low micromolar activity or limited pharmacokinetics. Two IDO1 inhibitors are currently being tested in phase I / II clinical trials for the treatment of recurrent or refractory solid tumors (in Dolusic et al., Expert Opin Ther Pat. 2013, 23, 1367-81). Is discussed).

  At the same time, the importance of awakening and uniting tumor immune surveillance is now widely accepted as an important aspect of anticancer therapy (Motz et al., Immunity, 2013, 39, 1, 61-73). As a biomarker approach, immunoscoring methods for infiltrating T cell subsets are under development and are expected to allow for the determination of patient responsiveness to treatment (Galon et al., J Transl Med, 2012, 10, 1). As such, finding new powerful IDO1 inhibitors remains an important concern.

Munn et al., Trends Immunol, 2013, 34, 137-43. Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274. Holmgard et al., J Exp Med, 2013, 210, 7, 1389-1402. Munn et al., Front Biosci, 2012, 4, 734-45 Godin-Ethier et al., Clin Cancer Res 2011, 17, 6985-6991 Johnson et al., Immunol Invest 2012, 41, 6-7, 765-797 Dolusic et al., Expert Opin The Pat. 2013, 23, 1367-81 Motz et al., Immunity, 2013, 39, 1, 61-73. Galon et al., J Transl Med, 2012, 10, 1

  Accordingly, there is a need for new IDO1 inhibitors with improved efficacy for cancer treatment and / or prevention.

  The compounds, compositions, crystalline forms, and methods described herein meet the current need for IDO1 inhibitors that can be administered to patients diagnosed with cancer or to subjects at risk of developing cancer. It will help.

  In one aspect, a crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione (Form 1) of about 6.7 degrees 2θ, about 14.2 degrees 2θ A crystalline form having a powder X-ray diffraction pattern comprising characteristic peaks at one or more of about 15.0 degrees 2θ, about 16.4 degrees 2θ, and about 24.4 degrees 2θ. In another embodiment, the crystalline form 1 has 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 15.0 ± 0.2 degrees 2θ, 16.4 ± 0.2 degrees 2θ. And a powder X-ray diffraction pattern including characteristic peaks at one or more of 24.4 ± 0.2 degrees 2θ. In another embodiment, crystalline form 1 has 2, 3, 4, or more of these characteristic peaks.

In another embodiment, a crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione (Form 1) comprising about 39.2, about 124.7, and about A crystalline form is provided having one or more solid (SS) nuclear magnetic resonance (NMR) ¹³ C chemical shifts at 127.5 parts per million (ppm). In one embodiment, crystalline Form I has one or more ¹³ C SS NMR chemical shifts at about 39.2 ± 0.2 ppm, 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm.

In yet another embodiment, a crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione (Form 1), comprising about ^{19 at} about -122.8 million parts A crystalline form is provided having an SS NMR spectrum with an F chemical shift. In one embodiment, the ¹⁹ F chemical shift is at -122.8 ± 0.2 ppm.

In yet another aspect, crystalline Form I comprises a powder X-ray diffraction pattern comprising characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ; It has one or more ¹³ C SS NMR chemical shifts at about 39.2 ppm, about 124.7 ppm, and about 127.5 ppm.

In yet another aspect, crystalline Form I comprises a powder X-ray diffraction pattern comprising characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ; It has a ¹⁹ F SS NMR chemical shift at about -122.8 ppm.

  In one embodiment, crystalline Form I includes the characteristic peaks represented in FIGS. 1A and / or 1B. In another embodiment, crystalline form 1 lacks a peak at about 9.5 degrees 2θ and / or about 12.3 degrees 2θ. In yet another embodiment, 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 1 has a melting point higher than 195 ° C. or higher than 196 ° C., ie at 197 ° C. is there.

  In another aspect, the crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione (Form 2), about 9.5 degrees 2θ, about 12.3 degrees A crystalline form is provided having a powder X-ray diffraction pattern comprising characteristic peaks at 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ. In one embodiment, these characteristic peaks are as represented in FIG. In another embodiment, the compound lacks a peak at about 6.7 degrees 2θ. In yet another embodiment, 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 2 has a melting point greater than 195 ° C., ie, 196 ° C.

  Other aspects and advantages of the present invention are expected to become apparent from the following detailed description of the invention.

3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 1 Powder X, performed as described in the first powder X-ray diffraction (PXRD) analysis technique of Example 1 It is a line diffraction spectrum. 2 is a powder X-ray diffraction spectrum of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 1 performed as described in the alternative PXRD analysis technique of Example 1. 3 is a powder X-ray diffraction spectrum of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 2. 1 is a ¹³ C solid state NMR spectrum of Form I prepared as described in Example 1, Part C. Peaks marked with a number sign are spinning sidebands. 1 is a solid state ¹⁹ F NMR spectrum of Form I prepared as described in Example 1, Part C. Peaks marked with a number sign are spinning sidebands.

Crystalline polymorphic form 1 and crystalline polymorphic form 2 of the compound 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione are provided herein. Also provided is a composition or medicament containing Form 1, Form 2, or a combination thereof in a pharmaceutically acceptable carrier or excipient. Its use is also described. Such new polymorphic forms have properties that can be advantageous in terms of pharmacokinetics, ease of manufacture (formulation), and dosage form stability that improves ease of storage and / or packaging.

  The term “characteristic peak” refers to the crystalline form (form) of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione due to the presence of its powder X-ray diffraction peak. It means that it is clearly identified as 1 or form 2). Typically, powder X-ray diffraction analysis is performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source, or other suitable apparatus.

  In one embodiment, polymorphic form 1 of 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione is about 6.7 degrees 2θ, about 14.2 degrees 2θ, about 15 Characterized by a powder X-ray diffraction pattern that includes a characteristic peak at one or more of 0.0 degrees 2θ, about 16.4 degrees 2θ, or about 24.4 degrees 2θ. In one embodiment, Form 1 includes two or more, three or more, four or more, or all five of these characteristic peaks. For example, Form I is about 6.7 and about 14.2, about 14.2 and about 15.0, about 15.0 and about 16.4, about 6.7 and about 15.0, about 6.7. And about 14.2, or about 14.2 and about 16.4 may include a combination of characteristic peaks of the powder X-ray diffraction pattern. In another example, three characteristic peaks may be at about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ, which are further in addition to the fourth peak. It may be a combination. In some cases, all five peaks may be present.

  For example, polymorphic form 1 of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione has 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ. Featuring a powder X-ray diffraction pattern that includes a characteristic peak at one or more of 15.0 ± 0.2 degrees 2θ, 16.4 ± 0.2 degrees 2θ, or 24.4 ± 0.2 degrees 2θ. To do. In one embodiment, Form 1 includes two or more, three or more, four or more, or all five of these peaks. For example, Form I has 6.7 ± 0.2 degrees and 14.2 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees and 15.0 ± 0.2 degrees 2θ, 15.0 ± 0. 2 and 16.4 ± 0.2, 6.7 ± 0.2 and 15.0 ± 0.2, 6.7 ± 0.2 and 14.2 ± 0.2, or 14.2 ± 0.2 And 16.4 ± 0.2 degrees 2θ may include a combination of characteristic peaks of the powder X-ray diffraction pattern. In another example, there may be three characteristic peaks at 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, and 24.4 ± 0.2 degrees 2θ. May be further combined with a fourth peak. In some cases, all five peaks may be present.

In yet another embodiment, Form I comprises one or more ¹³ C solid (SS) nuclear magnetic resonance (NMR) at about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm. Characterized by chemical shift. Form I may be characterized by two or more of these chemical shifts, or all three of these chemical shifts. In another embodiment, Form I is characterized by one or more ¹³ C SS NMR chemical shifts at 39.2 ± 0.2 ppm, 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm. Form I may be characterized by two or more of these chemical shifts, or all three of these chemical shifts.

In yet another embodiment, Form I is characterized by an SS NMR spectrum of ¹⁹ F chemical shift at about -122.8 ppm. In yet another embodiment, Form I is characterized by an SS NMR spectrum of ¹⁹ F chemical shift at -122.8 ± 0.2 ppm.

In yet another embodiment, Form I may be characterized by a combination of one or more of these powder X-ray diffraction characteristic peaks with one or more of the SS NMR chemical shift peaks for ¹³ C. Form I may be characterized by the presence of two or more or three or more powder X-ray diffraction peaks. Form I may be characterized by the presence of two or more or three or more of the SS NMR chemical shift peaks. In one embodiment, Form I is about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees, optionally further combined with the SS NMR chemical shift peak for ¹³ C shown herein. Characterized by one or more combinations of characteristic peaks of the powder X-ray diffraction pattern at one or more of 2θ.

In another embodiment, Form I is characterized by a combination of one or more of these characteristic powder X-ray diffractions and an SS NMR chemical shift peak for ¹⁹ F. Form I may be characterized by the presence of two or more or three or more powder X-ray diffraction peaks. In one embodiment, Form I is about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees, optionally further combined with the SS NMR chemical shift peak for ¹⁹ F shown herein. Characterized by one or more combinations of characteristic peaks of the powder X-ray diffraction pattern at one or more of 2θ. In another embodiment, Form I features one or more combinations of SS NMR chemical shift peaks for ¹³ C and SS NMR chemical shift peaks for ¹⁹ F. Form I may be characterized by the presence of two or more or three or more powder X-ray diffraction peaks. In one embodiment of this combination, Form I is about 6.7 degrees 2θ, optionally further combined with one or more of the SS NMR chemical shift peaks for ¹³ C and / or the SS NMR chemical shift peaks for ¹⁹ F. Characterized by one or more combinations of characteristic peaks of the powder X-ray diffraction pattern at one or more of about 14.2 degrees 2θ, or about 24.4 degrees 2θ.

  In one embodiment, Form I has a characteristic peak of the powder X-ray diffraction pattern at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees 2θ, or a combination thereof. Characterized by one or more combinations of In another embodiment, Form I is characterized by having, at a minimum, these three peaks.

  In one embodiment, the compound does not include Form 2, ie Form 2 includes about 9.5 degrees 2θ, about 12.3 degrees 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ. Lack of characteristic peaks.

  In one embodiment, 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 1 has a melting point higher than 195 ° C. (ie, higher than 195.0 ° C., 195.9). Up to ℃). In another embodiment, 3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 1 has a melting point from about 197 ° C., such as from 196.6 ° C. to 199.99. It is in the range up to ° C or 197 ° C. In one embodiment, polymorph form 1 is anhydrous, i.e. free of water and non-hygroscopic. In another embodiment, Form I is substantially free of water and other solvents.

  In one embodiment, the crystalline form 1 prepared herein is at least 90% pure, at least 95% pure, at least 97% pure, at least 99% pure, about 99.5% pure, or about 99.7% pure. is there. “Pure” means free of contaminants including, for example, solvents, other crystalline forms, and / or amorphous forms. In another embodiment, the crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione (Form 2), which is about 9.5 degrees 2θ, about 12.3. Crystal forms are provided that are characterized by a powder X-ray diffraction pattern that includes characteristic peaks at two or more of degrees 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ. In one embodiment, Form 2 is about 9.5 degrees 2θ and about 12.3 degrees 2θ, about 9.5 degrees 2θ and about 13.5 degrees 2θ, about 9.5 degrees 2θ and about 14.3 degrees 2θ. Characterized by peaks at about 12.3 degrees 2θ and about 14.3 degrees 2θ, about 12.3 degrees 2θ and about 13.5 degrees 2θ, and / or about 13.5 degrees 2θ and about 14.3 degrees 2θ. To do. Form 2 may contain more than two or all four of these characteristic peaks. Suitably the compound comprises about 6.7 degrees 2θ, about 14.2 degrees 2θ, about 15.0 degrees 2θ, about 16.4 degrees 2θ, and / or about 24.4 degrees 2θ. Lack of characteristic peaks. In another embodiment, the characteristic peaks of powder X-ray diffraction for Form 2 are 9.5 ± 0.2 degrees 2θ, 12.3 ± 0.2 degrees 2θ, 13.5 ± 0.2 degrees 2θ. , And 14.3 ± 0.2 degrees 2θ.

  3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione Form 2 has a melting point higher than 195 ° C. (eg, 196 ° C. or higher) or approximately 196 ° C. In one embodiment, polymorph form 2 is anhydrous, i.e. free of water and non-hygroscopic. In another embodiment, Form 2 is substantially free of water and other solvents.

  Crystalline Form 1 and / or Crystalline Form 2 can be used in medicaments and pharmaceutical compositions as described herein. References in these compositions and uses discussions may also refer to “compounds”.

  As used herein, the term “3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione” refers to the structure:

を有するラセミ化合物を指す。

Refers to a racemic compound having

  As used herein, the term “polymorph” refers to crystalline forms that have the same chemical composition but differ in the spatial arrangement of molecules, atoms, and / or ions that make up the crystal. In general, throughout this specification refers to polymorphs of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione racemate. As described herein, the racemic compound of Formula II is about 50% R enantiomer and about 50% S enantiomer (about 48-48) based on the molar ratio of the two isomers / enantiomers. About 52 mol%, or about 1: 1 ratio)).

  The compounds described herein in the examples were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

  As used herein, the term “free acid” refers to the non-salt form of a compound.

Methods of Manufacture The compounds of the present invention can be prepared by different methods using reactions known to those skilled in the art. An exemplary scheme for preparing 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione is described in “Pyrrolidine-2,5-dione derivatives, incorporated herein by reference. US Provisional Patent Application No. 61 / 996,976, filed March 15, 2014, entitled “Pharmaceutical Compositions and Methods for Use as IDO Inhibitors”, and corresponding PCT and US Applications filed on the same date as this application It is described in.

According to one embodiment, starting from the corresponding racemates, the separation of the enantiomers of sift-friendly, but are not limited to, supercritical CO _2, ethanol, methanol, a mixture of suitable solvents, such as hexane Realized by chiral HPLC, such as, but not limited to, using Chiralpak® AS-H, Chiralcel® OJ-H, or Chiralpak® IC columns while using as eluent. Can do.

  The reaction schemes described in the Examples section are for illustration only and are not to be construed as limiting the invention in any way.

Use The present invention is further directed to a medicament comprising as an active ingredient at least one compound of the present invention (eg, Form I or Form II).

  The present invention also provides a pharmaceutical composition comprising a compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant. A carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, is not deleterious to its recipients in the amounts used in medicine.

  According to one embodiment, the present invention also covers pharmaceutical compositions containing, in addition to the compounds of the present invention as active ingredients, additional therapeutic agents and / or active ingredients.

  According to non-limiting examples, the compounds of the invention can be administered orally, parenterally (eg, by intravenous, intramuscular, or subcutaneous injection, or intravenous infusion), topical (such as administration to the eye), It can be formulated as a pharmaceutical preparation in a form suitable for administration by inhalation, skin patch, implant, suppository and the like. Such suitable dosage forms (which may be solid, semi-solid, or liquid depending on the mode of administration), as well as the methods, carriers, diluents, and excipients used in their preparation will be apparent to those skilled in the art. The latest version of Remington's Pharmaceutical Sciences is cited as a reference.

  Some preferred but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, Ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and packaging for administration as a bolus and / or continuous administration (usually redissolved before use) Sterilized powders, which are themselves suitable carriers for such formulations, excipients and diluents such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid Salt, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene Recall, cellulose can be formulated with (sterile) water, methylcellulose, methyl- and propyl, talc, magnesium stearate, edible oils, vegetable oils, and mineral oils or suitable mixtures thereof. The formulation may be other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, fillers, preservatives, sweetening agents, flavoring agents. Agents, flow regulators, mold release agents and the like may optionally be included. The composition can also be formulated so that rapid, sustained or delayed release of the active compound contained therein is achieved.

  The pharmaceutical preparation of the present invention is preferably in unit dosage form, such as a box, blister, vial, bottle, sachet, ampoule, or any other suitable single or multi-dose holder or container ( May be appropriately labeled) and optionally packaged with one or more folded prints containing product information and / or instructions for use.

  Depending on the condition to be prevented or treated and the route of administration, the active compounds of the invention are essentially as a single daily dose, divided into one or more daily doses or using, for example, infusion Can be administered continuously.

  The invention also relates to the use of the compounds of the invention in the treatment and / or prevention of cancer and endometriosis. In one embodiment, the invention relates to the use of a compound of the invention in the treatment and / or prevention of cancer. In another embodiment, the invention relates to the use of a compound of the invention in the treatment and / or prevention of endometriosis.

  In one embodiment, the compounds of the invention are for use in the treatment and / or prevention of cancer and endometriosis. According to one embodiment, the compounds of the invention are for use in the treatment and / or prevention of cancer. According to another embodiment, the compounds of the invention are for use in the treatment and / or prevention of endometriosis.

  The invention further relates to a method of treating or preventing cancer and endometriosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention. In one embodiment, the present invention relates to a method of treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention. In another embodiment, the present invention relates to a method for treating or preventing endometriosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention.

  In one embodiment, the compounds of the invention are for use in enhancing immune recognition and destruction of cancer cells.

  Accordingly, the compounds of the present invention are useful as medicaments, particularly in the prevention and / or treatment of cancer.

  The invention further provides the use of a compound according to the invention for the manufacture of a medicament for treating and / or preventing cancer.

  Various cancers are known in the art. Cancer may be metastatic or non-metastatic. Cancer can be familial or sporadic. In some embodiments, the cancer is selected from the group consisting of leukemia and multiple myeloma. In one embodiment, the cancer is leukemia. In one embodiment, the cancer is multiple myeloma.

  Additional cancers that can be treated using the methods of the present invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors. In one embodiment, the cancer is a benign solid tumor. In one embodiment, the cancer is a malignant solid tumor. In one embodiment, the cancer is a benign non-solid tumor. In one embodiment, the cancer is a malignant non-solid tumor.

  Examples of solid tumors include, but are not limited to, biliary tract cancers, brain tumors (including glioblastoma and medulloblastoma), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrium Cancer, esophageal cancer, gastric cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (epithelium) Cells, stromal cells, embryonic cells, and those resulting from mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcoma (leiomyosarcoma) , Including rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), germinal tumor Testicular cancer, including seminoma, Nonseminoma) such as teratomas and choriocarcinoma and, stromal tumors, germ cell tumors, and include thyroid cancer (thyroid adenocarcinoma and medullary carcinoma) and the like.

  In one embodiment, the cancer is a biliary tract cancer. In one embodiment, the cancer is a brain tumor, including glioblastoma and medulloblastoma. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is cervical cancer. In one embodiment, the cancer is choriocarcinoma. In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is an intraepithelial neoplasia, including Bowen's disease and Paget's disease. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is oral cancer including squamous cell carcinoma. In one embodiment, the cancer is ovarian cancer, including those arising from epithelial cells, stromal cells, embryonic cells, and mesenchymal cells. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is rectal cancer. In one embodiment, the cancer is renal cancer, including adenocarcinoma and Wilms tumor. In one embodiment, the cancer is a sarcoma, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma. In one embodiment, the cancer is skin cancer, including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma. In one embodiment, the cancer is testicular cancer, including germ cell tumors (seminomas, and non-seminomas such as teratomas and choriocarcinomas). In one embodiment, the cancer is a stromal tumor. In one embodiment, the cancer is a germ cell tumor. In one embodiment, the cancer is thyroid cancer, including thyroid cancer and medullary cancer.

  Examples of non-solid tumors include, but are not limited to, blood tumors. As used herein, a blood tumor is a terminology that encompasses lymphoid disorders, myeloid disorders, and leukemias associated with AIDS.

  Lymphatic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin lymphoma, and lymphocytic lymphoma. Examples of chronic lymphocytic leukemia include T cell chronic lymphocytic leukemia and B cell chronic lymphocytic leukemia.

  In one embodiment, the lymphatic disorder is acute lymphocytic leukemia. In one embodiment, the lymphatic disorder is a chronic lymphoproliferative disorder (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). In one embodiment, the lymphoma is Hodgkin's disease. In one embodiment, the lymphoma is non-Hodgkin lymphoma. In one embodiment, the lymphoma is lymphocytic lymphoma. In one embodiment, the chronic lymphocytic leukemia is T cell chronic lymphocytic leukemia. In one embodiment, the chronic lymphocytic leukemia is B cell chronic lymphocytic leukemia.

  The present invention also provides a method of delaying the onset of cancer in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound according to the present invention.

  The present invention relates to the use of polymorphic compounds as IDO1 inhibitors.

  Thus, in another aspect, the invention relates to the use of such compounds for synthesizing IDO1 inhibitors.

  According to another feature of the invention, a method of modulating IDO1 activity in a subject in need of such treatment, comprising administering to said subject an effective amount of a compound of the invention. Provided.

  According to another feature of the present invention, the use of a compound of the present invention for the manufacture of a medicament that modulates IDO1 activity in a subject in need of such treatment, said subject comprising an effective amount of the present invention. Uses comprising administering a compound are provided.

Definitions In the present invention, the following terms have the following meanings.
In the case where a group may be substituted, such a group may be substituted with one or more substituents, preferably one, two or three substituents. Substituents can be selected from the group including, but not limited to, for example, halogen, hydroxyl, oxo, nitro, amide, carboxy, amino, cyano, haloalkoxy, and haloalkyl.

  The term “halogen” or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferred halo groups are fluoro and chloro.

The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of the formula C _n H _{2n + 1} where n is a number greater than or equal to 1. Generally, the alkyl group of the present invention has 1 to 6 carbon atoms (including C1, C2, C3, C4, C5, or C6 carbon, including both ends), preferably 1 to 4 carbon atoms, and more. Preferably it contains 1 to 3 carbon atoms. Alkyl groups can be linear or branched and can be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (eg, n-pentyl, isopentyl). And hexyl and its isomers (eg, n-hexyl, isohexyl). Optionally, the alkyl may be substituted with 1, 2, or 3 substituents. Such substituents may be hydroxy, amino-, halogen, or C1-C3 alkyl groups. In one embodiment, the halogen substituent is F or Br. In another embodiment, the alkyl substituent is a methyl group. The term “alkoxy” refers to any O-alkyl group.

The term “amino” refers to an —NH ₂ group or any group derived therefrom by replacement of one or two hydrogen atoms with an aliphatic or aromatic organic group. Groups derived from —NH ₂ are preferably “alkylamino” groups, ie N-alkyl groups, including monoalkylamino and dialkylamino. According to a detailed embodiment, the term “amino” refers to NH ₂ , NHMe, or NMe ₂ .

  The term “amino protecting group” refers to a protecting group for an amine function. According to a preferred embodiment, the amino protecting group is selected from the group comprising arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, or benzyl.

  The term “solvate” is used herein to describe a compound in the present invention that contains a stoichiometric amount or sub-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. use. The term “hydrate” refers to the case where the solvent is water.

  The present invention also generally covers all pharmaceutically acceptable pre- and prodrugs of the compounds described herein.

  As used herein, the term “prodrug” means a pharmacologically acceptable derivative, such as an amide, in which a biotransformation product in vivo yields a biologically active drug. Prodrugs are generally characterized by increased bioavailability and are readily metabolized in vivo to biologically active compounds.

  As used herein, the term “pre-drug” means any compound that, when modified, will form a drug species, where the modification may be made inside or outside the body, and the drug Before or after the pre-drug reaches the body region where administration of

  The term “subject” refers to a mammal, preferably a human. In one embodiment, the subject is “patient”, ie, warm, who is or will be receiving medical care, or who is / being a subject of medical treatment, or that is being monitored for disease progression. It may be a blood animal, more preferably a human.

  The term “human” refers to persons of all developmental stages (ie, neonates, children, boys, adolescents, adults) in both genders.

  As used herein, the terms “treat”, “treating”, and “treatment” are intended to include alleviating, reducing, or suppressing a condition or disease and / or symptoms associated therewith.

  As used herein, the terms “prevent”, “preventing”, and “prevention” refer to a subject suffering from a condition or disease that delays or prevents the onset of the condition or disease and / or associated symptoms. It refers to a method of preventing or reducing the risk that a subject will suffer from a condition or disease.

  As used herein, the term “therapeutically effective amount” (or more simply “effective amount”) is sufficient to obtain the desired therapeutic or prophylactic effect of the active agent or active ingredient in the subject to which it is administered. Means a large amount.

  The term “administration” or variations thereof (eg, “administering”) refers to an active agent or active ingredient, alone or pharmaceutically acceptable composition, in a subject to be treated or prevented from a condition, symptom, or disease. It is meant to be provided as part of the product.

  “Pharmaceutically acceptable” means that the components of the pharmaceutical composition are compatible with each other and are not deleterious to the subject to which it is administered.

  The term “inhibitor” has a biological effect of inhibiting, substantially reducing or down-regulating gene and / or protein expression, or inhibiting the biological activity of a protein, or substantially Refers to a natural or synthetic compound that has a biological effect that reduces it. As a result, an “IDO1 inhibitor” refers to a biology that inhibits, substantially reduces, or down-regulates the expression of a gene encoding IDO1 and / or the expression and / or biological activity of IDO1. Refers to a compound having a positive effect.

  “D” and “d” both refer to deuterium. “Dx.y” refers to substitution with x to y deuterium atoms. “Stereoisomer” refers to both enantiomers and diastereoisomers. When a group is “substituted” by a substituent, one or more hydrogen atoms of the group is the corresponding number of substituent atoms (if the substituent is an atom) or substituent (the substituent is a group) If) has been replaced. For example, “substituted with deuterium” refers to replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

  The terms “comprise”, “comprises”, and “comprising” are to be interpreted as non-limiting. The terms “consisting”, “consisting” and variations thereof are to be interpreted in a limited but not limiting manner.

  As used herein, the term “about” means (±) 10% variability from the indicated reference value, unless otherwise specified.

  The invention will be better understood with reference to the following examples. Such examples represent detailed embodiments of the invention and are not intended to limit the scope of the invention.

I. Chemical Examples MS data provided in the examples described below were obtained as follows. Mass spectrum: LC / MS Agilent 6110 (ESI) or Waters Acquity SQD (ESI).

  The NMR data provided in the examples described below was acquired as follows. Bruker Ultrashield ™ 400 PLUS and Bruker Fourier 300 MHz. TMS was used as an internal standard.

  Microwave chemistry events were performed in Biotage's single-mode microwave reactor Initiator Microwave System EU.

Preparative HPLC purification was performed on a Waters mass automatic purification Fractionlynx equipped with an Xbridge ™ Prep C18 OBD column 19 × 150 mm 5 μm unless otherwise reported. All HPLC purifications were performed using CH ₃ CN / H ₂ O / NH ₄ HCO ₃ (5 mM), CH ₃ CN / H ₂ O / TFA (0.1%), or CH ₃ CN / H ₂ O / NH ₃ H. Performed with a gradient of ₂ O (0.1%).

Compound 1: 3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione

Ａ．経路Ａ
５−フルオロ−１Ｈ−インドール（３００ｍｇ、２．２２ｍｍｏｌ）、マレイミド（６４６ｍｇ、６．６５ｍｍｏｌ）をＡｃＯＨ（２ｍＬ）に混ぜた混合物を、マイクロ波反応において１７０℃で２時間撹拌した。反応混合物を真空中で濃縮した。残渣を飽和ＮａＨＣＯ_３水溶液でｐＨ７〜８に中和し、ＥｔＯＡｃ（１０ｍＬ×３）で抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、分取ＨＰＬＣによって精製して、１８０ｍｇ（３５％）の表題化合物を黄色の固体として得た。LC-MS: C₁₂H₉FN₂O₂-H^-
[M-H]: 計算値231.1; 実測値: 231.0. ¹H
NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.30
(brs, 1H), 11.14 (s, 1H), 7.41(d, J = 2.5 Hz, 1H), 7.36 (dd, J = 9.0, 4.6 Hz, 1H), 7.20 (dd, J = 10.1, 2.5 Hz, 1H), 6.94 (ddd, J = 9.2, 9.0, 2.5 Hz, 1H), 4.33 (dd, J = 9.5, 5.5 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.79 (dd, J = 18.0, 5.5 Hz, 1H).

A. Route A
A mixture of 5-fluoro-1H-indole (300 mg, 2.22 mmol), maleimide (646 mg, 6.65 mmol) in AcOH (2 mL) was stirred at 170 ° C. for 2 hours in a microwave reaction. The reaction mixture was concentrated in vacuo. The residue was neutralized with saturated aqueous NaHCO ₃ to pH 7-8 and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give 180 mg (35%) of the title compound as a yellow solid. _{LC-MS: C 12 H 9} FN 2 O 2 -H -
[MH]: Calculated 231.1; Found: 231.0. ¹ H
NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.30
(brs, 1H), 11.14 (s, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 9.0, 4.6 Hz, 1H), 7.20 (dd, J = 10.1, 2.5 Hz, 1H), 6.94 (ddd, J = 9.2, 9.0, 2.5 Hz, 1H), 4.33 (dd, J = 9.5, 5.5 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.79 (dd , J = 18.0, 5.5 Hz, 1H).

Path B:
Alternatively, between 5-fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96 wt%, 1.00) and maleimide (1.5 eq, 5.17 g, 53.3 mmol, 1.50) The mixture was charged into a 50 mL container and then acetonitrile (3 L / kg, 15.0 mL, 11.7 g, 286 mmol, 100 wt%) and zinc chloride (1.05 eq, 5.08 g, 37.3 mmol, 100 Mass%) was added. The reaction was heated to 85 ° C. over 10 minutes and then kept at 85 ° C. for 24 hours. While still at 85 ° C., water (6 L / kg, 30.0 mL, 30.0 g, 1670 mmol, 100 wt%) was slowly added while maintaining the temperature above 80 ° C. A yellow solid precipitated. The reaction mixture was cooled to 50 ° C. over 1 hour, stirred at 50 ° C. for 2 hours, and then cooled to 10 ° C. over 1 hour. The reaction was stirred at 10 ° C. for 1 hour. The solid was filtered off and the filter cake was then washed twice with 5 ml of 1: 1 ACN / water to give the isolated compound (6.85 g, 6.85 g, 29.5 mmol, 83.1% yield). )

  For purification, the obtained isolated compound (6.85 g, 6.85 g, 29.5 mmol, 100% by mass) was charged into a container, and then tetrahydrofuran (6 L / kg, 41.1 mL, 36.4 g, 505 mmol, 100% by weight). The mixture was heated to 66 ° C. to make a homogeneous solution. Heptane (4 L / kg, 27.4 mL, 18.7 g, 187 mmol, 100 wt% was slowly added at 66 ° C., and solids began to precipitate after 5 volumes. The mixture was brought to 25 ° C. over 3 hours. Cooled, then filtered, washed with heptane and then dried in a high vacuum oven overnight Isolated compound (4.93 g, 4.93 g, 21.2 mmol, 100 wt%, yield 72.0% This isolated compound is Form 2 shown in FIG.

  This isolated compound 2 (1.00 g, 4.3 mmol, 100 wt%) was charged to a 50 ml container and tetrahydrofuran (6 L / kg, 6 mL, 100 wt%) and heptane (6 L / kg, 6 mL, 100% by weight). The slurry was stirred at 25 ° C. for 48 hours. The solid was filtered off and dried overnight in a high vacuum oven. Isolated compound: (0.89 g, 0.89 g, 3.83 mmol, 100 mass%, yield 89.00%). This isolated compound is Form 1 shown in FIG. 1A or FIG. 1B.

First powder X-ray diffraction:
Isolated Form 1 and 2 powder X-ray diffraction analysis, prepared as per Route B, was performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The divergence and scattering slits were set to 1 mm, and the light receiving slit was set to 0.6 mm. Diffracted radiation was detected with a PSD-Lynx Eye detector. The number of X-ray tube bolts and the number of amperes were set to 40 kV and 40 mA, respectively. Data was collected at Cu wavelengths from 3.0 degrees to 40.0 degrees 2θ using a step size of 0.020 degrees and a step time of 0.3 seconds in a θ-2θ goniometer. Samples were prepared in specially ordered cages and rotated during collection. Data was collected using Bruker DIFFRAC Plus software and analysis was performed with EVA Diffrac Plus software.

  The PXRD data file was not processed before the peak search. Using the peak search algorithm in EVA software, a peak was selected with a threshold value of 1 and a width value of 0.3, and a preliminary peak assignment was performed. The output of the automatic assignment was visually inspected to ensure certainty and was manually adjusted if necessary. Peaks having a relative intensity of 2% or more are summarized in Tables 1 and 2. Typical errors associated with peak positions from PXRD as described in USP and JP are up to +/− 0.2 ° 2θ. The spectrum from the PXRD method of this initial analysis is shown in FIG. 1A.

  In one embodiment, Form 1 is characterized by at least one of the characteristic peaks shown underlined. In another embodiment, Form 1 is characterized by two or more of the characteristic peaks indicated by underlining. In another embodiment, Form 1 is characterized by three or more, four or more, or all five of the characteristic peaks indicated by underlining. In some cases, Form 1 may additionally or alternatively be about 13.3 degrees 2θ, about 16.1 degrees 2θ, about 17.1 degrees 2θ, about 18.3 degrees 2θ, about 19.5 degrees 2θ, about 19. 9 degrees 2θ, about 20.1 degrees 2θ, about 20.7 degrees 2θ, about 21.3 degrees 2θ, about 22.2 degrees 2θ, about 23.6 degrees 2θ, about 23.8 degrees 2θ, about 24.6 Degree 2θ, about 26.1 degrees 2θ, about 26.6 degrees 2θ, about 27.1 degrees 2θ, about 27.7 degrees 2θ, about 28.0 degrees 2θ, about 28.6 degrees 2θ, about 29.9 degrees 2θ, about 32.5 degrees 2θ, about 32.9 degrees 2θ, about 33.1 degrees 2θ, about 35.2 degrees 2θ, about 35.6 degrees 2θ, about 36.1 degrees 2θ, about 37.1 degrees 2θ A powder X-ray diffraction spectrum comprising a peak at one or more of about 39.0 degrees 2θ, or about 39.9 degrees 2θ. In yet another alternative, Form I may additionally or alternatively 13.3 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ, 17.1 ± 0.2 degrees 2θ, 18.3 ± 0. 2 ° 2θ, 19.5 ± 0.2 ° 2θ, 19.9 ± 0.2 ° 2θ, 20.1 ± 0.2 ° 2θ, 20.7 ± 0.2 ° 2θ, 21.3 ± 0 2 ° 2θ, 22.2 ± 0.2 ° 2θ, 23.6 ± 0.2 ° 2θ, 23.8 ± 0.2 ° 2θ, 24.6 ± 0.2 ° 2θ, 26.1 ± 0 2 ° 2θ, 26.6 ± 0.2 ° 2θ, 27.1 ± 0.2 ° 2θ, 27.7 ± 0.2 ° 2θ, 28.0 ± 0.2 ° 2θ, 28.6 ± 0 2 ° 2θ, 29.9 ± 0.2 ° 2θ, 32.5 ± 0.2 ° 2θ, 32.9 ± 0.2 ° 2θ, 33.1 ± 0.2 ° 2θ, 35.2 ± 0 2 degrees 2θ, 35.6 ± 0.2 degrees 2θ, 36.1 ± 0.2 degrees 2θ, 37.1 ± 0.2 degrees 2θ, 9.0 ± 0.2 degrees 2 [Theta], or 39.9 may have a powder X-ray diffraction spectrum comprising a peak at one or more ± 0.2 degrees 2 [Theta].

  In one embodiment, Form 2 is characterized by at least one of the characteristic peaks indicated by underlining. In another embodiment, Form 2 is characterized by two or more of the characteristic peaks indicated by underlining. In another embodiment, Form 2 is characterized by three, or all four, of the characteristic peaks shown underlined. In some cases, Form 2 can additionally or alternatively be about 6.6 degrees 2θ, about 15.0 degrees 2θ, about 16.8 degrees 2θ, about 18.3 degrees 2θ, about 20.4 degrees 2θ, about 20. 9 degrees 2θ, about 21.6 degrees 2θ, about 23.0 degrees 2θ, about 23.2 degrees 2θ, about 23.9 degrees 2θ, about 24.3 degrees 2θ, about 24.7 degrees 2θ, about 24.9 Degree 2θ, about 25.1 degrees 2θ, about 27.5 degrees 2θ, about 28.6 degrees 2θ, about 28.8 degrees 2θ, about 29.7 degrees 2θ, about 31.7 degrees 2θ, about 36.5 degrees It may have a powder X-ray diffraction spectrum comprising a peak at one or more of 2θ, or about 37.3 degrees 2θ. In some cases, Form 2 may additionally or alternatively be 6.6 ± 0.2 degrees 2θ, 15.0 ± 0.2 degrees 2θ, 16.8 ± 0.2 degrees 2θ, 18.3 ± 0.2 degrees. 2θ, 20.4 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, 21.6 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, 23.2 ± 0.2 degrees 2θ, 23.9 ± 0.2 degrees 2θ, 24.3 ± 0.2 degrees 2θ, 24.7 ± 0.2 degrees 2θ, 24.9 ± 0.2 degrees 2θ, 25.1 ± 0.2 degrees 2θ, 27.5 ± 0.2 degrees 2θ, 28.6 ± 0.2 degrees 2θ, 28.8 ± 0.2 degrees 2θ, 29.7 ± 0.2 degrees 2θ, 31.7 ± 0.2 degrees It may have a powder X-ray diffraction spectrum including a peak at one or more of 2θ, 36.5 ± 0.2 degrees 2θ, or 37.3 degrees 2θ.

Path C:
Alternatively, between 5-fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96 wt%, 1.00) and maleimide (1.5 eq, 5.17 g, 53.3 mmol, 1.50) The mixture was charged into a 50 ml container and then acetonitrile (3 L / kg, 15.0 ml, 11.7 g, 286 mmol, 100 wt%) and zinc chloride (1.05 eq, 5.08 g, 37.3 mmol, 100 wt%). %). The reaction was heated to 85 ° C. over 10 minutes and then kept at 85 ° C. for 24 hours. While still at 85 ° C., water (6 L / kg, 30.0 ml, 30.0 g, 1670 mmol, 100 wt%) was slowly added while maintaining the temperature above 80 ° C. A yellow solid precipitated. The reaction mixture was cooled to 50 ° C. over 1 hour, stirred at 50 ° C. for 2 hours, and then cooled to 10 ° C. over 1 hour. The reaction was stirred at 10 ° C. for 1 hour. The solid was filtered off and the filter cake was then washed twice with 5 ml of 1: 1 ACN / water to give the isolated compound (6.85 g, 6.85 g, 29.5 mmol, 83.1% yield). )

  For purification, a sample of the above isolate (5.00 g, 21.5 mmol) is heated to reflux in acetonitrile (5 L / Kg, 25 ml). This is distilled under atmospheric pressure to a volume of 18 ml. Water (25 ml) is quickly added dropwise to the resulting slurry so that the reaction temperature remains at 70 to 75 ° C. After completion of the dropwise addition, the mixture is allowed to reach room temperature over about 90 minutes. Stir for another 2 hours at ambient temperature, then collect by suction filtration through filter paper, rinsing with acetonitrile / water (1/2). Transfer to a vacuum oven and dry at 50 ° C. overnight to give the product (4.72 g, 94.4% yield).

  For further purification, the product isolated as described above (5.02 g, 21.5 mmol) is heated in tetrahydrofuran (30 ml). The result is a solution at about 55 ° C. Heptane (30 ml) is introduced by rapid dropwise addition at such a rate that the reaction temperature remains at 50-55 ° C. When about 20 ml is added, a hazy precipitate begins to form. After the addition is complete, allow the mixture to reach 23 ° C over about 2 hours. Stir at ambient temperature for another 3 hours and then collect by suction filtration through filter paper, rinsing with heptane. Move to vacuum oven and dry overnight. In this way, the desired product (4.65 g, 92.6% yield), which is definitely Form 1, is obtained.

Alternative Powder X-Ray Diffraction Powder X-ray diffraction analysis was performed using a Bruker AXS D8 ADVANCE diffractometer equipped with a Cu radiation source (Kα average). This system is equipped with a 2.5-axis Soller slit on the primary side. On the secondary side, a 2.5-axis Soller slit and an electric slit are used. Diffracted radiation was detected with a Lynx Eye XE detector. The number of X-ray tube bolts and the number of amperes were set to 40 kV and 40 mA, respectively. Data was collected at Cu wavelengths from 3.0 degrees to 40.0 degrees 2θ using a step size of 0.037 degrees and a step time of 1920 seconds in a θ-θ goniometer. Samples were prepared in a Bruker sample holder (part number C79298A3244B261) and rotated during collection. Data was analyzed using Bruker EVA DIFFRAC software (version 3.1). The spectrum from this PXRD analysis is shown in FIG. 1B.

Solid state NMR:
Solid state NMR (ssNMR) analysis was performed at ambient temperature and pressure with a Bruker-BioSpin CPMAS probe installed on a Bruker-BioSpin Avance III 500 MHz (1H frequency) NMR spectrometer. A filled rotor containing approximately 80 mg of material was oriented at the magic angle and rotated at 15.0 kHz. Carbon ssNMR spectra were collected using proton-separated cross-polarization magic angle rotation (CPMAS) experiments. When acquiring the spectrum, a phase modulated proton separation field of 85 kHz was applied. The cross polarization contact time was set to 2 ms and the recirculation delay was set to 45 seconds. To obtain a reasonable signal to noise ratio, carbon ssNMR spectra were collected for 1024 scans. A carbon CPMAS experiment with a crystalline adamantane external standard was used to reference the carbon chemical shift scale, whose high field resonance was set to 29.5 ppm (determined from undiluted TMS). Fluorine ssNMR spectra were collected using proton separated direct polarization magic angle rotation (MAS) experiments. When acquiring the spectrum, a phase modulated proton separation field of 85 kHz was applied. The recirculation delay was set to 250 ms. Fluorine ssNMR spectra were collected for 32 scans. A direct polarization fluorine experiment with an external standard of 50/50 volume / volume trifluoroacetic acid and water was used and referenced to the fluorine chemical shift scale, whose resonance was set to -76.54 ppm. Automatic peak sorting was performed using Bruker-BioSpin TopSpin version 3.2 software. In general, a threshold of 5% relative intensity was used for the preselected peak. The output of the automatic peak selection was confirmed by visual inspection to ensure certainty, and was adjusted manually if necessary. Although detailed ¹³ C and ¹⁹ F solid state NMR peak values are reported herein, there is a range due to differences in instrumentation, sample, and sample preparation. This is a common skill in the field of solid-state NMR because the variability is inherent in the peak value. Typical variability of ¹³ C and ¹⁹ F chemical shift x-axis values is on the order of plus or minus 0.2 ppm for crystalline solids. The solid NMR peak heights reported herein are relative intensities. Solid state NMR intensity may vary depending on the actual setting of CPMAS experimental parameters and the thermal history of the sample.

  The purity of Form I prepared according to Methods B and C can be determined on an anhydrous solvent-free basis (ASFB) by high performance liquid chromatography (HPLC). In this HPLC procedure, a Waters Acquity UPLC system using a Waters HSS T3 2.1 × 150 mm, 1.8 μm column, 0.05% deionized methanesulfonic acid in water (v / v) and acetonitrile mobile phase, gradient chromatography conditions. And collect with 220 nM UV detection. Standards and samples are prepared in 75/25 deionized water / acetonitrile (v / v). Form I evaluated by this method is 99.5% pure for Form I prepared according to the method of Part B of this example and 99.7% pure for Form I prepared according to the method of Part C of this example. I know that.

  All publications cited herein are hereby incorporated by reference, US Provisional Patent Application No. 62 / 253,478 filed November 10, 2015, and United States Application filed May 15, 2015. The same applies to provisional patent application 62/161534. Although the invention has been described with reference to particular embodiments, it will be understood that modifications may be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims (40)

  A crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione (Form 1) of about 6.7 degrees 2θ, about 14.2 degrees 2θ, about 15. A crystalline form having a powder X-ray diffraction pattern that includes characteristic peaks at two or more of 0 degrees 2θ, about 16.4 degrees 2θ, or about 24.4 degrees 2θ.   The crystalline form of claim 1 comprising three or more of the peaks.   The crystalline form of claim 2, wherein the three or more peaks include peaks at least about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ.   The crystalline form of claim 1 comprising four or more peaks.   3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione crystal form (Form I), 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 A powder X-ray diffraction pattern containing characteristic peaks at two or more of degrees 2θ, 15.0 ± 0.2 degrees 2θ, 16.4 ± 0.2 degrees 2θ, or 24.4 ± 0.2 degrees 2θ. Having a crystalline form.   6. The crystalline form of claim 5, comprising three or more of the peaks.   7. The three or more peaks include at least peaks at 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, and 24.4 ± 0.2 degrees 2θ. Crystal form.   The crystal form according to any one of claims 1 to 7, having a powder X-ray diffraction pattern as shown in Fig. 1A or Fig. 1B.   The powder X-ray diffraction pattern was 13.3 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ, 17.1 ± 0.2 degrees 2θ, 18.3 ± 0.2 degrees 2θ, 19. 5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 20.1 ± 0.2 degrees 2θ, 20.7 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ, 22. 2 ± 0.2 degrees 2θ, 23.6 ± 0.2 degrees 2θ, 23.8 ± 0.2 degrees 2θ, 24.6 ± 0.2 degrees 2θ, 26.1 ± 0.2 degrees 2θ, 26. 6 ± 0.2 degrees 2θ, 27.1 ± 0.2 degrees 2θ, 27.7 ± 0.2 degrees 2θ, 28.0 ± 0.2 degrees 2θ, 28.6 ± 0.2 degrees 2θ, 29. 9 ± 0.2 degrees, 32.5 ± 0.2 degrees 2θ, 32.9 ± 0.2 degrees 2θ, 33.1 ± 0.2 degrees 2θ, 35.2 ± 0.2 degrees 2θ, 35.6 ± 0.2 degrees 2θ, 36.1 ± 0.2 degrees 2θ, 37.1 ± 0.2 degrees 2θ, 39.0 ± 0.2 degrees 2θ, or 9.9 further comprising peaks at one or more ± 0.2 degrees 2 [Theta], crystalline form according to any one of claims 1 to 8.   9. A compound according to any one of claims 1 to 8, lacking a peak at about 9.5 degrees 2θ and / or about 12.3 degrees 2θ.   The crystalline form according to any one of claims 1 to 10, wherein the melting point is higher than 195 ° C and up to 198 ° C. 3- (5-fluoro) having two or more ¹³ C solid state (ss) nuclear magnetic resonance (NMR) chemical shifts at about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm -H-indole-3-yl) pyrrolidine-2,5-dione crystal form. Has three ¹³ C solid (ss) nuclear magnetic resonance (NMR) chemical shifts at 39.2 ± 0.2 million parts per million (ppm), 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm , 3- (5-Fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione crystal form (Form 1).   14. Crystal form according to claim 12 or 13, having the ssNMR spectrum of FIG. 15. A crystalline form according to any one of claims 12 to 14, further characterized by a ¹⁹ F solid (ss) nuclear magnetic resonance (NMR) chemical shift at about -122.8 million fraction. Of 3- (5-Fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione having a solid (ss) nuclear magnetic resonance (NMR) ¹⁹ F chemical shift at about -122.8 million fraction Crystal form (Form 1).   The crystalline form of claim 16 having the ssNMR spectrum of FIG. Powder X-ray diffraction including characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, about 15.0 degrees 2θ, about 16.4 degrees 2θ, or about 24.4 degrees 2θ Pattern and one or more ¹³ C solid (ss) nuclear magnetism at (a) or (b), ie (a) about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm Resonance (NMR) chemical shift,
(B) a crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione characterized by at least one of the ssNMR spectra of the ¹⁹ F chemical shift at about -122.8 ppm ( Form 1). 19. The crystalline form of claim 18, wherein the one or more ¹³ C ssNMR chemical shifts are 39.2 ± 0.2 ppm, 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm. The crystal form according to claim 18 or 19, wherein the chemical shift of ¹⁹ F ssNMR is -122.8 ± 0.2 ppm.   21. A crystalline form according to any one of claims 18 to 20 comprising two or more of the X-ray peaks.   The crystal form according to any one of claims 18 to 21, comprising three or more of the X-ray peaks.   23. A crystalline form according to any one of claims 18 to 22 comprising two or more of the chemical shifts of (a).   24. A crystalline form according to any one of claims 16 to 23 comprising (a) and (b). (A) a powder X-ray diffraction pattern comprising a characteristic peak at one or more of 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, or 24.4 ± 0.2 degrees 2θ; And (b) characterized by one or more ¹³ C solid nuclear magnetic resonance chemical shifts at 39.2 ± 0.2 million parts per million (ppm), 124.7 ± 0.2 ppm, or 127.5 ppm ± 0.2 ppm A crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione (Form 1). (A) a powder X-ray diffraction pattern comprising a characteristic peak at one or more of 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, or 24.4 ± 0.2 degrees 2θ; And (b) a crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidin-2,5-dione having a solid state NMR spectrum of ¹⁹ F chemical shift at -122.8 ± 0.2 ppm ( Form 1).   A purified crystalline form of 3- (5-fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione (Form 1), comprising at least about 95% solvent and other solid forms of the compound A crystalline form characterized by the absence of.   28. A purified crystalline form according to claim 27 which is at least 97% pure.   28. A purified crystalline form according to claim 27 which is at least 99% pure.   30. The purified crystalline form of claim 29, which is at least 99.5% pure.   31. The purified crystalline form of claim 30, which is 99.7% pure.   32. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier or diluent.   32. A method of treating cancer or endometriosis in a mammal in need thereof, comprising administering to said mammal an effective amount of a crystalline form according to any one of claims 1-31. ,Method.   32. Crystalline form 1 according to any of claims 1 to 31, for use in treating cancer or endometriosis in a mammal in need thereof.   3- (5-Fluoro-1H-indole-3 having a powder X-ray diffraction pattern comprising characteristic peaks at two or more of about 9.5, about 12.3, and / or about 13.5 degrees 2θ -Yl) Crystalline form of pyrrolidine-2,5-dione (Form 2).   36. The crystalline form of claim 35, comprising three or more of the peaks.   37. A crystalline form according to claim 35 or 36 having a powder X-ray diffraction pattern as shown in FIG.   38. A crystalline form according to any one of claims 35 to 37, lacking characteristic peaks at about 6.7, about 15.0, and about 16.4 degrees 2θ.   The powder X-ray diffraction pattern is about 6.6, about 15.0, about 16.8, about 18.3, about 20.4, about 20.9, about 21.6, about 23.0, about 23. .2, 2, 23.9, 24.3, 24.7, 24.9, 25.1, 27.5, 27.5, 28.6, 28.8, 29.7, 31 39. The crystalline form according to any one of claims 35 to 38, further comprising a peak at one or more of .7, about 36.5, or about 37.3 degrees 2θ.   The powder X-ray diffraction pattern was 6.6 ± 0.2 degrees 2θ, 15.0 ± 0.2 degrees 2θ, 16.8 ± 0.2 degrees 2θ, 18.3 ± 0.2 degrees 2θ, 20. 4 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, 21.6 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, 23.2 ± 0.2 degrees 2θ, 23. 9 ± 0.2 degrees 2θ, 24.3 ± 0.2 degrees 2θ, 24.7 ± 0.2 degrees 2θ, 24.9 ± 0.2 degrees 2θ, 25.1 ± 0.2 degrees 2θ, 27. 5 ± 0.2 degrees 2θ, 28.6 ± 0.2 degrees 2θ, 28.8 ± 0.2 degrees 2θ, 29.7 ± 0.2 degrees 2θ, 31.7 ± 0.2 degrees 2θ, 36. 39. The crystalline form of any one of claims 35 to 38, further comprising a peak at one or more of 5 ± 0.2 degrees 2θ, or 37.3 degrees 2θ.

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