TW201706264A - Polymorph forms of pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO1 inhibitors - Google Patents

Abstract

Two distinct crystalline forms of a 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione are provided. Also provided are the use of these polymorphs as IDO1 inhibitors and/or for the treatment and/or prevention of cancer and endometriosis.

Description

Polymorphic form of pyrrolidine-2,5-dione derivative, pharmaceutical composition and method for use as guanamine 2,3-dioxygenase 1 (IDO1) inhibitor

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

Indole 2,3-dioxygenase 1 (IDO1) is an intracellular monomer containing proto-heme enzyme that catalyzes the first rate-limiting rate of L-tryptophanate (Trp) catabolism along the kynurenine pathway. The step leads to the production of N-methionine uridine. 95% of Trp is metabolized by this canine uryl acid pathway. The kynurenine pathway (KYN) initiates neural activity and production of immunomodulatory metabolites (collectively referred to as kynurenine) and provides dietary nicotinic acid precursors that complement the biosynthesis of NAD+ and NADP+.

By locally consuming tryptophan and increasing kynurenine, IDO1 expressed by antigen-presenting cells (APCs), such as dendritic cells (plasma-like DCs in tumor-draining lymph nodes), can greatly affect T-cells. Proliferate and survive and activate regulatory T cells, thereby reducing pro-inflammatory responses. Therefore, IDO1 provides an “immunity waiver” for organizations that experience chronic inflammation (eg, infectious and allergic diseases), transplants, and cancer. Since it is expected that this tolerogenic response can be carried out under various physiological and pathological conditions, the tryptophan metabolism and kynurenine production by IDO1 can represent a critical interface between the immune system and the nervous system. The performance of IDO1 can be Pro-inflammatory interleukins are up-regulated and detectable in a variety of tissues, including the placenta, spleen, thymus, lung, digestive tract, and central nervous system (reviewed in Munn et al, Trends Immunol, 2013, 34, 137-43).

IDO1 appears as a promising molecular target for novel therapeutics for the treatment of cancer and other disorders characterized by decreased local Trp levels and/or cytotoxic metabolites produced by the kynurenic pathway. Disease (reviewed in Munn et al, Trends Immunol, 2013, 34, 137-43). In fact, inhibition of IDO1 activity has been tested as a therapeutic strategy in preclinical models of many diseases, using the most widely used IDO1 inhibitor, the tryptophan analog L-1-methyltryptophan (L-1MT). . L-1MT alone or in combination with other agents in animal models of arthritis, ischemia-reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation and cancer Treatment attenuates disease severity (Uyttenhove et al, Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al, J Exp Med, 2013, 210, 7, 1389-1402). For cancer, IDO1 induction has been observed during the rejection of allogeneic tumors in vivo, indicating the possible role of this enzyme in tumor rejection (Uyttenhove et al, Nat Med, 2003, 9, 10, 1269-1274). ; Holmgaard et al, J Exp Med, 2013, 210, 7, 1389-1402). Cervical cancer cells (or HeLa cells) co-cultured with peripheral hemolymphocytes (PBL) are up-regulated by IDO1 activity to obtain an immunosuppressive phenotype. It is believed that the decrease in PBL proliferation when treated with interleukin-2 (IL2) is due to the release of IDO1 by tumor cells in response to PBL secretion of gamma interferon (IFN)-g (γ). Therefore, IDO1 activity in tumor cells can be used to attenuate the anti-tumor response process in which IFNγ plays a major role. Additional evidence based on the mechanism of tumor immunoresistance by tryptophan degradation by IDO1 is derived from the observation that most human tumors constitutively express IDO1 and that IDO1 in immunogenic mouse tumor cells prevents their rejection (reviewed in 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 specific T cells in the tumor The cumulative loss of position can be partially restored in the absence of significant toxicity by systemic treatment of mice with IDO1 inhibitors (Holmgaard et al, J Exp Med, 2013, 210, 7, 1389-1402).

IDO1 expression has been demonstrated by immunohistochemistry in a number of cancer patients. The ratio of IDO1 mRNA, protein or tryptophan to kynurenine has been altered especially in malignant melanoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, prostate cancer, cervical cancer, brain cancer, and uterus. Detected in the blood of patients with endometrial cancer and ovarian cancer. In several malignancies, the presence of IDO1 is an independent predictor of clinical outcomes (reviewed in Munn et al, Front Biosci, 2012, 4, 734-45).

Despite the significant interest in the potential of IDO1 inhibitors as agents, the initial inhibitors were identified by the modification of Trp rather than the discovery of molecules with novel structural backbones. In the early 2000s, the best IDO1 inhibitors contained predominantly competitive Trp derivatives (such as L-1-MT) and non-competitive porphyrins, which exhibited affinity in the micromolar range. Since 2006, some of the potent Nemo-level IDO1 inhibitors with novel structural backbones have been discovered by high-throughput screening, computational screening, or natural product isolation and optimization of core pharmacophores in the structure. Many of these IDO1 inhibitors have low micromolar activity or limited pharmacokinetics. Phase I/II clinical trial testing is currently being conducted on two IDO1 inhibitors for the treatment of relapsed or refractory solid tumors (reviewed in Dolušić et al., Expert Opin Ther Pat. 2013, 23, 1367-81).

At the same time, the importance of awakening and curing tumor immunosurveillance has been widely accepted as an important aspect of anti-cancer therapy (Motz et al., Immunity, 2013, 39, 1, 61-73). Immunological scoring of infiltrating T cell subsets is under development as a biomarker method and will allow for the determination of patient responsiveness to treatment (Galon et al, J Transl Med, 2012, 10, 1). Therefore, the industry is still very interested in finding new and powerful IDO1 inhibitors.

Therefore, there is a need for novel IDO1 inhibitors with improved cancer therapeutic and/or prophylactic efficacy.

The compounds, compositions, crystal forms and methods herein help to meet current demand for IDO1 inhibitors that can be administered to patients diagnosed with cancer or to individuals at risk of developing cancer.

In one aspect, a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) is provided, which has been included at about 6.7 degrees 2 θ , An X-ray powder diffraction pattern of characteristic peaks at one or more of about 14.2 degrees 2θ, about 15.0 degrees 2θ, about 16.4 degrees 2θ, and about 24.4 degrees 2θ. In another embodiment, the crystalline form 1 has a characteristic peak comprising one or more of 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 24.4 ± 0.2 degrees 2θ. X-ray powder diffraction pattern. In another embodiment, Crystalline 1 has two, three, four or more of the characteristic peaks.

In another aspect, there is provided a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having about 39.2, about 124.7 and Solid state (SS) nuclear magnetic resonance (NMR) of one or more ¹³ C chemical shifts at about 12.5 parts per million (ppm). In one embodiment, crystalline Form I has SS NMR at one or more ¹³ C chemical shifts at about 39.2 ± 0.2 ppm, 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm.

In another aspect, there is provided a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having a ratio of about -122.8 parts per million The SS NMR spectrum of the ¹⁹ F chemical shift at the rate. In one embodiment, the ¹⁹ F chemical shift is at -122.8 ± 0.2 ppm.

In another aspect, crystalline Form I has an X-ray powder 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, and at about 39.2 ppm, SS NMR of one or more ¹³ C chemical shifts at 124.7 ppm and about 127.5 ppm.

In another aspect, the crystalline Form I has an X-ray powder 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, and at about -122.8 ppm. SS NMR of the ¹⁹ F chemical shift.

In one embodiment, crystalline Form I comprises a characteristic peak as represented in Figures 1A and/or 1B. In another embodiment, Form 1 lacks a peak at about 9.5 degrees 2θ and/or about 12.3 degrees 2θ. In another embodiment, the melting point of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 1 is above 195 ° C or above 196 ° C, ie, 197 °C.

In another aspect, there is provided a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 2) having a composition comprising about 9.5 degrees 2θ, An X-ray powder diffraction pattern of characteristic peaks at about 12.3 degrees 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ. In one embodiment, the characteristic peaks are as represented in FIG. In another embodiment, the compound lacks a peak at about 6.7 degrees 22. In another embodiment, the melting point of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 2 is above 195 °C, ie, 196 °C.

Other aspects and advantages of the invention will become apparent from the Detailed Description.

Figure 1A is a 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form as described in the initial powder x-ray diffraction (PXRD) analysis technique of Example 1. 1 X-ray powder diffraction spectrum.

Figure 1B is an X-ray powder diffraction of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 1 as described in Example 1 in place of the PXRD analysis technique. spectrum.

Figure 2 is an X-ray powder diffraction spectrum of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione Form 2.

Figure 3 is a ¹³ C solid state NMR spectrum of Form I prepared as described in Part C of Example 1. The peak side of the peak is marked by a hash mark.

Figure 4 is a ¹⁹ F solid state NMR spectrum of Form I prepared as described in Part C of Example 1. The peaks rotated by the hash marks are rotated sidebands.

Compound

Provided herein are crystalline polymorphic forms 1 and crystalline polymorphic forms 2 of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione. Compositions or medicaments containing Form 1, Form 2, or a combination thereof, in a pharmaceutically acceptable carrier or excipient are also provided. It also describes its use. These novel polymorphic forms have advantageous properties in terms of pharmacokinetics, ease of manufacture (provisioning), and stability of the dosage form for improved storage and/or packaging convenience.

The term "characteristic peak" means a powder which clearly identifies 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione as the crystalline form (Form 1 or Form 2) mentioned. The presence of x-ray diffraction peaks. Typically, powder X-ray diffraction analysis is performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source or other suitable equipment.

In one embodiment, the polymorphic form 1 of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione is characterized by comprising at about 6.7 degrees 22. and about 14.2 degrees. An X-ray powder diffraction pattern of characteristic peaks at one or more of 2θ, about 15.0 degrees 2θ, about 16.4 degrees 2θ, or about 24.4 degrees 2θ. In one embodiment, Form 1 contains two or more, three or more, four or more, or all five of the characteristic peaks. For example, Form I can contain X-ray powder at 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. A combination of diffraction pattern characteristic peaks. In another example, there may be three characteristic peaks at about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ, which may be further combined with the fourth peak. All five peaks can exist as appropriate.

For example, polymorphic form 1 of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione is characterized by being comprised at 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees. An X-ray powder diffraction pattern of characteristic peaks at one or more of 2θ, 15.0±0.2 degrees 2θ, 16.4±0.2 degrees 2θ, or 24.4±0.2 degrees 2θ. In one embodiment, Form 1 contains two or more, three or more, four or more, or all five of the peaks. For example, Form I can be contained at 6.7 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ and 15.0 ± 0.2 degrees 2θ, 15.0 ± 0.2 degrees 2θ and 16.4 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ. With 15.0 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees A combination of characteristic peaks of X-ray powder diffraction patterns at 2θ and 14.2 ± 0.2 degrees 2θ or 14.2 ± 0.2 degrees 2θ and 16.4 ± 0.2 degrees 2θ. 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, which may be further combined with the fourth peak. All five peaks can exist as appropriate.

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

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

In another embodiment, Form I can be characterized by one or more of a combination of one or more of the powder X-ray powder diffraction characteristic peaks and a SS NMR chemical shift peak of ¹³ C. Form I can be characterized by the presence of two or more or three or more of the powder X-ray diffraction peaks. Form I can 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 characterized by a combination of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees 2θ, as appropriate Further combination with the SS NMR chemical shift peak of ¹³ C provided herein.

In another embodiment, Form I is characterized by a combination of one or more of the characteristic X-ray powder diffractions and an SS NMR chemical shift of ¹⁹ F. Form I can be characterized by the presence of two or more or three or more of the powder X-ray diffraction peaks. In one embodiment, Form I is characterized by a combination of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees 2θ, as appropriate Further combined with the SS NMR chemical shift peak of ¹⁹ F provided herein. In another embodiment, Form I is characterized by one or more of the SS NMR chemical shift peaks of ¹³ C and a combination of SS NMR chemical shift peaks of ¹⁹ F. Form I can be characterized by the presence of two or more or three or more of the powder X-ray diffraction peaks. In one embodiment of this combination, Form I is characterized by a combination of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees 2θ, about 14.2 degrees 2θ, or about 24.4 degrees 2θ. Further, in combination with one or more of the ¹³ C SS NMR chemical shift peaks and/or the ¹⁹ F SS NMR chemical shift peak.

In one embodiment, Form I is characterized by a combination of one or more of the X-ray powder diffraction pattern characteristic peaks 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. . In another embodiment, Form I is characterized by having a minimum of the three peaks.

In one embodiment, the compound does not contain Form 2, ie, lacks the characteristic peak of Form 2, including, about 9.5 degrees 2θ, about 12.3 degrees 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ.

In one embodiment, the melting point of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 1 is above 195 ° C (ie, above 195.0 ° C to 195.9 ° C) . In another embodiment, the melting point of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 1 is in the range of about 197 ° C, for example, 196.6 ° C to 197.99 °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, crystalline Form 1 as 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. "Pure" means free of contaminants including, for example, solvents, other crystalline forms and/or amorphous forms. In another embodiment, a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 2) is provided, characterized in that it is included at about 9.5 degrees An X-ray powder diffraction pattern of characteristic peaks at two or more of 2θ, about 12.3 degrees 2θ, about 13.5 degrees 2θ, and about 14.3 degrees 2θ. In a In one embodiment, Form 2 is characterized by at 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, 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. Form 2 may also contain three or more or all four of the characteristic peaks. Suitably, the compound lacks the characteristic peak of Form 1, including 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. In another embodiment, the powder X-ray diffraction characteristic peak of Form 2 is at two or more of 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. .

The melting point of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione form 2 is above 195 ° C (eg, 196 ° C or higher) or about 196 ° C. In one embodiment, polymorphic 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 pharmaceutical and pharmaceutical compositions as described herein. References to the discussion of such compositions and uses may refer to "compounds."

The term "3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione" as used herein refers to a racemic compound having the following structure:

The term "polymorph" as used herein refers to a crystalline form having the same chemical composition but differing in the spatial arrangement of molecules, atoms and/or ions forming crystals. In general, as used throughout the specification, reference is made to the polymorph of the racemic 3-(5-fluoro-1H-indol-3-yl)pyrrolidin-2,5-dione compound. As described herein, the racemic compound of Formula II is based on the molar ratio of the two isomer/mironomers (about 48 mol% to about 52 mol% or about 1:1 ratio). It contains about 50% of the R-mirromer and about 50% of the S-mirromer.

Set forth in the Examples herein-based compound used ChemBioDraw ^® Ultra 12.0 Edition (PerkinElmer) named.

The term "free acid" as used herein refers to a non-salt form of the compound.

Production method

The compounds of the present invention can be prepared in a variety of ways by reactions known to those skilled in the art. An illustrative protocol for the preparation of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione is provided under the heading "Pyrrolidine-2" filed on March 15, 2014. U.S. Provisional Patent Application Serial No. 61/996,976, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in In the application.

According to one embodiment, selective separation of the mirror image isomers starting from the corresponding racemic compound can be achieved by chiral HPLC, such as, but not limited to, using Chiralpak® AS-H, Chiralcel® OJ-H or Chiralpak® IC tubes. The column is a mixture of suitable solvents, such as, but not limited to, supercritical CO ₂ , ethanol, methanol, hexane.

The reaction schemes set forth in the Examples section are merely illustrative and are not to be construed as limiting the invention in any way.

use

The invention further relates to an agent comprising as an active ingredient at least one compound of the invention (for example, Form I or Form II).

The invention also provides a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. By "acceptable" is meant to be compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, it is meant to be injurious to the recipient in such amounts.

According to one embodiment, the invention also encompasses pharmaceutical compositions which, besides containing the compound of the invention as an active ingredient, also contain additional therapeutic agents and/or active ingredients.

In a non-limiting example, the compounds of the invention may be formulated as pharmaceutical preparations suitable for the following administration forms: oral administration, parenteral administration (for example by intravenous, intramuscular or subcutaneous injection or intravenously) Infusion), local administration (including transocular), administration by inhalation, by skin patch, by implant, by suppository, and the like. Such suitable administration forms (which may be solid, semi-solid or liquid depending on the mode of administration), as well as methods and carriers, diluents and excipients used in the preparation thereof, will be familiar to the art. It is clear; refer to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, non-limiting examples of such formulations include lozenges, pills, powders, lozenges, sachets, cachets, elixirs for administration as a bolus and/or for continuous administration. Suspending agents, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and aseptically packaged powders (which are usually reconstituted before use) It may be formulated with carriers, excipients and diluents which are themselves suitable for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, yellow Silicone, gelatin, calcium citrate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methyl cellulose, methyl hydroxybenzoate and propyl hydroxybenzoate, Talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulation may optionally contain other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, accumulating agents, fillers, preservatives, sweeteners, flavorings. Agent, flow regulator, release agent, etc. The compositions may also be formulated to provide rapid, sustained or delayed release of the active compounds contained therein.

The pharmaceutical preparations of the invention are preferably in unit dosage form and may be suitably packaged, for example, in a cartridge, blister, vial, vial, sachet, ampule or in any other suitable single or multiple dose holder or container ( It may be suitably labeled); as appropriate, with one or more single pages containing product information and/or instructions for use.

The active compound of the present invention depends on the condition and the route of administration to be prevented or treated. The subject can be administered as a single daily dose, divided into one or more daily doses, or administered substantially continuously, for example using a drip infusion.

The invention also relates to the use of a compound of the invention for 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 used to treat and/or prevent 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 used to treat and/or prevent endometriosis.

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

In one embodiment, the compounds of the invention are used to promote immunological recognition and destruction of cancer cells.

Thus, the compounds of the invention are useful as medicaments, especially 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 the treatment and/or prevention of cancer.

Various cancers are known in the industry. Cancer can 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.

Other cancers that can be treated using the methods of the 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 cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophagus 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 ( Including epithelial cells, stromal cells, germ cells and stromal cells, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms tumor, sarcoma ( Including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma, skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma), testicular cancer, including embryonic tissue Tumors (seminoma and non-seminoma, such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, and thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma).

In one embodiment, the cancer is biliary tract cancer. In one embodiment, the cancer is a brain cancer, 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 Paeder's disease. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is oral cancer, including squamous cell carcinoma. In one embodiment, the cancer is ovarian cancer, including those derived from epithelial cells, stromal cells, germ cells, and mesenchymal cells. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In a In one embodiment, the cancer is rectal cancer. In one embodiment, the cancer is a 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 a skin cancer, including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma. In one embodiment, the cancer is a testicular cancer, including embryonic tissue tumors (spermatogonia and non-seminoma, such as teratoma and choriocarcinoma). 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 adenocarcinoma and medullary carcinoma.

Examples of non-solid tumors include, but are not limited to, hematological tumors. As used herein, hematological oncology is an industry term that includes lymphoid disorders, bone marrow disorders, and AIDS-related leukemia.

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's lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemia includes, for example, T cell chronic lymphocytic leukemia and B cell chronic lymphocytic leukemia.

In one embodiment, the lymphoid disorder is acute lymphocytic leukemia. In one embodiment, the lymphoid 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 a non-Hodgkin's lymphoma. In one embodiment, the lymphoma is lymphocytic lymphoma. In one embodiment, the chronic lymphocytic leukemia is a T cell chronic lymphocytic leukemia. In one embodiment, the chronic lymphocytic leukemia is a B cell chronic lymphocytic leukemia.

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

This 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 the synthesis of IDO1 inhibitors.

According to another feature of the invention, there is provided a method for modulating IDO1 activity in an individual in need of such treatment comprising administering to the individual an effective amount of a compound of the invention.

According to another feature of the invention, there is provided the use of a compound of the invention for the manufacture of a medicament for modulating IDO1 activity in an individual in need of such treatment comprising administering to the individual an effective amount of a compound of the invention.

definition

In the present invention, the following terms have the following meanings: Where the group may be substituted, such groups may be substituted with one or more substituents, and are preferably substituted with one, two or three substituents. The substituent may be selected from, but not limited to, a group comprising, for example, a halogen, a hydroxyl group, a pendant oxy group, a nitro group, a decylamino group, a carboxyl group, an amine group, a cyano group, a halogenated alkoxy group, and a haloalkyl group.

The term "halogen" or "halo" means fluoro (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halo groups are fluorine and chlorine.

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl group of the formula C _n H _2n+1 wherein n is greater than or equal to 1. In general, the alkyl group of the present invention contains 1 to 6 carbon atoms (C1, C2, C3, C4, C5 or C6 carbon, including C1 and C6), preferably 1 to 4 carbon atoms, more preferably 1 to 3 One carbon atom. The alkyl group can be straight or branched and can be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and tert-butyl, pentyl and isomers thereof (eg n-pentyl, iso-) Butyl) and hexyl and their isomers (eg, n-hexyl, isohexyl). The alkyl group may be substituted with 1, 2 or 3 substituents, as the case may be. This substituent may be a hydroxyl group, an amine group, a halogen or a C1-C3 alkyl group. In one embodiment, the halogen substituent is F or Br. In another embodiment, the alkyl substituent is methyl. The term "alkoxy" refers to any O-alkyl group.

The term "amino" means -NH ₂ group or by combined organic aliphatic or aromatic groups substituted with one or two hydrogen atoms of any group derived therefrom. Preferably, the group derived from -NH ₂ is an "alkylamino" group, i.e., an N-alkyl group, which comprises a monoalkylamino group and a dialkylamino group. According to certain embodiments, the term "amino" means NH _2, NHMe or NMe _2.

The term "amino protecting group" refers to a protecting group for an amine functional group. According to a preferred embodiment, the amine protecting group is selected from the group consisting of an arylsulfonyl group, a third butoxycarbonyl group, a methoxymethyl group, a p-methoxybenzyl group or a benzyl group.

The term "solvate" is used herein to describe a compound of the invention containing one or more pharmaceutically acceptable solvent molecules (e.g., ethanol) in stoichiometric or substoichiometric amounts. The term "hydrate" means the case when the solvent is water.

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

The term "prodrug" as used herein means a pharmacologically acceptable derivative, such as guanamine, which bioinverts the in vivo to produce a bioactive drug. Prodrugs are typically characterized by increased bioavailability and are readily metabolized into bioactive compounds in vivo.

The term "prodrug" as used herein means any compound that will be modified to form a drug substance, wherein the modification can occur in vivo or in vitro, and occurs before or after the prodrug reaches the body region indicative of administration of the drug.

The term "individual" refers to a mammal, preferably a human. In one embodiment, the individual may be a "patient", ie, a warm-blooded animal, a better human being, who is awaiting or receiving medical care or has been/being a medical procedure, or is being monitored for disease. development of.

The term "human" refers to two genders and is at any stage of development (ie, newborn, infant, juvenile, adolescent, adult).

The term "treat, treating, and treating" as used herein is intended to include Alleviates, attenuates or eliminates the condition or disease and/or its accompanying symptoms.

The term "prevent, prevention, and prevention" as used herein refers to delaying and/or preventing the onset of a condition or disease and/or its accompanying symptoms, preventing the individual from suffering from a condition or disease, or reducing the condition or disease of the individual. The method of risk.

The term "therapeutically effective amount" (or more simply "effective amount") as used herein means an amount of the active agent or active ingredient in the individual to which it is administered sufficient to achieve the desired therapeutic or prophylactic effect.

The term "administration" or variants thereof (eg, "administering") means that the individual to be treated or prevented for its condition, symptom or disease is provided alone or as a pharmaceutically acceptable composition. A portion of the active agent or active ingredient.

"Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition are compatible with each other and are not deleterious to the individual to whom they are administered.

The term "inhibitor" refers to a natural or synthetic compound that has a biological effect of inhibiting or significantly reducing or downregulating the expression of a gene and/or protein or having a biological effect of inhibiting or significantly reducing the biological activity of the protein. Thus, "IDO1 inhibitor" refers to a compound that has a biological effect of inhibiting or significantly reducing or downregulating the expression of a gene encoding IDO1 and/or the performance of IDO1 and/or the biological activity of IDO1.

Both "D" and "d" are indicators. "dx.y" means a radical substituted by x to y. "Stereoisomer" means both enantiomers and diastereomers. When one or more hydrogen atoms of a group are replaced by a corresponding number of substituent atoms (if a substituent atom) or a group (if a substituent group), the group is "substituted with a substituent". For example, "substituted by hydrazine" means that one or more hydrogen atoms are replaced by a corresponding number of deuterium atoms.

The words "including" ("comprise", "comprises" and "comprising") are interpreted in an inclusive manner and not in an exclusive manner. The words "consist, consingting" and their variants are interpreted in an exclusive manner and not in an inclusive manner.

The term "about" as used herein, unless otherwise specified, means that the reference amount given is (±) 10%.

Instance

The invention will be better understood with reference to the following examples. The examples are intended to represent a particular embodiment of the invention and are not intended to limit the scope of the invention.

I. Chemistry example

The MS data provided in the examples described below was obtained as follows: Mass Spectrum: LC/MS Agilent 6110 (ESI) or Waters Acquity SQD (ESI).

NMR data in the system provided in the Examples below was obtained as follows: Bruker Ultrashield ^TM 400 PLUS and Bruker Fourier 300MHz and using TMS as an internal standard.

Microwave chemistry was performed on a single mode microwave reactor Initiator Microwave System EU from Biotage.

Unless otherwise reported, otherwise, equipped with a mass Xbridge ^TM Prep C18 OBD column (19 × 150mm 5μm) of the orientation from Waters autopurification Fractionlynx be purified by preparative HPLC. Using gradient 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 ₂ O (0.1%) All HPLC purifications were performed.

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

A. Route A

A mixture of 5-fluoro- 1H -indole (300 mg; 2.22 mmol) and maleimide (646 mg; 6.65 mmol) in AcOH (2 mL) was stirred at 170 ° C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was neutralized to pH 7 ~ 8 and extracted with EtOAc (10mL × 3) with saturated aqueous NaHCO _3. The organic layer was dried over anhydrous Na ₂ SO ₄ dried, filtered, concentrated, and purified by preparative HPLC to give 180mg (35%) of the title compound as a yellow solid. _{C 12 H 9 FN 2 O 2} -H - [MH] The LC-MS: Calcd: 231.1; Found: 231.0. ^{1 H NMR (300MHz, DMSO- d} 6) δ [ppm]: 11.30 (brs, 1H), 11.14 (s, 1H), 7.41 (d, J = 2.5Hz, 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).

Route B:

Alternatively, a mixture of 5-fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96% by mass, 1.00) and maleimide (1.5 equivalents, 5.17 g, 53.3 mmol, 1.50) is placed in a 50 mL container. Then, acetonitrile (3 L/kg, 15.0 mL, 11.7 g, 286 mmol, 100% by mass) and zinc chloride (1.05 equivalent, 5.08 g, 37.3 mmol, 100% by mass) were added. The reaction was heated to 85 ° C over 10 minutes and then maintained at 85 ° C for 24 hours. While still at 85 ° C, water (6 L/kg, 30.0 mL, 30.0 g, 1670 mmol, 100% by mass) 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, then 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, and then the filter cake was 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 the purification, the obtained isolated compound (6.85 g, 6.85 g, 29.5 mmol, 100% by mass) was charged to a container, followed by the addition of tetrahydrofuran (6 L/kg, 41.1 mL, 36.4 g, 505 mmol, 100% by mass). This mixture was heated to 66 ° C to form a homogeneous solution. Heptane (4 L/kg, 27.4 mL, 18.7 g, 187 mmol, 100% by mass) was slowly added at 66 ° C; solids began to precipitate after 5 volumes. Allow the mixture to cool to 3 hours It was filtered at 25 ° C, then washed with heptane and then dried overnight in a high vacuum oven. The compound was isolated (4.93 g, 4.93 g, 21.2 mmol, 100% yield, 72.0% yield). This isolated compound is Form 2 shown in Figure 2.

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

Initial powder X-ray diffraction:

Powder X-ray diffraction analysis of isolated forms 1 and 2 as prepared in Route B was carried out using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit and the scattering slit were set to 1 mm, and the receiving slit was set to 0.6 mm. The diffraction radiation is detected by a PSD-Lynx Eye detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data were collected at Cu wavelength from 3.0 degrees 2θ to 40.0 degrees 2θ in a θ-2θ goniometer using a step length of 0.020 degrees and a step of 0.3 seconds. The sample was prepared by placing it in a guest holder and rotating during collection. Data was collected using the Bruker DIFFRAC Plus software and analyzed by the EVA Diffrac Plus software.

The PXRD data file is not processed before the peak search. Using the peak search algorithm in the EVA software, the peak is selected with a threshold of 1 and a width of 0.3 to obtain a preliminary peak assignment. Visually check the output of the automatic attribution to ensure validity and manual adjustment if necessary. Relative Strength The 2% peaks are summarized in Tables 1 and 2. Typical errors associated with peak positions from PXRD as described in USP and JP are as high as +/- 0.2° 2θ. The spectrum of the PXRD method from this initial analysis is provided in Figure 1A.

In one embodiment, Form 1 is characterized by at least one of the underlined characteristic peaks. In another embodiment, Form 1 is characterized by two or more of the underlined characteristic peaks. In another embodiment, Form 1 is characterized by three or more, four or more, or all five of the underlined characteristic peaks. Optionally, Form 1 may further or alternatively have a powder X-ray diffraction spectrum comprising one or more of the following peaks: 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 degrees 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, about 39.0 degrees 2θ, or about 39.9 degrees 2θ. In another option, Form I may further or alternatively have a powder X-ray diffraction spectrum comprising one or more of the following peaks: 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 Degree 2θ, 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 39.9 ± 0.2 degrees 2θ.

In one embodiment, Form 2 is characterized by at least one of the underlined characteristic peaks. In another embodiment, Form 2 is characterized by two or more of the underlined characteristic peaks. In another embodiment, Form 2 is characterized by three or all four of the underlined characteristic peaks. Optionally, Form 2 may further or alternatively have a powder X-ray diffraction spectrum comprising one or more of the following peaks: 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 degrees 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 2θ, or about 37.3 degrees 2θ. Optionally, Form 2 may further or alternatively have a powder X-ray diffraction spectrum comprising one or more of the following peaks: 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, 36.5±0.2 degrees 2θ or 37.3 degrees 2θ.

Route C:

Alternatively, a mixture of 5-fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96% by mass, 1.00) and maleimide (1.5 equivalents, 5.17 g, 53.3 mmol, 1.50) is placed in a 50 ml container. Then, acetonitrile (3 L/kg, 15.0 ml, 11.7 g, 286 mmol, 100% by mass) and zinc chloride (1.05 equivalent, 5.08 g, 37.3 mmol, 100% by mass) were added. The reaction was heated to 85 ° C over 10 minutes and then maintained at 85 ° C for 24 hours. While still at 85 ° C, water (6 L/kg, 30.0 ml, 30.0 g, 1670 mmol, 100% by mass) 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, then 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, and then the filter cake was 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) was heated to reflux in acetonitrile (5 L / Kg, 25 mL). This was distilled under atmospheric pressure to a volume of 18 ml. Water (25 ml) was quickly added dropwise to the resulting slurry to maintain the reaction temperature at 70-75 °C. After the addition was completed, it was allowed to reach room temperature over about 90 minutes. It was stirred for an additional 2 hours at ambient temperature and then collected by suction filtration through paper and rinsed with acetonitrile/water (1/2). Transfer to The product was dried (50.

The product isolated above (5.02 g, 21.5 mmol) A solution was produced at about 55 °C. Heptane (30 ml) was quickly introduced dropwise at a rate to maintain the reaction temperature at 50-55 °C. After addition of about 20 ml, a cloudy precipitate began to form. After the addition was completed, the mixture was allowed to reach 23 ° C over about 2 hours. It was stirred for an additional 3 hours at ambient temperature and then collected by filtration through a paper suction and rinsed with heptane. Transfer to a vacuum oven overnight. The desired product of the correct form 1 (4.65 g, 92.6% yield) was thus 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 (K-alpha average). The system is equipped with a 2.5-axis Soller slit on the primary side. The secondary side utilizes a 2.5-axis Soller slit and a motorized slit. The diffraction radiation is detected by a Lynx Eye XE detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data were collected at Cu wavelength from 3.0 degrees 2θ to 40.0 degrees 2θ in a θ-θ goniometer using a step length of 0.037 degrees and a step of 1920 seconds. Samples were prepared by placing them on a Bruker sample holder (part number: C79298A3244B261) and rotating during collection. Data was analyzed using the Bruker EVA DIFFRAC software (version 3.1). The spectroscopy from this PXRD analysis is provided in Figure 1B.

Solid state NMR:

Solid state NMR (ss NMR) analysis was performed on a Bruker-BioSpin CPMAS probe positioned in a Bruker-BioSpin Avance III 500 MHz (1H frequency) NMR spectrometer at ambient temperature and pressure. The filled rotor containing approximately 80 mg of material was oriented at a magic angle and rotated at 15.0 kHz. Carbon ssNMR spectra were collected using a Proton Decoupled Cross Polarized Magic Angle Rotation (CPMAS) experiment. A phase modulation proton decoupling field of 85 kHz is applied during spectral acquisition. The cross polarization contact time was set to 2 ms and the cycle delay was set to 45 seconds. Carbon scans of 1024 scans were collected to obtain sufficient signal to noise ratio. The high-field resonance was set to 29.5 ppm (as determined from pure TMS) using a carbon CPMAS experiment on an external standard for crystalline adamantane with reference to a carbon chemical shift scale. Fluorine ssNMR spectra were acquired using a proton decoupled direct polarization magic angle rotation (MAS) experiment. A phase modulation proton decoupling field of 85 kHz is applied during spectral acquisition. Set the loop delay to 250ms. Fluorine ssNMR spectra of 32 scans were collected. The fluorine chemical shift scale was referenced using a direct polarized fluorine test of 50/50 (vol/vol) trifluoroacetic acid and an external standard of water, and the resonance was set to -76.54 ppm. Automated peak selection was performed using Bruker-BioSpin TopSpin version 3.2 software. Typically, a threshold of 5% relative intensity is used to initially select the peak. Visually check the output of the automatic peak selection to ensure validity and manual adjustment if necessary. Although specific ¹³ C and ¹⁹ F solid state NMR peaks are reported herein, these peaks are subject to a range of instrument, sample, and sample preparation differences. This is a common practice in solid state NMR technology due to inherent variations in peaks. A typical change in the x-axis value of the ¹³ C and ¹⁹ F chemical shifts of the crystalline solid is about ± 0.2 ppm. The solid state NMR peak height reported herein is the relative intensity. The solid state NMR intensity can vary depending on the actual settings of the 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 by high performance liquid chromatography (HPLC) on an anhydrous solvent free base (ASFB). The HPLC procedure was performed using a Waters Acquity UPLC system and a Waters HSS T32.1 x 150 mm, 1.8 μm column using a 0.05% methanesulfonic acid (v/v) and acetonitrile mobile phase in deionized water and gradient chromatography conditions at 220 nM UV detection. Collect under. Standards and samples were prepared in 75/25 deionized water/acetonitrile (v/v). It was found that for Form I prepared according to the method of Part B of this example, Form I evaluated by this method was 99.5% pure, and for Form I prepared according to the method of Part C of this example, it was 99.7. %pure.

All publications cited in the present specification are hereby incorporated by reference in their entirety in U.S. U.S. Serial No. 62/253,478, filed on November 10, 2015, and filed on May 15, 2015 U.S. Provisional Patent Application No. 62/161534. Although the invention has been described with reference to the specific embodiments thereof, it is 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 accompanying claims.

Claims (40)

A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having a powder comprising characteristic peaks at two or more of the following X-ray diffraction pattern: 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. A crystalline form of claim 1, which comprises three or more such peaks. The crystalline form of claim 2, wherein the three or more peaks comprise the peaks at least at about 6.7 degrees 2θ, about 14.2 degrees 2θ, and about 24.4 degrees 2θ. A crystalline form of claim 1, which comprises four or more peaks. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form I) having a powder comprising characteristic peaks at two or more of the following X-ray diffraction pattern: 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 15.0 degrees ± 0.22θ, 16.4 ± 0.2 degrees 2θ, or 24.4 ± 0.2 degrees 2θ. A crystalline form of claim 5, which comprises three or more such peaks. The crystalline form of claim 6, wherein the three or more peaks comprise the peaks at least at 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, and 24.4 ± 0.2 degrees 2θ. A crystalline form according to any one of claims 1 to 7, which has an X-ray diffraction pattern as shown in Fig. 1A or Fig. 1B. The crystalline form of any one of claims 1 to 7, wherein the powder X-diffraction pattern further comprises a peak at one or more of the following: 13.3 ± 0.2 degrees 2θ, 16.1, ± 0.2 degrees 2θ, 17.1 ± 0.2 Degree 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 2θ, 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 39.9 ± 0.2 degrees 2θ. The crystalline form of any one of claims 1 to 7, which lacks a peak at about 9.5 degrees 2θ and/or about 12.3 degrees 2θ. The crystalline form of any one of claims 1 to 7, which has a melting point of from 195 ° C. to 198 ° C. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione having about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm Solid state (ss) nuclear magnetic resonance (NMR) of two or more ¹³ C chemical shifts. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having a ratio of 39.2 ± 0.2 parts per million (ppm), 124.7 ± Solid state (ss) nuclear magnetic resonance (NMR) of three ¹³ C chemical shifts at 0.2 ppm or 127.5 ± 0.2 ppm. The crystalline form of claim 12 or claim 13 has the ssNMR spectrum of Figure 3. The crystalline form of claim 12 or claim 13, wherein the crystalline form is further characterized by solid state (ss) nuclear magnetic resonance (NMR) of ¹⁹ F chemical shift at about -122.8 parts per million. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having a ¹⁹ F chemical shift at about -122.8 parts per million Solid state (ss) nuclear magnetic resonance (NMR). The crystalline form of claim 16 has the ssNMR spectrum of Figure 4. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) characterized by comprising about 6.7 degrees 2θ, about 14.2 degrees 2θ, about A powder X-ray diffraction pattern of one or more characteristic peaks of 15.0 degrees 2θ, about 16.4 degrees 2θ, or about 24.4 degrees 2θ, and at least one of (a) or (b): (a) at about 39.2 parts per million. Solid (ss) nuclear magnetic resonance (NMR) of one or more ¹³ C chemical shifts at (ppm), about 124.7 ppm or about 127.5 ppm, and (b) ssNMR spectra of ¹⁹ F chemical shifts at about -122.8 ppm . The crystalline form of claim 18, wherein the one or more ¹³ C chemical shifts of the ssNMR are 39.2 ± 0.2 ppm, 124.7 ± 0.2 ppm, or 127.5 ± 0.2 ppm. The crystalline form of claim 18 or 19, wherein the ssNMR of the ¹⁹ F chemical shift is -122.8 ± 0.2 ppm. A crystalline form of claim 18 or 19 which comprises two or more of said X-ray peaks. A crystalline form of claim 18 or 19 comprising three or more of said X-ray peaks. A crystalline form of claim 18 or 19 which comprises two or more of the chemical shifts of (a). The crystalline form of any one of claims 16 to 19, which comprises (a) and (b). A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1), characterized in that: (a) is contained in 6.7 ± 0.2 degrees 2θ, 14.2 a powder X-ray diffraction pattern of characteristic peaks of one or more of ± 0.2 degrees 2θ or 24.4 ± 0.2 degrees 2θ, and (b) at 39.2 ± 0.2 parts per million (ppm), 124.7 ± 0.2 ppm or 127.5 ppm ± Solid state nuclear magnetic resonance with one or more ¹³ C chemical shifts at 0.2 ppm. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) having (a) contained at 6.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 A powder X-ray diffraction pattern of characteristic peaks at one or more of 2θ or 24.4 ± 0.2 degrees 2θ, and (b) a solid-state NMR spectrum of ¹⁹ F chemical shift at -122.8 ± 0.2 ppm. A purified crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 1) characterized in that at least about 95% is free of solvent and other compounds of the compound Solid shape formula. The purified crystalline form of claim 27, wherein the crystalline form is at least 97% pure. The purified crystalline form of claim 27, wherein the crystalline form is at least 99% pure. The purified crystalline form of claim 29, wherein the crystalline form is at least 99.5% pure. The purified crystalline form of claim 30, wherein the crystalline form is at least 99.7% pure. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 31 and a pharmaceutically acceptable carrier or diluent. Use of a crystalline form according to any one of claims 1 to 31 for the manufacture of a medicament for the treatment of cancer or endometriosis in a mammal. . Crystalline Form 1 according to any one of claims 1 to 7, 12, 13, 16 to 19 and 25 to 31 for use in the treatment of cancer or endometriosis in a mammal in need thereof. a crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (Form 2) having a composition comprising about 9.5 degrees 2θ, about 12.3 degrees 2θ, and/or A powder X-ray diffraction pattern of characteristic peaks at two or more points of about 13.5 degrees 22. The crystalline form of claim 35, which comprises three or more of these peaks. A crystalline form of claim 35 or claim 36 having a powder X-ray diffraction pattern as shown in FIG. The crystal form of claim 35 or claim 36 lacks a characteristic peak at about 6.7 degrees 2θ, about 15.0 degrees 2θ, and about 16.4 degrees 2θ. The crystal form of claim 35 or claim 36, wherein the powder X-diffraction pattern further comprises a peak at one or more of: 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 degrees 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 2θ, or about 37.3 degrees 2θ. The crystal form of claim 35 or claim 36, wherein the powder X-diffraction pattern is further The step includes one or more of the following peaks: about 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, 36.5 ± 0.2 degrees 2θ or 37.3 degrees 2θ.