WO2023092049A1

WO2023092049A1 - Azirine pharmaceutical compositions

Info

Publication number: WO2023092049A1
Application number: PCT/US2022/080100
Authority: WO
Inventors: David Sloan AYERS; Kenneth Joseph Fraunhoffer; Thomas E. LA CRUZ
Original assignee: Bristol-Myers Squibb Company
Priority date: 2021-11-19
Filing date: 2022-11-18
Publication date: 2023-05-25

Abstract

This invention relates pharmaceutical compositions comprising azirine compounds.

Description

Azirine Pharmaceutical Compositions

FIELD

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/264,315, filed November 19, 2021, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year overall survival of 8% in patients of all stages. (Kleeff, J., et al., Pancreatic cancer. Nat Rev Dis Primers, 2016. 2: p. 16022.) The duration of response to existing radiation and/or chemotherapy regimens is low in PDAC. Cancer immunotherapy, particularly the immune checkpoint inhibitor (ICI), has caused a paradigm shift in our treatment of cancer in the past decade, but it has minimal clinical effect in PDAC. (Royal, R.E., et al., Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother, 2010. 33(8): p. 828-33; Morrison, A.H., K.T. Byrne, and R.H. Vonderheide, Immunotherapy and Prevention of Pancreatic Cancer. Trends Cancer, 2018. 4(6): p. 418-428.) The resistance of PDAC to ICIs is mainly attributed to the immune- quiescent or “cold” nature of the PDAC tumor microenvironment (TME).

Most of the tumor-infiltrating immune cells in PDAC are immunosuppressive cells, including T regulatory cells (Treg), M2 (pro-tumor) macrophages, and myeloid cells, which impede the effects of cancers vaccines, T-cell therapies, ICIs, or combinations thereof.

CSF-1/CSF-1R (CSF-1 receptor) axis is important to the differentiation of myeloid cells including granulocytes, macrophages, and dendritic cells, the C-C motif chemokine receptor 2 and chemokine receptor 5 (CCR2 and CCR5) are important mediators of myeloid cell migration to nonhematopoietic organs and tissues including TME of pancreatic, colorectal, hepatocellular, and lung carcinomas. Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Charo et al., New Eng. J. Med., 354:610-621 (2006); Luster, New Eng. J. Med., 338:436-445 (1998); and Rollins, Blood, 90:909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil -activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-l. alpha., MIP-Lbeta., the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CX3C chemokine) that do not fall into either of the major chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins (reviewed in: Horuk, Trends Pharm. Sci., 15: 159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns (reviewed in Zlotnik et al., Immunity, 12: 121 (2000)): CCR-1 (or "CKR-1" or "CC-CKR-1") [MIP-L alpha., MCP-3, MCP-4, RANTES] (Ben-Barruch et al., Cell, 72:415-425 (1993), and Luster, New Eng. J. Med., 338:436-445 (1998)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR- 2B" or "CC-CKR-2A"/"CC-CKR-2B") [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91 :2752-2756 (1994), and Luster, New Eng. J. Med., 338:436-445 (1998)); CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere et al., J. Biol. Chem., 270: 16491-16494 (1995), and Luster, New Eng. J. Med., 338:436-445 (1998)); CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MDC] (Power et al., J. Biol. Chem., 270: 19495-19500 (1995), and Luster, New Eng. J. Med., 338:436-445 (1998)); CCR-5 (or "CKR-5" OR "CC-CKR-5") [MIP-1. alpha., RANTES, MIP- l.beta.] (Samson et al., Biochemistry, 35:3362-3367 (1996)); CCR-6 (or "CKR-6" or "CC- CKR-6") [LARC] (Baba et al., J. Biol. Chem., 272: 14893-14898 (1997)); CCR-7 (or "CKR- 7" or "CC-CKR-7") [ELC] (Yoshie et al., J. Leukoc. Biol., 62:634-644 (1997)); CCR-8 (or "CKR-8" or "CC-CKR-8") [1-309] (Napolitano et al., J. Immunol., 157:2759-2763 (1996)); CCR-10 (or "CKR-10" or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al., DNA Cell Biol., 16: 1249-1256 (1997)); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickart et al., J. Biol. Chem., 275:9550 (2000)).

CCR2 and its cognate ligand, CCL2, are implicated in the infiltration of immunosuppressive cells into tumors, notably M2 tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSCs). (Schmall, A., et al., Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. Am J Respir Crit Care Med, 2015. 191(4): p. 437-47; Hartwig, T., et al., The TRAIL-Induced Cancer Secretome Promotes a Tumor- Supportive Immune Microenvironment via CCR2. Mol Cell, 2017. 65(4): p. 730-742. e5.)

SUMMARY

The application relates to pharmaceutical formulations comprising compounds of formula I and formula II:

In one aspect, the application relates to a compound formula II, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

In one aspect, compounds of formula I and the formula II are generally present in a weight ratio of formula I to II from about 10:1 to about 100,000: 1.

In one aspect the application relates to the use of pharmaceutical compositions comprising compounds of formula I and II for the treatment of inflammatory diseases, cancer, immunological diseaseas and cardiovascular and metabolic diseases.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 : spectrum of compound of formula II

DETAILED DESCRIPTION

The application relates to pharmaceutical formulations comprising a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a compound of formula II or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof:

Formula I Formula II.

In one aspect, the application relates to a pharmaceutical formulation comprising compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a compound of formula II or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, in a weight ratio of formula I to formula II from about 10: 1 to about 100,000: 1.

Diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), eosinophiliamyalgia syndrome due to the ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, vasculitis, vulnerable plaques, venous neointimal hyperplasia reperfusion injury, dialysis-graft neointimal hyperplasia, artio-venous shunt intimal hyperplasia, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. Infectious diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migraines (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larva migraines (Ancylostona braziliense, Ancylostoma caninum). The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory, infectious and immunoregulatory disorders and diseases.

In addition, treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for promoters of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.

As used herein, and in the absence of a specific reference to a particular pharmaceutically acceptable salt and/or solvate of a compound of formula I, the weight ratios, should be taken as referring to the amount of compound of formula I free base. As used herein, and in the absence of a specific reference to a particular pharmaceutically acceptable salt and/or solvate of a compound of formula II, the weight ratios, should be taken as referring to the amount of compound of formula II free base.

EXAMPLES

Synthesis of compound of Formula IE

Formula I Formula II

/V-((1 R,2S,5R)-2-((3S)-3-((4-(3-(fert-butyl)-2H-azirin-2-yl)-1 ,3,5-triazin-2- yl)amino)-2-oxopyrrolidin-1 -yl)-5-(fert-butylamino)cyclohexyl)acetamide

Compound of formula I was exposed to light under standard ICH Q1B conditions. (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, Stability Testing: Photostability Testing of New Drug Substances and Products Q1B. Step 4, November 6, 1996.) Compound of formula II appeared in the HPLC chromatogram at RRT 0.88. By HPLC, compound of formula II was present at 0.2 area-percent (AP) at one week and 0.4 AP at three weeks. Compound of formula II was isolated by HPLC and crystallized in DMSO-tL. Analytical HPLC. Reversed-phase HPLC was carried out on a Waters (Milford, MA, USA) Acquity. The HPLC method was as follows: Column: Waters XBridge C18, 4.6* 150mm, 3.5pm. A: 95:5 H₂O:MeCN w/ 0.05% NH₄OH, B: 5:95 H₂O:MeCN w/ 0.05% NH₄OH, 1.4 mL/min, 30°C, 210 nm. Gradient: 0- 3 min, 0%B; 3- 27 min, 0- 81.5%B; 27- 29 min, 81.5%B.

Preparative HPLC. Reversed-phase preparative-HPLC for the isolation of compound of formula II was carried out on a Waters (Milford, MA, USA) FractionLynx system with a YMC-Pack Pro C18 column, 20* 150mm, 5 pm (Kyoto, Japan). A: H2O w/ 0.05% NH4OH, B: MeCN w/ 0.05% NH4OH. Gradient: 0^12 min, 10^82%B; 12^12.5 min, 82^ 10%B; hold 10%B to 16 min at 19 mL/min, monitored at 220 nm. The white solid containing the degradant (478.6 mg) was dissolved in 2.5 mL MeCN + 1.5 mL H2O. Isolation was conducted with 20 200-pL injections. Fractions were placed in a -20°C freezer immediately upon elution and lyophilized after all injections were combined to yield 12.1 mg of compound of formula II.

Claims

WE CLAIM:

1. A compound of formula II:

Formula II or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

2. A pharmaceutical composition comprising a compound of claim 1 and a compound of formula I:

Formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

3. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 100,000 to about 1 : 10.

4. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 100,000 to about 1 : 100.

5. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of less than about 1 : 10,000 to about

6. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of less than about 1 : 1,000 to about 1 :100.

7. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 10,000 to about 1 : 10.

8. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 1,000 to about 1 : 10. . The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 1,000 to about 1 :25.

10. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 1,000 to about 1 :50.

11. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 :500 to about 1 : 10.

12. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 :500 to about 1 :25.

13. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 :500 to about 1 :50.

14. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 100 to about 1 :50.

15. The composition according to claim 2 wherein said compound of formula II and said compound of formula I are present in a weight ratio of about 1 : 100 to about 1 :25.

16. A method for treating a disorder or condition selected from the group consisting inflammatory diseases, cancer, immunological diseaseas, cardiovascular diseases and metabolic diseases comprising the step of administering to a subject in need thereof, an effective amount of a composition according to any of claims 2-15.

17. The method according to claim 16, wherien said cancer is selected from cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, uterine cancer, renal cancer, hepatic cancer, gastric cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer. The method according to claim 16 wherein said cardiovascular disease or metabolic disease is selected from hypertriglyceridemia, atherosclerosis, myocardial infarction, dyslipidemia, coronary heart disease, hyper apo B lipoproteinemia, ischemic stroke, type 2 diabetes mellitus, glycemic control in patients with type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, insulin resistance and impaired glucose metabolism.

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