Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics

Definitions

• the present invention relates to the use of triterpenoid antifungals to treat and/or to prevent Pneumocystis spp. pneumonia. More particularly, the invention relates to the use of enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereof) that are inhibitors of (l,3)- -D-glucan synthesis resulting in a deficiency in (l,3)- -D-glucan (a fungal cell structure building block), in the treatment and/or the prevention of Pneumocystis spp. pneumonia.
• enfumafungin derivative triterpenoids or pharmaceutically acceptable salts or hydrates thereof
• ibrexafungerp shows potent antifungal activity against Pneumocystis spp., exhibits adequate tissue penetration into lungs, and is well tolerated.
• the use of ibrexafungerp can provide advantages in the treatment and/or in the prevention of Pneumocystis spp.
• Fungal infections are a major healthcare problem and are most commonly manifested as invasive or systemic fungal disease (e.g., candidemia, invasive aspergillosis), mucocutaneous infections (e.g., oral, esophageal and vulvovaginal candidiasis) and localized fungal infections (e.g., pneumonia, pleural empyema and abscess localized in abdomen, brain, bone, etc.).
• invasive or systemic fungal disease e.g., candidemia, invasive aspergillosis
• mucocutaneous infections e.g., oral, esophageal and vulvovaginal candidiasis
• localized fungal infections e.g., pneumonia, pleural empyema and abscess localized in abdomen, brain, bone, etc.
• the type and scope of the infection depends on the virulence factors of the fungal pathogen, the host’s defenses, and the anatomic areas involved.
• Severe systemic or invasive fungal infections are more common in immune- compromised patients such as patients receiving chemotherapy to treat malignancies, or receiving immunomodulatory agents to treat chronic inflammatory conditions, or suffering from immune deficiencies, either acquired (such as in the case of AIDS) or due to genetic disorders.
• systemic fungal infections are associated with a mortality rate of up to 50%, depending on the pathogen and the underlying condition of the patient.
• Mucocutaneous fungal infections can occur in immuno-compromised as well as in non-compromised individuals. The most common mucocutaneous fungal infections are vulvovaginal yeast infections, followed by oropharyngeal candidiasis and esophageal candidiasis, which are predominantly caused by species of Candida.
• Localized fungal infections can occur in immuno-compromised as well as in non-compromised individuals and may originate via dissemination of the fungi from a local area where they normally colonize to an area that is normally sterile (e.g., abscess in abdominal cavity after gut perforation or surgery), from fungi entering the blood or lymphatic system that reaches a particular organ (e.g., lung, liver, spleen) or by acquisition from the environment (e.g. , Pneumocystis spp. pneumonia) and that develops a deep seated infection.
• sterile e.g., abscess in abdominal cavity after gut perforation or surgery
• fungi entering the blood or lymphatic system that reaches a particular organ (e.g., lung, liver, spleen) or by acquisition from the environment (e.g. , Pneumocystis spp. pneumonia) and that develops a deep seated infection.
• Pneumocystis pneumonia in humans is caused by Pneumocystis jirovecii, a ubiquitous fungus.
• Pneumocystis jirovecii is an opportunistic fungal organism that causes disease in individuals who are immuno-compromised, particularly those infected with human immunodeficiency virus (HIV).
• HIV human immunodeficiency virus
• ART anti-retroviral therapy
• PCP remains the most common opportunistic infection in patients with AIDS.
• an increase in the non-HIV immuno-compromised population including bone marrow transplant recipients and solid organ transplant recipients), noncompliance with current treatments, the emergence of drug-resistant
• Pneumocystis jirovecii was previously referred to as Pneumocystis carinii, but the taxonomy of the organism has been changed: P. carinii now properly refers only to the Pneumocystis species that infects rats, while P. jirovecii refers to the distinct species that infects humans. However, the abbreviation“PCP” is still used to designate Pneumocystis pneumonia.
• Initial infection with P. jirovecii usually occurs in early childhood; two-thirds of healthy children have antibodies to P. jirovecii by age 2 years to 4 years.
• PCP Pneumocystis spreads by the airborne route. Disease probably occurs by new acquisition of infection via the respiratory tract or reactivation of a latent infection.
• PCP prophylaxis and ART PCP occurred in 70% to 80% of patients with AIDS; the course of treated PCP was associated with a 20% to 40% mortality rate in individuals with profound immunosuppression.
• Other factors associated with a higher risk of PCP include low CD4 cell percentage, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, higher plasma HIV RNA levels, and
• PCP immunosuppressive therapy.
• the incidence of PCP has declined with widespread use of PCP prophylaxis and ART, and most cases of PCP now occur in patients who are unaware of their HIV infection or are not receiving ongoing care for HIV, and in those with advanced immunosuppression due to other conditions such as malignancies.
• PCP cardiovascular disease
• TMP-SMX Trimethoprim-sulfamethoxazole
• TMP-SMX a progressive disease 2019
• rates of adverse reaction to TMP-SMX are high (20% to 85% of patients).
• Common adverse effects are rash (30% to 55% of patients) (including Stevens-Johnson syndrome), fever (30% to 40% of patients), leukopenia (30% to 40% of patients), thrombocytopenia (15% of patients), azotemia (1% to 5% of patients), hepatitis (20% of patients), and hyperkalemia.
• Pneumocystis Pneumonia Last Updated: March 28, 2019; Last Reviewed: June 26, 2019.
• Pneumocystis spp. are yeast-like fungi that reside extracellularly in the lung alveoli and can infect mammals, with P. jirovecii infecting humans, P. carinii rats, and P. murina mice.
• Pneumocystis cannot be cultured in vitro in typical fungal growth media, and most of what is known of its life cycle comes from observations in animal models of infection. The inability to culture the organism in vitro has been a major obstacle to studying therapies for this opportunistic infection, and most research relies on in vivo observations.
• Pneumocystis has a tropism for the alveoli.
• Microscopic observations and molecular genetic studies suggest a life cycle that includes an asexual mode of replication via binary fission of the amoeba-like trophozoite (trophic) form and a sexual mode resulting in formation of an ascus (cyst) containing eight ascospores.
• PCP currently has limited treatment options.
• Standard antifungal drugs targeting ergosterol and ergosterol biosynthesis such as amphotericin B and the azoles, are ineffective.
• the echinocandins (caspofungin, anidulafungin, and micafungin) inhibit synthesis of (l,3)- -D-glucan, an essential component of the cell wall of many fungi, including the cyst form of Pneumocystis spp.
• reports on the efficacy of echinocandins on PCP in patients reveal uncertainties and limitations with this class of agents.
• a murine model (Cushion MT, Linke MJ, Ashbaugh A, Sesterhenn T, Collins MS, Lynch K, Brubaker R, Walzer PD. Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.
• PLoS One. 2010 Jan 29;5(l):e8524) assessing the activity of the echinocandins on murine PCP showed that parenteral (intraperitoneal) administration of echinocandin for 3 weeks significantly reduced cyst burdens versus in untreated mice. No dose response was observed for any echinocandin.
• echinocandins as potential alternatives for the treatment or prevention of PCP are that they are only available in intravenous form, and the treatment or prevention of PCP often requires several weeks or months of therapy. Long term IV administration is not optimal and often is not feasible.
• tissue concentrations achieved in lung are typically lower than in plasma (Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014 Jan;27(l):68-88), which may result in sub-efficacious concentrations at the site of infection (i.e., lung).
• Enfumafungin is a hemiacetal triterpene glycoside that is produced in fermentations of a Hormonema spp. associated with living leaves of Juniperus communis (U.S. Pat. No. 5,756,472; Pelaez et al, Systematic and Applied Microbiology , 23:333-343 (2000); Schwartz et al, JACS, 122: 4882-4886 (2000); Schwartz, R.E., Expert Opinion on Therapeutic Patents, 11(11): 1761-1772 (2001)).
• Enfumafungin is one of the several triterpene glycosides that have in vitro antifungal activities.
• the mode of the antifungal action of enfumafungin and other antifungal triterpenoid glycosides was determined to be the inhibition of fungal cell wall glucan synthesis by their specific action on (l,3)- -D-glucan synthase (Onishi et al Antimicrobial Agents and Chemotherapy, 44: 368-377 (2000); Pelaez et al, (2000)).
• l,3- -D-glucan synthase remains an attractive target for antifungal drug action because it is present in many pathogenic fungi and therefore affords a broad antifungal spectrum.
• the enfumafungin derivatives described herein have little or no mechanism-based toxicity.
• the triterpenoid compound derivatives of enfumafungin used according to this invention have demonstrated activity against fungal isolates of Candida spp., including those isolates that are resistant to azoles or other glucan synthase inhibitors (e.g., lipopeptides agents such echinocandins), indicating that the biological and molecular target of the enfumafungin derivatives is different from that of other glucan synthase inhibitors.
• WH rats were used for mass balance and pharmacokinetic (PK) determinations after i.v. and oral doses, and both WH and LE rats were used for Quantitative whole-body autoradiography (QWBA) determinations.
• PK pharmacokinetic
• QWBA Quantitative whole-body autoradiography
• Quantification was performed by image densitometry with MCID image analysis software (v. 7.0; Interfocus Imaging Ltd., Linton, Cambridge, UK), and a standard curve was constructed from the integrated response (molecular dynamics counts [MDC]/mm 2 ) and the nominal concentrations of the 14 C-calibration standards.
• concentrations of radioactivity were expressed as [ 14 C]SCY-078 pg equiv/g tissue.
• the lower limit of quantitation was 0.024 and 0.049 pg equiv/g of tissue for i.v. and oral doses of SCY-078, respectively.
• Tissue to blood AUC ratios of total radioactivity after 15 mg/kg oral dose of [ 14 C]-SCY-078 to male pigmented Long-Evans rats are illustrated in the table below:
• SCY-078 The safety and tolerability of SCY-078 has been evaluated in more than 900 subjects in ⁇ 20 clinical trials, at different doses and treatment durations, including administration for up to 1 year.
• the most common adverse events have been mild to moderate, transient gastrointestinal disorders such as nausea, diarrhea and abdominal pain.
• Serious adverse events possibly related to SCY-078 have been very rare and interruption or discontinuation of therapy due to adverse reactions has been uncommon.
• the safety profile of oral SCY-078 has been evaluated in standard long-term non-clinical toxicology studies including administration for 9 months in dogs and 6 months in rats, at doses and exposures higher than those anticipated in humans, in line with ICH guidelines. The results from these non-clinical studies support the long-term administration of oral SCY- 078 in humans.
• SCY-078 is currently under evaluation in ongoing clinical trials for the treatment of fungal infections such as candidiasis and aspergillosis.
• SCY-078 has not been evaluated in clinical trials for the treatment or prevention of PCP
• ibrexafungerp a representative compound of enfumafungin derivatives described herein— shows a high level of efficacy in the treatment and/or prevention of PCP, in murine models.
• SCY-078 shows potent antifungal activity against Pneumocystis spp., exhibits adequate tissue penetration into lungs, and is well tolerated.
• SCY- 078 or ibrexafungerp can be used to treat and/or prevent Pneumocystis spp. pneumonia in humans.
• SCY-078 unexpectedly demonstrated pharmacologic activity equivalent to the positive control, Bactrim ® (trimethoprim/sulfamethoxazole), which is the current gold standard for treatment of PCP. More surprisingly, the compound showed burden reduction of both cyst (asci) and trophic forms (nuclei).
• the life-cycles of Pneumocystis spp. exist in two forms: cysts and trophs.
• the cystic form has a (l,3)- -D-glucan-containing cell wall, whereas this feature is absent in the trophic form.
• SCY-078 as an inhibitor of (l,3)- -D-glucan synthase resulted in pharmacologic effect on the cystic form, e.g., a reduction in cyst burden.
• treatment with SCY-078 also resulted in a significant reduction in nuclei (nuclei are indicative of troph burdens).
• reductions in cysts and trophs occurred in both the prophylaxis and treatment models of PCP.
• SCY-078 can be administered orally, which provides an advantage in the prevention and treatment of PCP, given that long term antifungal administration is typically needed in the case of PCP.
• the present invention relates to using enfumafungin derivatives for the treatment and/or prevention of PCP.
• Enfumafungin derivatives, and pharmaceutically acceptable salts or hydrates thereof are useful in the inhibition of (l,3)- -D-glucan synthase, and are particularly useful in treatment and/or prevention of PCP, which is an infection where potent antifungal activity is needed in the art.
• the present invention addresses needs in the art such as those described above because the enfumafungin derivatives described herein (a) unexpectedly achieved high efficacy in the treatment and the prevention of PCP, (b) showed activity against both . jirovecii forms (cyst and trophic), (c) surprisingly achieved concentrations in lung that are several-fold higher than in plasma, (d) can be administered orally allowing for optimal therapy in these infections which often require several months of therapy, and (e) were well tolerated, allowing for safe administration over long periods of time.
• Applications of this invention include but are not limited to the ability to more easily achieve a successful outcome in the treatment and/or prevention of PCP because of the reasons outlined above.
• the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof:
• X is O or H, H;
• R e is C(0)NR f R g or a 6-membered ring heteroaryl group containing 1 or 2 nitrogen atoms wherein the heteroaryl group is optionally mono-substituted on a ring carbon with fluoro or chloro or on a ring nitrogen with oxygen;
• R f , R g , R 6 and R 7 are each independently hydrogen or C1-C3 alkyl
• R 8 is C1-C4 alkyl, C3-C4 cycloalkyl or C4-C5 cycloalkyl-alkyl;
• R 9 is methyl or ethyl
• R 8 and R 9 are optionally taken together to form a 6-membered saturated ring containing 1 oxygen atom
• the invention also provides methods of treating and/or preventing PCP in a subject by administering the compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof. Further, the invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of PCP in a subject.
• enfumafungin derived triterpenoid antifungal agents can reduce both troph burden (as evidenced by reductions in nuclei) and cyst burden (as evidenced by reductions in asci) in a Pneumocystis spp. model of infection.
• FIG. 1 is a graph of logio mean nuclei and asci counts after a 6-week study showing that prophylaxis administration of SCY-078 resulted in a statistically significant reduction of both nuclei and asci counts when compared to untreated controls.
• FIG. 2 is a graph of logio mean nuclei and asci counts after 7, 14, and 21 days of treatment with SCY-078 compared with untreated controls and TMP/SMX.
• FIG. 3 is a graph of logio mean nuclei and asci counts after 28, 35, and 42 days of treatment with SCY-078 compared with untreated controls and TMP/SMX.
• the present invention relates to the use of enfumafungin derivative triterpenoid antifungal compounds to treat and/or prevent Pneumocystis spp. pneumonia.
• the invention relates to the use of enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereol) that are inhibitors of (1,3)-b- ⁇ - glucan synthesis, in the treatment and/or prevention of PCP for which adequate tolerability to long-term antifungal therapy (more than 4 weeks) is needed, burden reduction of cyst and trophic forms of P. jirovecii is desirable, and sufficient antifungal penetration into the affected tissues is needed, for treatment and/or prevention of the infection.
• the present invention provides a needed, advantageous alternative to trimethoprim/sulfamethoxazole (TMP/SMX), which is currently considered the treatment of choice for PCP but which is limited by significant toxicities associated with its use (with the few other currently available options all having meaningful safety concerns as well).
• TMP/SMX trimethoprim/sulfamethoxazole
• the enfumafungin derivative triterpenoids described herein show potent antifungal activity against Pneumocystis spp., exhibit adequate tissue penetration into lungs, and are well tolerated, providing advantages in the treatment and/or prevention of Pneumocystis spp. pneumonia.
• the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof:
• X is O or H, H;
• R e is C(0)NR f R g or a 6-membered ring heteroaryl group containing 1 or 2 nitrogen atoms wherein the heteroaryl group is optionally mono-substituted on a ring carbon with fluoro or chloro or on a ring nitrogen with oxygen;
• R f , R g , R 6 and R 7 are each independently hydrogen or C1-C3 alkyl
• R 8 is C1-C4 alkyl, C3-C4 cycloalkyl or C4-C5 cycloalkyl-alkyl;
• R 9 is methyl or ethyl
• R 8 and R 9 are optionally taken together to form a 6-membered saturated ring containing 1 oxygen atom
• the invention also provides methods of treating and/or preventing PCP in a subject by administering the compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof. Further, the invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of PCP in a subject.
• the present invention also provides the use of a compound of Formula (la), or a pharmaceutically acceptable salt or hydrate thereof:
• the invention also provides methods of treating and/or preventing PCP in a subject by administering the compound of Formula (la) or a pharmaceutically acceptable salt or hydrate thereof. Further, the invention provides the use of a compound of Formula (la) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of PCP in a subject.
• R e is either pyridyl or pyrimidinyl optionally mono- substituted on a ring carbon with fluoro or chloro or on a ring nitrogen with oxygen, and the other substituents are as provided in embodiment 1 or in Formula (I).
• R e is 4-pyridyl and the other substituents are as provided in embodiment 1 or in Formula (I).
• R e is C(0)NH2 or C(0)NH(CI-C3 alkyl) and the other substituents are as provided in embodiment 1 or in Formula (I).
• R 8 is C1-C4 alkyl and R 9 is methyl; and the other substituents are as provided in embodiment 1, 2, 3, or 4, or in Formula (I).
• R 8 is t-butyl, R 9 is methyl; and the other substituents are as provided in embodiment 1, 2, 3, or 4, or in Formula (I).
• R 6 and R 7 are each independently hydrogen or methyl and the other substituents are as provided in embodiment 1, 2, 3, 4, 5, or 6, or in Formula (I).
• X is H, H, and the other substituents are as provided for in Formula (la).
• R e is either pyridyl or pyrimidinyl optionally mono- substituted on a ring carbon with fluoro or chloro or on a ring nitrogen with oxygen, and the other substituents are as provided in embodiment G or in Formula (la).
• R e is 4-pyridyl and the other substituents are as provided in embodiment G or in Formula (la).
• R e is C(0)NH2 or C(0)NH(CI-C3 alkyl) and the other substituents are as provided in embodiment G or in Formula (la).
• R 8 is C1-C4 alkyl and R 9 is methyl; and the other substituents are as provided in embodiment G, 2', 3', or 4', or in Formula (la).
• R 8 is t-butyl, R 9 is methyl; and the other substituents are as provided in embodiment G, 2', 3', or 4', or in Formula (la).
• R 6 and R 7 are each independently hydrogen or methyl and the other substituents are as provided in embodiment G, 2', 3', 4', 5', or 6', or in Formula (la).
• the present invention provides the use of a compound of Formula (II):
• the invention also provides methods of treating and/or preventing PCP in a subject by administering the compound of Formula (II) or a pharmaceutically acceptable salt or hydrate thereof. Further, the invention provides the use of a compound of Formula (II) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of PCP in a subject.
• the present invention provides the use of a compound of Formula (Ila) (herein referred to as SCY-078 or ibrexafungerp):
• the invention also provides methods of treating and/or preventing PCP in a subject by administering the compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof. Further, the invention provides the use of a compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of PCP in a subject.
• the phosphate salt of a compound of Formula (I), (la), (II), or (Ila) is used or administered as described herein.
• the citrate salt of a compound of Formula (I), (la), (II), or (Ila) is used or administered as described herein.
• the compounds of Formula (I), (la), (II), and (Ila), or pharmaceutically salts or hydrate forms thereof, are administered orally.
• the compounds of Formula (I), (la), (II), and (Ila), or pharmaceutically salts or hydrate forms thereof, are administered intravenously.
• the present invention also provides the use of a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I), (la), (II), or (Ila), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, in a subject for the treatment and/or prevention of PCP.
• the present invention also provides methods of treating and/or preventing PCP in a subject by administering a pharmaceutical composition comprising the compound of Formula (I), (la), (II), or (Ila), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the present invention provides methods for treating and/or preventing PCP, comprising administering an effective amount of a compound of Formula (I), (la), (II), or (Ila) (or a pharmaceutically acceptable salt or hydrate thereol).
• the compounds of Formula (I), (la), (II), and (Ila), and pharmaceutically acceptable salts and hydrate forms thereof, have antimicrobial (e.g., antifungal) activities against yeasts and other fungi, including one or more of Acremonium, Absidia (e.g. , Absidia corymbifera ), Alt ernaria, Aspergillus (e.g., Aspergillus clavatus, Aspergillus flavus,
• Blastoschizomyces e.g., Blastoschizomyces capitatus
• Candida e.g., Candida albicans, Candida auris, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis , Candida pseudotropicalis, Candida stellatoidea, Candida tropicalis, Candida utilis, Candida lipolytica, Candida famata and Candida rugosd
• Cladosporium e.g., Cladosporium carrionii and Cladosporium trichloides
• Coccidioides e.g., Coccidioides immitis
• Cryptococcus e.g., Cryptococcus neoformans
• Curvularia Cunninghamella (e.g., Cunninghamella elegans), Dermatophyte, Exophiala (e.g., Exophiala dermatitid
• Microsporum e.g., Microsporum canis and Microsporum gypseum
• Mucor e.g., Mucor
• Paracoccidioides e.g., Paracoccidioides brasiliensis
• Penicillium e.g., Penicillium marneffei
• Phialophora Phityrosporum ovale
• Pneumocystis e.g., Pneumocystis jirovecii
• Pseudallescheria e.g., Pseudallescheria boydii
• Rhizopus e.g., Rhizopus microsporus var.
• Saccharomyces e.g., Saccharomyces cerevisiae
• Scedosporium e.g., Scedosporium apiosperum
• Scopulariopsis e.g., Sporothrix schenckii
• Trichoderma e.g., Trichophyton mentagrophytes and Trichophyton rubrum
• Trichosporon e.g., Trichosporon asahii, Trichosporon beigelii, and
• Trichosporon cutaneum Trichosporon cutaneum
• “alkyl” refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
• “Ci-6 alkyl” refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
• “Ci-4 alkyl” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
• cycloalkyl refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range.
• “C3-4 cycloalkyl” refers to cyclopropyl and cyclobutyl.
• cycloalkyl-alkyl refers to a system that includes an alkyl portion as described above and also includes a cycloalkyl portion as described above. Attachment to a“cycloalkyl-alkyl” (or“alkyl- cycloalkyl”) may be through either the cycloalkyl or the alkyl portion.
• the specified number of carbon atoms in“cycloalkyl-alkyl” systems refers to the total number of carbon atoms in both the alkyl and the cycloalkyl parts.
• C4-C5 cycloalkyl-alkyl examples include but are not limited to methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, ethylcyclopropyl, cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl.
• halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
• a heterocyclic ring described as containing from“1 to 4 heteroatoms” means the ring can contain 1, 2, 3, or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from“1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, and so forth.
• any of the various cycloalkyl and heterocyclic/heteroaryl rings and ring systems defined herein may be attached to the rest of the compound at any ring atom (i.e.. any carbon atom or any heteroatom) provided that a stable compound results.
• Suitable 5- or 6-membered heteroaromatic rings include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl.
• A“stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein ( e.g ., therapeutic or prophylactic administration to a subject).
• Reference to a compound also includes stable complexes of the compound such as a stable hydrate.
• substituted includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g. , an aryl, a cycloalkyl, a heteroaryl, or a heterocyclyl) provided such ring substitution is chemically allowed and results in a stable compound.
• a ring e.g. , an aryl, a cycloalkyl, a heteroaryl, or a heterocyclyl
• a bond terminated by a wavy line is used herein to signify the point of attachment of a substituent group or partial structure. This usage is illustrated by the following example:
• the compounds of Formula (I), (la), (II), and (Ila), and pharmaceutically acceptable salts and hydrate forms thereof, are also useful in the preparation and execution of screening assays for antifungal compounds.
• the compounds are useful for isolating mutants, which are excellent screening tools for identifying further antifungal compounds.
• the compounds of Formula (I), (la), (II), and (Ila) may be administered in the form of“pharmaceutically acceptable salts” or hydrates as appropriate.
• Other salts may, however, be useful in the preparation of the compounds or of their pharmaceutically acceptable salts.
• the compounds when they contain a basic amine group, they may be conveniently isolated as trifluoroacetic acid salts (e.g., following HPLC purification). Conversion of the trifluoroacetic acid salts to other salts, including pharmaceutically acceptable salts, may be accomplished by a number of standard methods known in the art.
• an appropriate ion exchange resin may be employed to generate the desired salt.
• conversion of a trifluoroacetic acid salt to the parent free amine may be accomplished by standard methods known in the art (e.g., neutralization with an appropriate inorganic base such as NaHCCh).
• Other desired amine salts may then be prepared in a conventional manner by reacting the free base with a suitable organic or inorganic acid.
• Representative pharmaceutically acceptable quaternary ammonium salts include the following: hydrochloride, sulfate, phosphate, carbonate, acetate, tartrate, citrate, malate, succinate, lactate, stearate, fumarate, hippurate, maleate, gluconate, ascorbate, adipate, gluceptate, glutamate, glucoronate, propionate, benzoate, mesylate, tosylate, oleate, lactobionate, laurylsulfate, besylate, caprylate, isetionate, gentisate, malonate, napsylate, edisylate, pamoate, xinafoate, napadisylate, hydrobromide, nitrate, oxalate, cinnamate, mandelate, undecylenate, and camsylate. Many of the compounds of Formula (I), (la), (II), and (Ila) carry an
• alkaline earth metal salts e.g., calcium or magnesium salts
• suitable organic ligands e.g., quaternary ammonium salts
• the present invention includes within its scope the use of prodrugs of Formula (I), (la), (II), and (Ila).
• prodrugs will be functional derivatives of the compounds, which are readily convertible in vivo into the required compound.
• the term“administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound that converts to the specified compound in vivo after administration to the patient.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety.
• Metabolites of the compounds of Formula (I), (la), (II), and (Ila) include active species produced upon introduction of the compounds into the biological milieu.
• administration and variants thereof (e.g.,“administering” a compound) mean providing a compound (optionally in the form of a salt or hydrate thereol) or a prodrug of the compound to the subject in need of treatment.
• a compound of Formula (I), (la), (II), and (Ila) or pharmaceutically acceptable salt thereof or a hydrate or prodrug thereof is provided in combination with a second active agent (e.g., other antifungal and/or antibacterial agents useful for treating fungal and/or bacterial infections),
• a second active agent e.g., other antifungal and/or antibacterial agents useful for treating fungal and/or bacterial infections
• administration and its variants are each understood to include concurrent and sequential provision of the compound (or the salt, hydrate, or prodrug thereol) and of the other active agent.
• composition is intended to encompass a product comprising the specified ingredients, as well as any product that results, directly or indirectly, from combining the specified ingredients.
• pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation, or experiment.
• the term“effective amount” as used herein means an amount of active ingredient or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.
• the“effective amount” can be a therapeutically effective amount that alleviates the symptoms of the disease or condition being treated.
• the“effective amount” can be a prophylactically effective amount for prophylaxis of the symptoms of the disease or condition being prevented or for reducing the likelihood of occurrence.
• the term can also refer to an inhibition effective amount of the enfumafungin derivative sufficient to inhibit (l,3)- -D-glucan synthase and thereby elicit the response being sought.
• references to“treat,”“treating,”“treatment,” and variants thereof generally refer to a treatment that, after it is administered, results in resolution or improvement of one or more signs or symptoms associated with a fungal infection, or that results in eradication of the fungi responsible for an infection, or any combination of these outcomes.
• the compound of Formula (I), (la), (II), or (Ila) (optionally in the form of a salt or a hydrate) can be administered in conventional ways available for use in conjunction with pharmaceuticals.
• the compound of Formula (I), (la), (II), or (Ila) (optionally in the form of a salt or a hydrate) can be administered alone as an individual therapeutic agent or with one or more other antimicrobial agents
• the compound of Formula (I), (la), (II), or (Ila) (optionally in the form of a salt or a hydrate) can be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
• the compounds of Formula (I), (la), (II), and (Ila), and pharmaceutically salts and hydrate forms thereof can be administered by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intra-lesion injection or infusion techniques), by inhalation (e.g., nasal or buccal inhalation spray, aerosols from metered dose inhalator, and dry powder inhalator), by nebulizer, ocularly, topically, transdermally, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
• routes can be administered by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intra-lesion injection or infusion techniques), by inhalation (e.g., nasal or buccal inhalation spray, aerosols from metered dose inhalator, and dry powder inhal
• Liquid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ the usual media such as water, glycols, oils, alcohols and the like.
• Solid preparations suitable for oral administration e.g., powders, pills, capsules and tablets
• Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid.
• Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.
• the compounds of Formula (I), (la), (II), and (Ila), and pharmaceutically acceptable salts and hydrate forms thereof can be administered, e.g., orally or intravenously, in a dosage range of, for example, 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
• a dosage range is 0.01 to 500 mg/kg body weight per day orally or intravenously in a single dose or in divided doses.
• Another example of a dosage range is 0.1 to 50 mg/kg body weight per day orally or intravenously in single or divided doses.
• compositions can be provided in the form of tablets or capsules containing, for example, 1.0 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of
• a pharmaceutically acceptable salt of the compound of Formula (Ila) is administered to a subject to provide a total daily dose of 150 to 1500 mg of the compound of Formula (Ila).
• a total daily dose of 150 mg, or a total daily dose of 250 mg, or a total daily dose of 500 mg, or a total daily dose of 750 mg, or a total daily dose of 1000 mg, or a total daily dose of 1500 mg of the compound of Formula (Ila) is administered; the total daily dose may be administered on a once-daily basis or it may be divided such as for BID (twice daily) dosing or TID (thrice daily) dosing or it may be administered less frequent such as three- times-a-week, twice-a-week or once-a-week particularly for treatment and/or the prevention of PCP.
• a pharmaceutically acceptable salt of the compound of Formula (Ila) is administered QD (once daily) or BID to provide 150 to 750 mg, or to provide 250 to 750 mg, or to provide 250 to 1000 mg, of the compound of Formula (Ila) per day.
• the compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof is administered orally and provides a total daily dose of from 250 mg to 1000 mg of the compound.
• the compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof is administered for 2 to 6 weeks.
• the compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof is administered orally and provides a total daily dose of from 150 mg to 750 mg of the compound.
• the compound of Formula (Ila) or a pharmaceutically acceptable salt or hydrate thereof is administered for 4 weeks or more.
• Antifungal activity of compounds against Pneumocystis spp. can be demonstrated by various assays known in the art, for example, by prophylaxis or treatment model of Pneumocystis murina pneumonia in mice.
• the activity of the compound is typically assessed by measuring survival and lung fungal burden as indicated by quantitative assessment of cyst (a.k.a. asci) and trophic (a.k.a. nuclei) forms of the Pneumocystis in lung.
• cyst a.k.a. asci
• trophic a.k.a. nuclei
• Pneumocystis spp. has species specificity according to the mammal they infect.
• Pneumocystis jirovecii the species responsible for infection in humans, does not efficiently infect mice.
• Pneumocystis murina is the species specific to mice. Immune and
• the present invention provides methods of treating Pneumocystis spp.
• the triterpenoid antifungal agent is ibrexafungerp.
• the Pneumocystis species is P. jirovecii.
• the ibrexafungerp is administered orally.
• troph burden and cyst burden are both reduced.
• the present invention further provides methods of preventing Pneumocystis spp. pneumonia in a subject, comprising administering a triterpenoid antifungal agent to the subject.
• the triterpenoid antifungal agent is ibrexafungerp.
• the Pneumocystis species is P. jirovecii.
• the ibrexafungerp is administered orally.
• troph burden and cyst burden are both reduced.
• SCY-078 (ibrexafungerp) was prepared in 0.5 % methyl cellulose for oral administration. A correction factor of 1.37 for this lot was taken into account for salt and water content. Mice in the high dose group received 0.6 mg of SCY- 078 BID, mid dose group received 0.3 mg of SCY-078 BID, and low dose group received
• P. muring prophylaxis study method C3H/HeN mice (Charles River) were infected by intranasal inoculation of P. murina organisms at 2 x 10 6 /50 pi from a liquid nitrogen repository. Prior to inoculation, the P. murina were pre-incubated overnight in
• mice RPMI 1640 medium supplemented with calf serum and antibiotics to eliminate any bacterial contamination.
• the immune systems of the mice were suppressed by the addition of dexamethasone at 4 mg/liter to acidified drinking water (hydrochloric acid at 1 ml/liter). Acidification is used to prevent secondary microbial infections.
• the mice were divided into a negative (non-treated) control group (control steroid - C/S), positive control group
• mice trimethoprim/sulfamethoxazole - TMP/SMX
• SCY-078 was administered orally (po) BID at the specified doses.
• the mice were started on the prophylaxis regimen at the same time they were inoculated. Immune suppression and treatment continued for the entire 6-week study. At the conclusion of that time, the mice were euthanized by CC and lungs processed for analysis by homogenization. Slides were made from the lung homogenates at different dilutions and stained with Diff-Quik to quantify total nuclei (trophic forms) and with cresyl echt violet to quantify the asci (cyst forms).
• Efficacy was based on the reduction of organism burden between the treatment groups and the negative control group as determined by microscopic evaluation.
• the nuclei and asci counts for each lung were log transformed and statistical analysis was determined by the analysis of variance (ANOVA); individual groups were compared by the Student-Newman-Keuls t test for multiple comparisons using GraphPad Prism. Statistical significance was accepted at a P value ⁇ 0.05.
• FIG. 1 shows logio mean nuclei and asci counts after 6 weeks of treatment.
• C/S refers to vehicle treated negative control.
• TMP/SMX refers to trimethoprim/ sulfamethaxozole. Bracket denotes statistically significant difference between treatment groups and C/S group. # denotes no statistically significant difference between treatment group and TMP/SMX. Significance was accepted at a P value ⁇ 0.05.
• SCY-078 at 30 mg/kg performed equally as well at reducing the asci burden as the gold standard for treatment of Pneumocystis pneumonia, TMP/SMX.
• SCY-078 at 30 mg/kg showed a significant improvement in survival versus the vehicle treated negative control group.
• SCY-078 showed potent antifungal activity against both cyst and trophic forms of P. murina.
• SCY-078 represents a viable potential prophylaxis candidate to treat
• SCY-078 ibrexafungerp
• SCY-078 ibrexafungerp
• a correction factor of 1.37 was taken into account for salt and water content.
• Mice in the high dose group received 0.3 mg of ibrexafungerp BID and mice in the low dose group received 0.1 mg of ibrexafungerp BID, based on average mouse weights of 20 g.
• Study design (groups ' ): The study groups were as follows.
• P. muring treatment study methods C3H/HeN mice ordered from Charles River were infected with P. murina pneumonia through exposure to mice with a fulminant P. murina infection (seed mice). These mice were immune suppressed by the addition of dexamethasone at 4 mg/liter to the drinking water. Sulfuric acid at 1 ml/liter was also added to the drinking water for disinfection. The seed mice were rotated within the cages for 2 weeks and then removed. After the mice developed a moderate infection level
• mice were divided into a negative control group (control steroid), positive control group (TMP/SMX) and treatment groups.
• Drugs to be tested were administered by oral gavage (PO) on a mg/kg/day basis for up to 3 weeks.
• PO oral gavage
• the mice were euthanized by CO2 and lungs were processed for analysis. Slides were made from the lung homogenates at different dilutions and stained with Diff-Quik to quantify the nuclei (all life cycle stages) and with cresyl echt violet to quantify the asci.
• FIG. 2 shows logio mean nuclei and asci counts after 7, 14 and 21 days of treatment.
• C/S refers to vehicle treated negative control.
• TMP/SMX refers to trimethoprim/ sulfamethoxazole. Bracket denotes statistically significant difference between treatment groups and C/S group. # denotes statistically significant difference between treatment group and TMP/SMX. Significance was accepted at a P value ⁇ 0.05.
• SCY-078 showed potent antifungal activity against both cyst and trophic forms of P. murina.
• SCY-078 is viable potential treatment option for Pneumocystis pneumonia in humans.
• SCY-078 ibrexafungerp
• SCY-078 ibrexafungerp
• a correction factor of 1.37 was taken into account for salt and water content.
• Mice in the high dose group received 0.3 mg of ibrexafungerp BID and mice in the low dose group received 0.1 mg BID, based on average mouse weights of 20 g.
• mice were infected with P. murina pneumonia through exposure to mice with a fulminant P. murina infection (seed mice). These mice were immune suppressed by the addition of dexamethasone at 4 mg/liter to the drinking water. Sulfuric acid at 1 ml/liter was also added to the drinking water for disinfection. The seed mice were rotated within the cages for 2 weeks and then removed. After the mice developed a moderate infection level
• mice were divided into a negative control group (control steroid), positive control group (TMP/SMX), and treatment groups.
• Drugs to be tested were administered by oral gavage (PO) on a mg/kg/BID basis for up to 6 weeks.
• PO oral gavage
• the mice were euthanized by CC and lungs were processed for analysis. Slides were made from the lung homogenates at different dilutions and stained with Diff-QuikTM to quantify the nuclei (all life cycle stages) and with cresyl echt violet to quantify the asci.
• Efficacy was based on the reduction of organism burden between the treatment groups and the negative control group as determined by microscopic evaluation.
• the nuclei and asci counts for each lung were log transformed and statistical analysis was determined by the analysis of variance (ANOVA); individual groups were compared by the Student-Newman-Keuls I test for multiple comparisons using GraphPad Prism. Statistical significance was accepted at a P value ⁇ 0.05.
• FIG. 3 shows logio mean nuclei and asci counts after 28, 35, and 42 days of treatment.
• C/S refers to vehicle treated negative control.
• TMP/SMX refers to trimethoprim/ sulfamethoxazole. Bracket denotes statistically significant difference between treatment groups and C/S group. * denotes no statistically significant difference between treatment group and TMP/SMX. Significance was accepted at a P value ⁇ 0.05.
• SCY-078 at all dose levels worked equally well at reducing asci burden at day 42 as the positive control (TMP/SMX).
• TMP/SMX positive control
• 15 and 10 mg/kg groups worked equally as well at reducing asci burden as the positive control.
• SCY-078 is viable potential treatment option for Pneumocystis pneumonia in humans.

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