Antifungal agents, like ibrexafungerp for candida auris decolonization

Abstract

To provide a method for decolonizing Candida auris from anatomic areas of a subject colonized by Candida auris.SOLUTION: The above problem is solved by a method comprising administration of a compound represented by the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof, wherein X is O or H, and H; Re is C(O)NRfRg or a 6-membered heteroaryl group containing one or two nitrogen atoms; and Rf, Rg, R6, and R7 are each independently hydrogen or C1-C3 alkyl.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides an enzyme for decolonizing a subject colonized by a susceptible fungus. The present invention relates to the use of fumafungin derivative triterpenoid antifungal compounds. has developed an enfumafungin derivative, triterpene, which is an inhibitor of (1,3)-β-D-glucan synthesis. Such a strategy may be effective using penoids (or pharmaceutically acceptable salts or hydrates thereof). Candida auris in subjects who may benefit Decolonizing body parts from Candida auris auris) is, for example, a true virus that can remain on the skin of a person who has previously been infected. The enfumafungin derivative triterpenoid antifungal agent of the present invention described herein Use of the compound requires prior use of Candida auris (Cand Ida auris) infection and may be prone to recurrence and / or infection Candida auris, which can transmit the fungus to other individuals These include, but are not limited to, decolonization of the skin or mucous membranes in patients colonized with It is not intended to decolonize inanimate objects (e.g., floors, furniture, appliances) per se. Although not related to the present invention, the present invention provides a method for preventing Candida auris from being decolonized by contact. Decolonizing populations where Candida auris is thought to be prevalent Thus, colonization of such subjects can be reduced, and this reduction can be achieved by This is particularly beneficial in settings such as nursing homes. [Background technology]

[0002] Fungal infections are a major healthcare problem, most commonly invasive or systemic fungal diseases. (e.g., candidemia, invasive aspergillosis), localized fungal infections (e.g., empyema and and abscesses confined to the abdomen, brain, lungs, etc.), and mucocutaneous infections (e.g., oral, esophageal, and external The type and extent of infection depend on the virulence factors of the fungal pathogen, the host's It depends on the defense and the anatomical area involved.

[0003] Severe systemic or invasive fungal infections, undergoing chemotherapy to treat malignancies patients receiving immunomodulatory agents to treat chronic inflammatory conditions, or patients with acquired or those with immunodeficiency due to genetic disease, Despite currently available antifungal therapies, systemic fungal infections are common. It is associated with a mortality rate of up to 50% or more, depending on the patient's underlying condition.

[0004] Localized and systemic fungal infections are usually sterile from the local area they colonize. via fungal dissemination to areas (e.g., intestinal perforation or intraperitoneal abscess after surgery) or to specific organs blood or liver that reaches the organs (lungs, liver, spleen, etc.) and develops into fungemia or deep infection It is often caused by fungi that invade the immune system. Fungal colonization in the context of this application is Anatomical areas in which there is no clinically discernible host inflammatory response caused by the presence of the organism means that a fungus is present in the tissue (i.e., the fungus does not cause infection or symptoms of infection). Fungal colonization in susceptible individuals may be a sign of infection by the colonizing pathogen. This may facilitate the establishment of a pathogen and the spread of the pathogen to other individuals. fungi that are difficult to isolate, have developed resistance to antifungal drugs, and / or are associated with high mortality rates This can be particularly problematic when dealing with flowing fungi.

[0005] Candida auris is a multidrug-resistant, healthcare-associated It is a fungal pathogen and has emerged as a global issue. Recent reports have shown that the organism is misidentified, with a high incidence of Highlighting the ongoing problem of antifungal resistance and significant patient mortality, This is likely facilitated by virulence factors that promote skin colonization and environmental persistence. transmission within and between health care facilities due to Candida auris ris) is unique among Candida species.

[0006] Candida auris is very often found on the skin of patients. This leads to long-term colonization of the skin and contamination of the surrounding environment, resulting in nosocomial illnesses in hospitals and long-term care facilities. Clinicians, infection prevention and control experts, and public health officials are currently We are working to reduce the threat posed by these pathogens. Therefore, patients with symptomatic disease should be treated immediately with antifungal agents, but Candida auris (C The optimal management of patients colonized with B. andida auris is not yet well defined. However, Candida auris colonizes -patients with HIV-1 infection may be at higher risk of developing symptomatic infection and may have other susceptible It is recognized that HIV can play an important role in the transmission of pathogens to young individuals. Summary of the Invention [Problem to be solved by the invention]

[0007] The U.S. Centers for Disease Control and Prevention (CDC) has s) poses a serious global health threat. The CDC considers Currently, there is concern about Candida auris. They are often drug-resistant, which is due to the multiple antibiotics commonly used to treat Candida infections. This means that the fungal agent is resistant to the drug. Furthermore, it cannot be detected by standard laboratory tests. It is difficult to identify the cause of the disease, and misidentification may occur in clinical laboratories without specific technology. Furthermore, the pathogen has been known to cause outbreaks in healthcare settings. It has been reported that hospitalized patients are infected with Candida auris. It can be identified quickly so that healthcare facilities can take extra precautions to prevent its spread. It is important to ensure that the CDC has the necessary information to prevent the spread of the virus. dc.gov / fungal / candida-auris / fact-sheets / c-auris-colonization.html, Candida auris (Can Dida auris colonization, and addressing the specific challenges posed by the He said the pathogen could spread from one patient to another in hospitals and nursing homes. Candida auris (Candida ) somewhere in the body that has not yet developed a fungus auris) can be carried by individuals in hospitals and nursing homes. Candida auris is a species that can move from their neighbors to nearby people or nearby It can easily spread to objects and then to other people. There are simple tests you can do to see if you have Candida anywhere in your body. People with Candida auris may not have symptoms of infection or infection. may pose a risk to others and may cause Candida auris It is possible that you may not even be aware that you are potentially spreading a . In humans, colonized with Candida auris, Because you can get illness from the fungus itself, your healthcare provider may take additional measures to prevent infection. The CDC recommends that people with Candida auris uris) in isolation with precautions against contacts. recommending that the cost of managing these cases increase for the health care system. do.

[0008] Candida albicans confirmed in the United States between May 2013 and August 2016 In the investigation of the first seven cases of squirrel (Candida auris) infection, the Candida auris on the skin and other body sites after a period of several months. uris) colonization, which can lead to contamination of the healthcare environment and the risk of continued infection. It has been shown that this is thought to result in n A, Tsay S, et al., Investigation of th e first seven reported cases of Candida auris, a newly emerging globally invasive, mul tidrug-resistant fungus-United States, M ay 2013-August 2016. Morb Mortal Wkly Re p 2016;65:1234-1237.DOI: http: / / dx.doi. org / 10.15585 / mmwr.mm6544e1 .) Echinocandins and other Currently recommended for Candida auris infections Treatment options are available to prevent residual fungal colonization in patients, especially on the skin. It did not stop Candida auris. Given that is often resistant to other antifungal agents such as azoles and polyenes, These other drugs do not offer suitable alternatives for decolonization. For example, azoles, despite their ability to achieve high concentrations in tissues, are not effective against fungal colonization. Candida auris is removed from the anatomical area where it formed. Currently, the CDC recommends that if there is no evidence of infection, noninvasive sites (e.g., respiratory tract) be used. Candida auris (Candida auris) identified from the stool, urine, and skin colonization ris) antifungal treatment is not recommended (https: / / www.cdc.gov / fungal / candida-auris / c-auris-treatment.h tml.).

[0009] Decolonization with topical 2% chlorhexidine aqueous wipes in hospitals reporting outbreaks A strategy of quantification has been attempted (Ruiz-Gaitan A et al., An outbr eak due to Candida auris with prolonged colonization and candidaemia in a tertia ry care European hospital, Mycoses 61:49 8-505 (2018). https: / / onlinelibrary.wile y.com / doi / epdf / 10.1111 / myc.12781.) Topical antiseptics A significant limitation of methicillin-resistant steroids is their inability to reach all skin and mucosal surfaces efficiently or at all. Additionally, the need to apply topical antiseptics up to several times a day can be cumbersome. do.

[0010] Enhumafungin is a plant of Juniperus communis Hemia spp., produced by fermentation of Hormonema spp. associated with living leaves of cetal triterpene glycosides (U.S. Pat. No. 5,756,472; Pelae z et al., Systematic and Applied Microbiology Schwartz et al., 23:333-343(2000); JACS, 122:4882-4886(2000);Schwartz, RE ., Expert Opinion on Therapeutic Patents , 11(11): 1761-1772 (2001)). Enhumafungin is It is one of several triterpene glycosides that have antifungal activity in vitro. The mechanism of antifungal action of fungin and other antifungal triterpenoid glycosides is (1,3 Fungal cell wall glucans due to their specific action on β-D-glucan synthase It was confirmed that the inhibition of ATP synthesis was due to the inhibition of ATP synthesis (Onishi et al., Antimicr Obial Agents and Chemotherapy, 44: 368-3 77 (2000); Pelaez et al., (2000)). 1,3-β-D -Glucan synthase is present in many pathogenic fungi, and therefore has a broad antifungal spectrum. It remains an attractive target for antifungal drug action because it provides a Since there is no mammalian counterpart to β-D-glucan synthase, The enfumafungin derivatives described herein have little or no mechanism-based toxicity. Triterpenoid compound derivatives of enfumafungin used in accordance with the present invention The azoles and other glucan synthase inhibitors (e.g., lipopolysaccharides such as echinocandins) It has shown activity against fungal isolates of the genus Candida, including isolates resistant to cephalosporins (peptide drugs). The biological and molecular targets of enfumafungin derivatives are similar to those of other glucan synthase inhibitors. This indicates that the target of the drug is different from that of the other drugs.

[0011] Various enfumafungin derivatives are disclosed, for example, in International Patent Publication No. WO2007 / 1269 00 and WO2007 / 127012. These enfumafungin derivatives Representatives of certain species can be administered orally and have antifungal activity against Candida species. It shows good activity and sufficient distribution in tissues such as the skin.

[0012] Ibrexafangelp (also known as SCY-078) is a compound that inhibits Candida auris (C andida auris) in vitro activity. Comparison of SCY-078 with a collection of 100 isolates of Candida auris In vitro susceptibility was reported by Berkow et al. in India, Pakistan, and elsewhere. Candida auris (C. auris) originating from countries around the world, including Taiwan, Colombia, South Africa, and the United States Isolates from each of the four known clades of Candida auris were included. All isolates were subjected to the standard of Clinical Laboratory Standards Institute reference method M27-A3. Ross microdilution was performed. The distribution of MIC values of SCY-078 was 0.0625 micrograms. The range was 1 microgram / mL to 2 micrograms / mL. / mL, MIC 50 and MIC 90 are 0.5 micrograms / mL and 1 microgram / mL, respectively. g / mL (Berkow EL, Angulo D, Lockhart SR, In vitro activity of a novel glucan synthase inhibitor, SCY-078, against cl inical isolates of Candida auris, Antimi crob Agents Chemother 61:e00435-17 (2017 ) https: / / doi.org / 10.1128 / AAC.00435-17 .) .

[0013] Persistent skin colonization by Candida auris have been reported after treatment with currently available systemic antifungal agents, and this phenomenon is associated with candidiasis. Increased risk of developing infections with Candida auris and associated with an increased risk of transmission of pathogens that may promote outbreaks. , Candida auris (Candida auris) from an anatomical area of the subject, particularly the skin or mucous membranes auris) to reduce the risk of disease recurrence in subjects and to prevent fungal and We need to be able to help prevent potential outbreaks. [Means for solving the problem]

[0014] The present invention relates to a method for treating Candida auris infection in patients who have previously suffered from a Candida auris infection and have had a recurrence. Candida, which can cause and / or transmit fungal infections to other susceptible individuals in patients colonized with Candida auris Specifically address the need for decolonization of the skin or mucous membranes. In these situations, a potent and effective Effective antifungal decolonization is particularly needed.

[0015] The enfumafungin derivatives described herein unexpectedly inhibit the formation of inflammatory bowel diseases in the skin after oral administration. Candida auris burden can be significantly reduced, Prevents infection and reduces the risk of developing Candida auris The enfumafungin derivatives described herein are believed to be a useful strategy for limiting is a method for achieving high concentrations in the skin (preferably in rats). 14 >10-fold higher than the plasma concentration demonstrated in the study ), Candida auris skin fungal burden reduction (preferably at least a 1 log reduction), Candida auris (E Potent antifungal activity against fungi (including quinocandin-resistant strains) and oral bioavailability These are derivatives of Candida auris (C. auris) from the anatomical region of the subject. Addressing the industry's need for agents to decolonize andida auris Glucan synthases that exhibit a combination of attributes, such as Unexpectedly, these attributes have a similar mechanism of action, but are higher in the skin than in the plasma. Does not achieve skin concentration (Felton T et al., Tissue Pene tration of Antifungal Agents, Clin. Biol. Rev. 2014, 27(1):68), oral bioavailability No evidence of rash in the nostrils, groin, axillae, and rectum for more than 3 months after initial intravenous echinocandin treatment Colonization of Candida auris in multiple body sites, including the rectum Knee formation has been detected (Jeffery-Smith A et al., Can dida auris:a Review of the Literature, C lin Microbiol Rev. 2017 Nov 15;31(1). pi i:e00029-17. doi:10.1128 / CMR.00029-17. P rint 2018 Jan. Review) Echinococcus aureus, a glucan synthase inhibitor This is in contrast to the attributes of the Candida species.

[0016] The use of the present invention includes the treatment of Candida auris on the skin or mucous membranes. ) including, but not limited to, the ability to decolonize colonized subjects Colonized subjects who may benefit from this invention include: Subject: I have had a systemic Candida auris infection. Survived but remained colonized and at risk of recurrent systemic infection (e.g., immunosuppression) (immune) subjects; colonized by contact with infected individuals; You are at risk of developing a systemic Candida auris infection colonized subjects who are kept in isolation on contact precautions in special rooms; Decolonization reduces the need for such special and costly control and prevention measures. where contact with other individuals is common (e.g., nursing homes) and where other Colonized subjects living in areas that may spread pathogens to susceptible individuals; pathogens Colonized health care workers who may spread the virus to other susceptible individuals; and Colonized patients should preferably be decolonized before medical treatment such as surgery. These include, but are not limited to, researchers.

[0017] The present invention relates to a method for treating a subject colonized with Candida auris. Decolonize the subject's anatomical region with Candida auris. of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof for the purpose of Provide use. [ka]

[0018] During the ceremony, X is O or H, H; R e is C(O)NR f R g or a six-membered heterocyclic ring containing one or two nitrogen atoms heteroaryl groups, heteroaryl groups can be substituted by fluoro or chloro on a ring carbon or by a ring nitrogen may be monosubstituted by oxygen; R f , R g , R 6 , and R 7 are each independently hydrogen or C1-C3 alkyl; R 8is C1-C4 alkyl, C3-C4 cycloalkyl or C4-C5 cycloalkyl - is alkyl; R 9 is methyl or ethyl; R 8 and R 9 may be joined together to form a six-membered saturated ring containing one oxygen atom. Solutions for subjects who can be decolonized with Candida auris Anatomical regions include, but are not limited to, skin and mucous membranes. Xafungelp (SCY-078) is a preferred compound of formula (I).

[0019] The present invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof. When administered to subjects, it was found that Candida auris Candida auris was isolated from the anatomical region of the subject colonized with In a preferred method, the method comprises decolonizing Candida auris. Candida auris is decolonized from the skin of a human subject. In a novel method, ibrexafungelp as a compound of formula (I) is administered to a human subject. Furthermore, the present invention provides a method for treating Candida auris. Candida auris was isolated from the anatomical region of the subject colonized with Candida auris. of formula (I) or a compound thereof in the manufacture of a medicament for decolonizing B. uris The use of a pharmaceutically acceptable salt or hydrate is provided. DETAILED DESCRIPTION OF THE INVENTION

[0020] Candida auris, which is associated with a mortality rate of approximately 60% Colonizing pathogens can cause life-threatening infections, as in the case of and / or are often reported to be resistant to currently available antifungal agents. As in the case of Candida auris, the pathogen and / or if they are resistant to Candida auris s) when the pathogen is capable of spreading from person to person and causing an outbreak , decolonization strategies are particularly important.

[0021] Prolapse in subjects colonized with Candida auris Topical application of disinfectants has been attempted as a colonization strategy, but this approach has limitations. Any part of the body that can act as a reservoir for Candida auris and that such disinfectants have broad antibacterial properties. Its properties affect the normal bacterial microbiome on the skin and may contribute to dysbiosis Systemic antifungal agents such as echinocandins have limitations, including an increased risk of For the treatment of systemic Candida auris disease (e.g., in the blood) Although reported to be effective, patients often report colonization after treatment, especially on the skin and mucous membranes. It has been reported that echinocandins remain in colonized individuals. This indicates that the Quinocandins are available only intravenously and are not available for non-hospital subjects (at home or in a nursing home). Their use in decolonizing human subjects (e.g., those with HIV infection) is considered impractical.

[0022] The optimal decolonizing agent will have activity against the pathogen to be decolonized; It causes minimal disruption to other colonizing bacteria that are part of the chromobiome; achieve adequate concentrations in the actual administration (e.g., BID, QD, once every 2 days, every 3 days) should remain active in those tissues for a period that allows for Especially in the case of skin decolonization, the drug becomes available to exert its antifungal activity. It should not have strong binding to keratin which may prevent it from being absorbed.

[0023] Ibrexafungelp (SCY-078), a triterpenoid derived from enfumafungin (a representative compound of the enfumafungin derivatives described herein) surprisingly Effective Candida auris (Candida aureus) on a subject's body site (e.g., skin) auris) have been found to exhibit unique characteristics that are believed to result in decolonization. Ibrexafungerp is a fungicide that can be used to treat high concentrations of Candida auris in the skin. Reduction of skin fungal burden of Candida auris Potent antifungal activity against echinocandin-resistant strains, including echinocandin-resistant strains, and oral bioavailability These attributes are in contrast to those of echinocandins. Candine has a similar mechanism of action, but does not achieve higher concentrations in the skin than in the plasma. It is not orally bioavailable and remains active for more than 3 months after initial intravenous echinocandin therapy. Candida auris (Candida) in multiple body sites, including the nostrils, groin, axillae, and rectum auris) colonization has been detected. The antifungal agent Ibrexafungelp can be administered orally to, for example, infect Candida albicans through the skin. Decolonization of the Candida auris prevents the disease from recurring in the individual. This will help reduce the risk of developing the fungus and prevent further spread and potential outbreaks. This strategy, along with appropriate infection control in hospital settings, can help reduce disease transmission. This will have a significant impact on limiting infections, management costs, and ultimately associated mortality. There is a possibility.

[0024] Surprisingly, Ibrexa van Gelb is a potent anti-candida fungus. Candida auris in an animal model of skin infection ) burden in human subjects, which has shown considerable activity in reducing Candida auris (Candida auris) as an effective systemic antifungal agent for skin decolonization Furthermore, Ibrexafungelp has good oral bioavailability. availability (e.g., estimated to be >20% in humans) and in mice and rats. It has been shown to have a wide tissue distribution after oral administration in rats, with measured plasma exposure increasing by 12-18%. A 2-fold higher skin exposure (measured as area under the curve) was achieved (Wring S, B orroto-Esoda K, Solon E, and Angulo D, S CY-078, a Novel Fungicidal Agent, Demons trates Distribution to Tissues Associate d with Fungal Infections during Mass Bal ance Studies with Intravenous and Oral [ 14 C]SCY-078 in Albino and Pigmented Rats , Antimicrob Agents Chemother, 2019 Jan 29;63(2). pii: e02119-18. doi: 10.1128 / A AC.02119-18. Print 2019 Feb. PMID: 30478 166). These characteristics are useful for the treatment and prevention of fungal infections and for the treatment of Candida auris (Ca This is important in achieving decolonization of susceptible fungal pathogens such as Streptococcus aureus (Andr. be.

[0025] Ibrexafungelp is a glucan synthase inhibitor, and its mechanism of action is echinocandin It is similar to acetaminophen but has a different chemical structure and a larger volume of distribution. Although these properties do not affect the efficacy of ibrexafungelp, they may be effective against skin ulcers after oral administration. It can achieve adequate concentrations in relevant tissues such as skin and mucous membranes, and can also be used to treat Candida auris (Ca and preferably inhibits the growth of Bacillus subtilis (Bacillus anguillis) and reduces the exposure observed in plasma. and more preferably >2-fold or >5-fold or >10-fold the exposure observed in plasma. Furthermore, other properties of this compound that have not yet been fully elucidated The properties of α- and β-glucan favor the retention of the active compound in tissues such as the skin and mucous membranes, and these tissues may contribute to the antifungal effect of Candida auris Ibrexa van Gelb is a decolonization strategy for multidrug-resistant pathogens such as Ibrexafungelp has clinically relevant antibacterial properties. and are not expected to have adverse effects on the normal bacterial microbiome of the skin and mucous membranes. It is considered impossible.

[0026] The present invention provides the use of a compound of the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof, for decolonizing Candida auris from an anatomical region of a subject such as a human subject. 、Candida auris from an anatomical region of a subject such as a human subject. uris) is provided. [Chemical formula]

[0027] In the formula, X is O or H, H; R e is C(O)NR f R g or a 6-membered heteroaryl group containing one or two nitrogen atoms, and the heteroaryl group may be mono-substituted by fluoro or chloro on the ring carbon or by oxygen on the ring nitrogen; On the ring carbon by fluoro or chloro, or on the ring nitrogen by oxygen may be mono-substituted; 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 may together form a 6-membered saturated ring containing one oxygen atom. Anatomical regions of a subject in which decolonization of Candida auris is possible include, but are not limited to, skin and mucosa. Ibrexafungerp gelp (SCY-078) is a preferred compound of formula (I). is a preferred compound of formula (I).

[0028] The present invention also provides a method for treating Candida auris colonization. and extracting Candida auris from an anatomical region of a subject, such as a human subject. auris) The present invention provides for the use of a salt or hydrate thereof that is acceptable for the treatment of rhodium. [ka]

[0029] In embodiment 1, X is H, H, and the other substituents are as provided in formula (I). do.

[0030] In embodiment 2, R e is substituted by fluoro or chloro on a ring carbon or by chloro on a ring nitrogen Either pyridyl or pyrimidinyl, optionally monosubstituted by oxygen; The substituents are as provided in embodiment 1 or formula (I).

[0031] In embodiment 3, R e is 4-pyridyl, and other substituents are as described in embodiment 1 or formula ( I) as provided in

[0032] In embodiment 4, R e is C(O)NH2 or C(O)NH(C1-C3 alkyl) and other substituents are as provided in embodiment 1 or formula (I).

[0033] In embodiment 5, R 8 is C1-C4 alkyl, and R 9 is methyl, and the other substituents are The substituents are as provided in embodiment 1, 2, 3 or 4, or in formula (I).

[0034] In embodiment 6: R 8 is t-butyl, and R 9 is methyl, and the other substituents are As provided in embodiment 1, 2, 3 or 4, or formula (I).

[0035] In embodiment 7: R 6 and R 7 are each independently hydrogen or methyl, and other substituents The substituents are as provided in embodiment 1, 2, 3, 4, 5 or 6, or in formula (I). .

[0036] In embodiment 1′, X is H, H, and the other substituents are as provided in formula (Ia). is.

[0037] In embodiment 2′, R e is substituted by fluoro or chloro on a ring carbon or by chloro on a ring nitrogen pyridyl or pyrimidinyl, each of which may be monosubstituted by oxygen; The substituents of are as provided in embodiment 1′ or formula (Ia).

[0038] In embodiment 3′, R e is 4-pyridyl, and other substituents are as in embodiment 1' or As provided in formula (Ia).

[0039] In embodiment 4′, R e is C(O)NH2 or C(O)NH(C1-C3 alkyl ), and other substituents are as provided in embodiment 1′ or formula (Ia).

[0040] In embodiment 5′, R 8 is C1-C4 alkyl, and R 9 is methyl, and the other The substituents are as provided in embodiment 1', 2', 3' or 4' or in formula (Ia). be.

[0041] In embodiment 6′, R 8 is t-butyl, and R 9 is methyl and the other substituents are , as provided in embodiment 1′, 2′, 3′ or 4′, or formula (Ia).

[0042] In embodiment 7′, R 6 and R 7 are each independently hydrogen or methyl, and the other The substituents are as provided in embodiments 1′, 2′, 3′, 4′, 5′ or 6′ or in formula (Ia). This is as expected.

[0043] In a preferred embodiment, the present invention provides a method for the treatment of Candida auris. Candida albicans from an anatomical region of a subject, such as a human subject, colonized by Candida albicans Compounds of formula (II) for decolonizing Candida auris or a pharmaceutically acceptable salt or hydrate thereof. [ka]

[0044] The compound is (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12aR ,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy] -8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1 H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a ,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl- 4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7-carboxylic acid is.

[0045] In another preferred embodiment, the present invention relates to a method for treating Candida auris. from an anatomical region of a subject, such as a human subject, colonized by Candida albicans (uris). For decolonizing Candida auris, ) (referred to herein as ibrexafungelp or SCY-078) or The use of a pharmaceutically acceptable salt or hydrate thereof is provided. [ka]

[0046] The compound is (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12aR ,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl ]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl Nyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,1 0,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tet tetramethyl-4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7- It is a carboxylic acid.

[0047] In a preferred embodiment, a compound of formula (I), (Ia), (II), or (IIa) The phosphate salts of are used or administered as described herein.

[0048] In a preferred embodiment, a compound of formula (I), (Ia), (II), or (IIa) The citrate salt of is used or administered as described herein.

[0049] The present invention also provides a method for treating Candida auris colonization. and extracting Candida auris from an anatomical region of a subject, such as a human subject. auris) Ia) or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable The use of a pharmaceutical composition comprising a carrier, adjuvant or vehicle is provided.

[0050] The present invention further provides a compound of formula (I), (Ia), (II) or (IIa), or By administering the pharmaceutically acceptable salt or hydrate thereof to a subject, Candida albicans can be inhibited. subjects, such as human subjects, colonized with Candida auris Decolonizing Candida auris from anatomical regions The present invention provides a method for preparing a compound of formula (I), (Ia), (II) or (IIa), a compound or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, 2. Therapeutic efficacy of Candida auris ( Anatomy of a subject, such as a human subject, colonized with Candida auris Method for decolonizing Candida auris from target areas In a preferred method, Candida auris is and decolonizing the skin of a human subject. The gelp is orally administered to a human subject. Further, the present invention provides a method for treating Candida auris (Ca an anatomical region of a subject, such as a human subject, colonized by Medical treatment for decolonizing Candida auris from the community a compound of formula (I), (Ia), (II) or (IIa), or The use of pharmaceutically acceptable salts or hydrates thereof is provided.

[0051] In the description of the compounds in the above embodiments, the indicated substitutions are those that are defined as follows: It is included only to the extent that a corresponding stable compound is provided.

[0052] Compounds of formula (I), (Ia), (II) and (IIa) and their pharmaceutically acceptable salts Acceptable salt and / or hydrate forms include those of Candida auris ) and other fungi.

[0053] In view of the antifungal activity, the compounds of formula (I), (Ia), (II) and (IIa), and their pharmaceutically acceptable salts and / or hydrate forms are useful for the treatment of Candida auris (C andida auris colonized anatomical parts or areas of the subject. It has been shown to be useful for decolonizing Candida auris. It is thought that colonization with Candida auris is more It is more commonly reported on the skin and mucous membranes of the respiratory, gastrointestinal, and urinary tracts. Possibly colonized subjects include Candida auris ris) have survived a systemic infection but remain colonized and Subjects at risk for recurrence of infection (e.g., immunocompromised); contact with infected individuals Colonization by systemic Candida auris (Cand Subjects at risk of developing Ida auris infection; special rooms and contact precautions Colonized subjects who are managed in isolation with measures to prevent the spread of the virus (decolonization is the process of reduce the need for special and costly management and precautionary measures; Contact is common (e.g., nursing homes) and can spread pathogens to other susceptible individuals. colonized subjects living in areas where the pathogen may spread to other susceptible individuals; and preferably decongestant before surgery, such as surgery. Including, but not limited to, colonized subjects who are to be colonized isn't it.

[0054] Decolonizing Candida auris from human subjects Compounds of formula (I), (Ia), (II) and (IIa) for the treatment of rheumatoid arthritis and their pharmaceutical use Candida albicans can be treated with steroids and / or other anti-cancer drugs through uses and methods involving the use of commercially available steroids and / or steroids containing steroids such as steroids containing ... It can reduce and prevent the transmission of Candida auris, Better manage and prevent outbreaks of Candida auris can be done.

[0055] Compounds of formula (I), (Ia), (II) and (IIa) and their pharmaceutically acceptable salts The salt and / or hydrate forms described herein may be used in combination with other environmental decontamination strategies. The above uses and methods are used to treat Candida auris infections. This can prevent infection and reduce the need for isolation precautions by colonized subjects.

[0056] Compounds of formula (I), (Ia), (II) and (IIa) and their pharmaceutically acceptable salts The salt and / or hydrate forms used have previously been used to treat Candida auris (Candida auric acid). is) from a human subject who has had an infection and is at risk for recurrence of such an infection The present invention relates to a method for decolonizing Candida auris. It can be used in the uses and methods described.

[0057] The uses and methods described herein are directed to the treatment of Candida auris In a body site colonized with a virus of formula (I), (Ia), (II) or (II a) (or a pharmaceutically acceptable salt and / or hydrate form thereof) at the site effective in decolonizing Candida auris In particular, ibrexafungelp may be provided in a dose sufficient to achieve a Clinical efficacy for blood infections caused by Candida auris has been reported. (Deven Juneja, Omender Singh, Bansidh ar Tarai, and David Angulo Gonzalez, Suc. cessful Treatment of Two Patients with C andida auris Candidemia with the Investi gational Agent, Oral Ibrexafungerp (form erly SCY-078) from the CARES Study, 13 A pril 2019, ECCMID 2019, Amsterdam, The N etherlands, Abstract publication), and in plasma It is possible to achieve higher dermal exposures than those achieved in human subjects. Effective in decolonizing Candida auris from the skin It is considered to be effective.

[0058] If left untreated, Candida auris can spread through contact. Human subjects who are considered to be candidates for the treatment of Candida auris Through the uses and methods described herein, decolonization can be performed on inanimate objects ( This can indirectly reduce colonization of surfaces (e.g., floors, furniture, appliances), which is particularly This may be useful in settings such as hospitals, hospices, and nursing homes.

[0059] Compounds of formula (I), (Ia), (II) and (IIa) and their pharmaceutically acceptable salts Acceptable salt and / or hydrate forms are described in U.S. Pat. No. 8,188,085, the contents of which are incorporated herein by reference. (The entire contents of which are incorporated herein by reference.) It is possible.

[0060] As used herein, the term "alkyl" refers to any group having a number of carbon atoms within the specified range. It represents any straight or branched chain alkyl group having the group "C 1-6 a "C1-C6 alkyl" includes hexyl alkyl and pentyl alkyl. All isomers of n-, iso-, sec- and t-butyl, n- and isopropyl Another example is "C 1-4 "Alkyl" includes n-, iso-, Represents sec- and t-butyl, n- and isopropyl, ethyl and methyl.

[0061] The term "cycloalkyl" refers to any of the radicals of an alkane having a number of carbon atoms in the specified range. Therefore, for example, "C 3-4 Cycloalkyl" (or "C3- C4 cycloalkyl) refers to cyclopropyl and cyclobutyl.

[0062] As used herein, "cycloalkyl-alkyl" (or, equivalently, "aryl" The term "cycloalkyl" (cycloalkyl) includes alkyl moieties as described above, The system also includes the cycloalkyl moiety described above. The bond to "alkyl" (or "alkyl-cycloalkyl") is a cycloalkyl moiety or The alkyl group can be substituted via either of the alkyl moieties. The number of carbon atoms specified in the formula is the number of carbon atoms in both the alkyl and cycloalkyl portions. The total number of carbon atoms in the alkyl group is indicated. Examples of C4-C5 cycloalkyl-alkyl include methyl, ... ethylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, ethylcyclopropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl, and cyclobutylmethyl. However, the present invention is not limited to these.

[0063] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine. (Alternatively referred to as fluoro, chloro, bromo and iodo).

[0064] As used herein, the term "or" refers to any combination of alternatives where appropriate. It means an alternative form.

[0065] Unless expressly stated to the contrary, all ranges set forth herein are inclusive. For example, a heterocyclic ring described as containing "1 to 4 heteroatoms" This means that the ring may contain 1, 2, 3 or 4 heteroatoms. Any range stated herein includes within it all subranges within that range. Thus, for example, a description containing "1 to 4 heteroatoms" should be understood to mean "a group containing 1 to 4 heteroatoms." The heterocyclic rings described above may have 2 to 4 heteroatoms, 3 or 4 heteroatoms. Heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms Including heterocyclic rings containing atoms, one heteroatom, two heteroatoms, etc. is intended.

[0066] The various cycloalkyl and heterocyclic rings / heterocyclic rings defined herein are Both heteroaryl and heterocyclic / heteroaryl ring systems result in stable provided that the remainder of the compound is free of any ring atom (i.e., any The bond can be at any one of the carbon atoms or any heteroatom. Aromatic rings include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples include, but are not limited to:

[0067] A "stable" compound is one that can be prepared and isolated, and whose structure and properties are consistent with those of the present invention. for the purposes described therein (e.g., therapeutic or prophylactic administration to a subject). Remains essentially unchanged or unchanged for a period of time sufficient to use the compound When a compound is mentioned, , which also includes stable complexes (eg, stable hydrates) of the compounds.

[0068] As a result of the selection of substituents and substitution patterns, the compounds of formula (I), formula (Ia), formula (II) and Certain compounds of formula (IIa) may have asymmetric centers and may be stereoisomeric. It may exist as a mixture of diastereomers or as individual diastereomers or enantiomers. Unless otherwise specified, all isomeric forms (as well as , their pharmaceutically acceptable salts and / or hydrate forms) may be used in isolation or in mixtures. In addition, tautomers of the compounds shown are within the scope of the present invention. The isomeric forms (and their pharmaceutically acceptable salt and / or hydrate forms) are also within the scope of the present invention. is included within the scope of

[0069] In any component or in the formula (I), formula (Ia), formula (II) or formula (IIa ), when any variable occurs more than once, its definition on each occurrence is In addition, any combination of substituents and / or variables is independent of its definition in every occurrence. is permissible only if such combinations result in stable compounds.

[0070] The term "substituted" includes both mono- and poly-substitutions (multiple substitutions at the same position). To the extent that substitution (including multiple substitutions) is chemically possible, Unless expressly stated to the contrary, the specified substitutions Substitution by groups can occur in rings (e.g., aryl, cycloalkyl, heteroaryl, or heterocycles). on any atom in provided that a stable compound results.

[0071] A bond ending in a wavy line is used herein to indicate the point of attachment of a substituent or moiety. This use is illustrated by the following example: [ka]

[0072] Compounds of formula (I), formula (Ia), formula (II) and formula (IIa) and their pharmaceutical uses The acceptable salts and / or hydrates are further useful in the manufacture of antifungal compounds and in the preparation of antifungal compounds. For example, the compounds may be used in the performance of further screening assays. Isolating mutants that are excellent screening tools for identifying antifungal compounds It is useful for

[0073] The compounds of formula (I), formula (Ia), formula (II) and formula (IIa) are, where appropriate, referred to as "pharmaceutically acceptable salts." However, other salts may be administered in the form of the "acceptable salts" or hydrates thereof. These compounds may be useful in the preparation of compounds or pharmaceutically acceptable salts thereof. When the compounds contain basic amine groups, they are conveniently reacted with trifluoroacetate salts. The trifluoroacetate salt can be isolated by HPLC purification. Conversion into other salts, including pharmaceutically acceptable salts, is well known in the art. This can be achieved by many standard methods known in the art, for example by using suitable ion exchange resins. Alternatively, the trifluoroacetate salt can be converted to the desired salt. Conversion of the compound to the free amine can be accomplished using standard methods known in the art (e.g., N This can be achieved by neutralizing with a suitable inorganic base such as HCl. and reacting the free base with an appropriate organic or inorganic acid to give another desired amine. The salts can be prepared by conventional methods. Representative pharmaceutically acceptable quaternary ammonium salts include: Salts include: hydrochlorides, sulfates, phosphates, carbonates, acetates, tartrates, and citrates. Salt, malate, succinate, lactate, stearate, fumarate, hippurate, maleate Salt, Gluconate, Ascorbate, Adipate, Gluceptate, Glutamine Phosphate, glucuronate, propionate, benzoate, methionine Silate, tosylate, oleate, lactobioate, lauryl sulfate, besylate, Caprylate, isethionate, gentisate, malonate, napsylate, edisyl acid salt, pamoate, xinafoate, napadisilate, hydrobromide, nitrate, oxalate, These include cinnamates, mandelates, undecylenates, and camsylates. ), many of the compounds of formula (Ia), formula (II) and formula (IIa) contain an acidic carboxylic acid moiety. in which case suitable pharmaceutically acceptable salts thereof include alkali metal salts, e.g. For example, sodium salts or potassium salts; alkaline earth metal salts, for example, calcium salts or maize salts; magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Examples include salt.

[0074] The present invention includes within its scope compounds of formula (I), formula (Ia), formula (II) and formula (IIa) Generally, such prodrugs are functional derivatives of the compounds. It is a compound that is easily converted in vivo to the required compound. In the methods of treatment described herein, the term "administering" refers to the various conditions described, particularly or by treating a patient with a compound identified as a compound identified after administration to the patient. This involves treating the patient with a compound that converts in vivo to a suitable prodrug derivative. Conventional procedures for the selection and manufacture of bodies are described, for example, in the "Design of Products" ugs,” ed. H. Bundgaard, Elsevier, 1985 The formula (I), the formula ( The metabolites of the compounds of formula (Ia), formula (II) and formula (IIa) are capable of introducing the compounds into the biological environment. This includes reactive chemical species produced when the substance is introduced.

[0075] The term "administration" and variations thereof (e.g., "administering" a compound) refers to a therapeutic A compound (optionally in the form of a salt or hydrate thereof) or a compound thereof is administered to a subject in need thereof. The present invention provides a prodrug of a compound of formula (I), formula (Ia), formula (II) and a compound of formula (IIa) or a pharmaceutically acceptable salt thereof or a hydrate or prodrug thereof The lag may be administered as a second active agent (e.g., another antifungal / antibacterial agent useful in treating fungal / bacterial infections). When provided in combination with a steroid or antibacterial agent, "administering" and variations thereof refer to administering the compound. (or a salt, hydrate or prodrug thereof) and the other active agent simultaneously and sequentially. It is understood to include providing.

[0076] As used herein, the term "composition" refers to a composition containing the specified ingredients. The product and any product resulting directly or indirectly from combining the specified ingredients It is intended to be inclusive.

[0077] "Pharmaceutically acceptable" means that the components of a pharmaceutical composition must be compatible with each other. This means that the product must not be harmful to the body or to the person receiving it.

[0078] The term "subject" (alternatively referred to herein as "patient") refers to a subject As used herein, an animal, preferably a mammal, that has been the object of treatment, observation or experiment. , and most preferably refers to a human.

[0079] The term "colonization" in the context of this application refers to the formation of a colony caused by the presence of microorganisms. The presence of fungi and other microorganisms in anatomical areas without a clinically discernible host inflammatory response colonization (i.e., the microorganism is not causing infection or symptoms of infection). can be preferably identified by culture, but other methods used in the art can also be used to identify Other methods that are acceptable for defining colony formation include polymerase chain reaction (PCR). PCR techniques, molecular sequencing, MALDI-TOF, microscopy or electron microscopy, and and magnetic resonance imaging, but are not limited to these.

[0080] The term "decolonization" refers, in embodiments, to the decolonization of a particular body site (e.g., skin). The burden of certain pathogens (e.g., Candida auris) Reduce the pathogen load to such an extent that it can no longer be identified by standard culture techniques. In other embodiments, "decolonization" refers to the process of decolonizing a plant to achieve a desired benefit (e.g., control of pathogen transmission). A reduction in the burden of a specific pathogen on a scale sufficient to achieve a reduction in the risk of recurrence of infection (minimum risk of infection). Point down.

[0081] The term "effective amount," as used herein, is intended to describe an amount that is effective by a researcher, veterinarian, physician, or other clinical Eliciting a biological or medical response in a tissue, system, animal, or human that the researcher is seeking In one embodiment, "effective amount" refers to the amount of active ingredient or medicament that is effective for treating the disease or condition being treated. may be a "therapeutically effective amount" that alleviates the symptoms of the condition. In another embodiment, an "effective amount" is used to prevent symptoms of or reduce the likelihood of developing the disease or condition being prevented. The term may also be used to refer to a "prophylactically effective amount" of (1,3)-β-D-glucan. Inhibition of leucane synthase to induce the desired response It may also refer to the enfumafungin derivative.

[0082] References to "treat," "treating," "treatment," and variations thereof generally refer to and, after administration, resolution or improvement of one or more signs or symptoms associated with a fungal infection. or eradication of the fungus causing the infection, or any of these results. This means a treatment that provides a combination of:

[0083] For decolonization, a compound of formula (I), formula (Ia), formula (II) or formula (IIa) (optionally in the form of a salt or hydrate) is a commonly available compound for use in combination with a pharmaceutical agent. It can be administered in a conventional manner.

[0084] For decolonization, a compound of formula (I), formula (Ia), formula (II) or formula (IIa) (optionally in salt or hydrate form) can be administered alone as an individual therapeutic agent or administered (sequentially or simultaneously) with one or more other antifungal drugs as a therapeutic combination. It is possible.

[0085] For decolonization, a compound of formula (I), formula (Ia), formula (II) or formula (IIa) (optionally in the form of a salt or hydrate) based on the chosen route of administration and standard pharmaceutical practice. It can be administered with a selected pharmaceutical carrier.

[0086] For example, compounds of formula (I), formula (Ia), formula (II) and formula (IIa) and their Pharmaceutically acceptable salts and / or hydrate forms can be prepared by the following route: administering an effective amount of the compound and a conventional A unit dose of a pharmaceutical composition comprising a non-toxic, pharmaceutically acceptable carrier, an adjuvant, and a vehicle. It can be administered orally, parenterally (which can be by subcutaneous injection, intravenous, intramuscular, intralesional injection or injection) in the form of a single dose. administration by inhalation (e.g., nasal or oral inhalation spray, metered dose inhaler) aerosol and dry powder inhalers), nebulizer administration, ocular administration, topical administration, transdermal or transcutaneous administration It can be administered by one or more of the following: rectal administration; liquid preparations suitable for oral administration (e.g. Suspensions, syrups and elixirs, etc., are prepared according to techniques known in the art. and can be used with common liquids such as water, glycols, oils and alcohols. The following vehicles can be used: Solid preparations suitable for oral administration (e.g., powders, pills, capsules, etc.) Capsules and tablets can be prepared according to techniques known in the art. and solid excipients such as starches, sugars, kaolin, lubricants, binders and disintegrants. Parenteral compositions can be prepared according to techniques known in the art. and typically uses sterile water as the carrier, optionally with a solubility aid such as Injection solutions can be prepared according to methods known in the art. In this case, the carrier may be a saline solution, a glucose solution, or a mixture of saline and glucose. The term "solution" includes a solution containing a mixture of sources.

[0087] Methods suitable for use in preparing pharmaceutical compositions and methods for use in such compositions Further information on suitable ingredients is available at Remington’s Pharmaceu tical Sciences , 20 th edition, edited by AR Gennaro, Mack Publishing Co., 2000 is described in.

[0088] Compounds of formula (I), formula (Ia), formula (II) and formula (IIa) and their pharmaceutical uses Acceptable salt and / or hydrate forms may be, for example, about 100 mg of a mammal (e.g., a human) per day. A single dose or divided doses in the dose range of 0.001 to 1000 mg per kg of body weight. The dosage ranges can be, for example, administered orally or intravenously. is administered orally or intravenously in divided doses at a dose of 0.01 to 5 kg of body weight per day. Another example of a dosage range is oral or intravenous administration in single or divided doses. The recommended dose is 0.1 to 50 mg per kg of body weight per day. The composition may be administered in a manner that allows for symptomatic adjustment of the dosage to the patient being treated, e.g., by administering the active ingredient 1.0 to 1000 milligrams, especially active ingredient 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750 and It can be provided in the form of tablets or capsules containing 1000 milligrams. The specific dose level and frequency of administration for a patient may vary and may include, but are not limited to, The activity of the particular compound used, the metabolic stability and length of action of that compound, age, weight, total body weight, physical health, sex, diet, dosage form and time, excretion rate, concomitant medications, severity of specific conditions The dosage will depend on various factors, such as the dosage and the host being treated. The pharmaceutically acceptable salts of the compounds of formula (IIa) are 150 to 150% by weight of the compounds of formula (IIa). is administered to the subject to provide a total daily dose of 750 mg. , a total daily dose of 150 mg of the compound of formula (IIa), a total daily dose of 300 mg, or a total daily dose of 500 mg of the compound of formula (IIa) mg total daily dose, or a 600 mg total daily dose, or a 750 mg total daily dose. The total daily dose can be administered once daily or it can be administered BID (twice daily). Or divided into TID (three times a day) doses, once every two days, or once every three days. It is also possible.

[0089] The antifungal activity of the compounds can be determined by various assays known in the art, for example, by assaying against yeast. Their minimum inhibitory concentrations (MICs) against filamentous molds and fungi in broth microdilution assays and dermatophytes, or by the minimum effective concentration (MEC) in mice, rabbits, or This can be demonstrated by in vivo evaluation of anti-Candida activity in a guinea pig model. The compound of formula (I) described in the examples of U.S. Pat. No. 8,188,085 is , and an increase in Candida spp. in the range of <0.03-32 μg / mL. It has been shown to inhibit the growth of Candida auris. uris), the distribution of MIC values of Ibrexafungelp is 0.0625 μg / mL The range is ~2 μg / mL, with an overall mode of 1 μg / mL, and the MIC 50 and MIC 90 were 0.5 micrograms / mL and 1 microgram / mL, respectively (Be rkow EL, Angulo D, Lockhart SR, In vitro activity of a novel glucan synthase inh ibitor, SCY-078, against clinical isolation es of Candida auris, Antimicrob Agents C Hemother 61:e00435-17(2017) https: / / doi. org / 10.1128 / AAC.00435-17 .). [Example]

[0090] The following examples serve only to illustrate the invention and its practice. should not be construed as a limitation on the scope or spirit of the invention.

[0091] Example 1 Cutaneous Candida auris in a guinea pig model Evaluation of Ibrexafungelp (SCY-078) in reducing stress The purpose of this study was to determine whether orally administered ibrexafungelp could be effective against Candida albicans in infected skin. To evaluate whether the burden of Candida auris can be reduced there were.

[0092] Materials and Methods Guinea pigs (n=5 per group) were randomized to receive 1 dose of 100 mg / kg of 1000 mg ... 0, 20, or 30 mg / kg of ibrexafungelp was administered twice daily (BID). Animals were given 30 mg / kg prednisolone 1 day before, 1 day after, and 3 days after infection. A single dose of zolon was administered to predispose animals to immunodeficiency and to the infection of Candida auris (Ca Candida auris (Candi) promotes the development of skin infections. 10 blastospores of Bacillus da auris 8 100 μL of the cell suspension containing the cells was applied by scraping the back of the animal. On day 7, tissue biopsies were examined histologically and tissue fungal burden was assessed from skin samples. The PK bioanalysis of Ibrexafungelp plasma concentrations was performed using colony counts. The cis was performed after the last administration (day 7).

[0093] result Candida auris tissue burden was significantly higher in the control group compared to the vehicle control group. In contrast to samples from untreated control animals, Eve No fungal elements were observed in biopsy samples from animals treated with lexafungelp. There were no significant differences in clinical scores (eschar formation, inflammation) between the active agent treatment groups. Plasma exposure in animals receiving 20 or 30 mg / kg BID of ibrexafungalp Exposure amount (AUC 0-24 ) were 2.8, 5.6, and 15 μ*hr / mL.

[0094] conclusion The results of this experimental model showed that treatment with ibrexafungelp significantly improved the survival of rhesus monkeys compared to untreated controls. and the fungal burden in skin infected with Candida auris. This indicates that the infection caused by Candida auris (Candi This supports the role of Ibrexa van Gelb in the decolonization of Ibrexa van Gelb. That is why.

[0095] Furthermore, previous animal models of systemic Candida spp. infection The exposure required to achieve efficacy was approximately 11.2 μg*hr / mL (Wr ing SA et al., Preclinical Pharmacokinet ics and Pharmacodynamic Target of SCY-07 8, a First-in-Class Orally Active Antifu ngal Glucan Synthesis Inhibitor, in Muri ne Models of Disseminated Candidiasis, A ntimicrob Agents Chemother, 2017 Mar 24; 61(4). pii: e02068-16. doi: 10.1128 / AAC. 02068-16. Print 2017 Apr.). This test showed strong antifungal activity. The potential for this effect may result in plasma exposures below those previously reported to be necessary to achieve a systemic effect. This has been observed in the skin at low doses, indicating that Ibrexafungelp has unique properties. It has a strong antifungal activity on the skin and is effective against Candida auris (Candida auris) on the skin. uris) colonization problems.

[0096] Example 2 Low MIC of Ibrexa van Gelb 50 The value is 102 cases from the New York outbreak. of Candida auris in clinical and research isolates The isolates included C. auris, which exhibited variable resistance to antifungal drugs. (resistance to one drug in one or two classes of antifungal drugs), multidrug-resistant isolates (resistance to two or more drugs between two antifungal drugs), and pan-resistant isolates (resistance to two or more drugs between two antifungal drugs). Resistance to azoles, all echinocandins tested, and amphotericin B Other tested antifungals (fluconazole, voriconazole, itraconazole) were included. azole, isabuconazole, posaconazole, anidulafungin, caspofungin , micafungin, amphotericin B, and flucytosine) In 97 isolates that were resistant to antimicrobials, the MIC of ibrexafungalp was 50 The range is 0. MIC of ibrexafungelp is 0.6-0.5 μg / mL 50 Median and mode of The concentrations of the five pan-resistant C. auris strains were 0.5 μg / mL, respectively. isolates, all of which had low MICs of 0.12–1 μg / mL. 50 Ivrek at range He was sensitive to safangelp.

[0097] The present invention has been specifically illustrated and described above with reference to preferred embodiments thereof. However, in view of this disclosure, one skilled in the art would be able to readily identify the invention encompassed by the appended claims. Various changes in form and detail may be made without departing from the scope of the present invention. It will be understood that

Claims

1. Subjects colonized with Candida auris decolonizing Candida auris from an anatomical region of a subject The method for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof administering a hydrate to said subject. 【Chemical 1】 [In the formula, X is O or H, H; R ｅ is C(O)NR ｆ R ｇ or a 6-membered heterocyclic ring containing one or two nitrogen atoms The heteroaryl group may be substituted on a ring carbon by fluoro or chloro or on a ring carbon by chloro or fluoro. may be monosubstituted on the nitrogen by oxygen; R ｆ , R ｇ , R ６ , and R ７ are each independently hydrogen or C １ -C ３ is alkyl; R ８ is C １ -C ４ Alkyl, C ３ -C ４ Cycloalkyl or C ４ -C ５ cycloalkyl - alkyl; R ９ is methyl or ethyl; R ８ and R ９ may be joined together to form a 6-membered saturated ring containing one oxygen atom. ］

2. The method of claim 1 , wherein the anatomical region is skin.

3. The method of claim 1 , wherein the anatomical region is a mucosal tissue.

4. 4. The method of claim 3, wherein the mucosal tissue is a mucosal tissue of the respiratory, gastrointestinal or urinary tract.

5. The method of claim 1 , wherein the subject is a human subject.

6. The compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof is orally administered. The method of claim 1 .

7. The compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof is administered intravenously. The method of claim 1 .

8. Subjects colonized with Candida auris decolonizing Candida auris from an anatomical region of a subject A method for producing a compound (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12 aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy] ci]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl) -1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,1 0a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl 4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7-carbo a compound of the following formula (II) which is a carboxylic acid, or a pharmaceutically acceptable salt or hydrate of said compound: to a subject. 【Chemistry 2】

9. The method of claim 8 , wherein the anatomical region is skin.

10. The method of claim 8 , wherein the anatomical region is a mucosal tissue.

11. 11. The method of claim 10, wherein the mucosal tissue is a mucosal tissue of the respiratory, digestive or urinary tract. 。

12. The method of claim 8 , wherein the subject is a human subject.

13. Oral administration of the compound of formula (II) or a pharmaceutically acceptable salt or hydrate thereof The method of claim 8 .

14. The compound of formula (II) or a pharmaceutically acceptable salt or hydrate thereof is administered intravenously. Item 9. The method according to item 8.

15. Candida auris from an anatomical region of a subject colonized by Candida auris auris), comprising administering to the subject a compound of formula (IIa) below, which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7-carboxylic acid, or a pharmaceutically acceptable salt or hydrate of the compound: 【Chemistry 3】

16. 16. The method of claim 15, wherein the anatomical region is skin.

17. 16. The method of claim 15, wherein the anatomical region is a mucosal tissue.

18. 18. The method of claim 17, wherein the mucosal tissue is a mucosal tissue of the respiratory, gastrointestinal, or urinary tract. 。

19. The method of claim 15 , wherein the subject is a human subject.

20. Oral administration of the compound of formula (IIa) or a pharmaceutically acceptable salt or hydrate thereof The method of claim 15 .

21. Intravenous administration of the compound of formula (IIa) or a pharmaceutically acceptable salt or hydrate thereof The method of claim 15 .

22. Humans colonized by Candida auris elimination of Candida auris from the anatomical region of the subject; A method for knee-forming, comprising the steps of: (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethyl butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4 -pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8 ,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10 a-Tetramethyl-4H-1,4a-propane-2H-phenanthro[1,2-c]pyra The method comprises administering to a human subject a compound of formula (IIa) which is a benzophenone-7-carboxylic acid: method. 【Chemistry 4】

23. 23. The method of claim 22, wherein the anatomical region is skin.

24. 23. The method of claim 22, wherein the anatomical region is a mucosal tissue.

25. 25. The method of claim 24, wherein the mucosal tissue is a mucosal tissue of the respiratory, gastrointestinal, or urinary tract. 。

26. Humans colonized by Candida auris elimination of Candida auris from the anatomical region of the subject; The method for immunizing the human comprises administering to the human a pharmaceutically acceptable salt of a compound of formula (IIa): administering to a subject. 【Chemistry 5】 [The compound is (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12a R,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl -8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridyl)- 1H-1,2,4-triazol-1-yl)-1,6,6a,7,8,9, 10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetrahydro- Tetramethyl-4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7 -carboxylic acid.]

27. 27. The method of claim 26, wherein the anatomical region is skin.

28. 27. The method of claim 26, wherein the anatomical region is a mucosal tissue.

29. 28. The method of claim 27, wherein the mucosal tissue is a mucosal tissue of the respiratory, gastrointestinal, or urinary tract. 。

30. Humans colonized by Candida auris elimination of Candida auris from the anatomical region of the subject; The method for immunizing a human subject comprises administering to a human subject a pharmaceutically acceptable salt of a compound of formula (IIa): orally administering to a subject. 【Chemistry 6】 [The compound is (1S, 4aR, 6aS, 7R, 8R, 10aR, 10bR, 12aR ,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl ]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridyl Nyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,1 0,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tet tetramethyl-4H-1,4a-propane-2H-phenanthro[1,2-c]pyran-7- is a carboxylic acid, The anatomical region is skin or mucosal tissue.

31. 31. The method of claim 30, wherein the citrate salt of the compound of formula (IIa) is administered.

32. 31. The method of claim 30, wherein the pharmaceutically acceptable salt of the compound of formula (IIa) is administered in a tablet form. How to post.

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