# US 10,369,188 B2 · Methods for preventing and treating pneumocystis infections

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- Number: US 10,369,188 B2
- Document ID: US10369188B2
- Status: Granted
- Kind: B2
- Application number: 16/067,713
- Filed: 2017-01-06
- Published: 2019-01-03
- Granted: 2019-08-06
- Earliest claimed: 2016-01-08
- Assignees: Cidara Therapeutics, Inc.
- Applicants: Cidara Therapeutics, Inc.
- Inventors: Kenneth Bartizal; Paul Daruwala; Voon Ong; Maureen Roden; Taylor Sandison; Dirk Thye
- Web page: https://patentgrep.com/patent/US10369188B2

## CPC

- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61K 38/005: {Enzyme inhibitors (protease inhibitors A61K38/55)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61P 31/10: Antimycotics
- C07K 7/50: Cyclic peptides containing at least one abnormal peptide link
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The disclosure relates to methods of prophylactic and therapeutic treatments of a Pneumocystis infection (i.e., an infection caused by Pneumocystis jirovecii) in a subject by administering to the subject a compound of any of formulas (1)-(111) (e.g., a salt of Compound 1, or a neutral form thereof). The disclosure also relates to methods of inhibiting the replication of a Pneumocystis spp. The methods of the disclosure can be useful in immunocompromized subjects.

## Claims

### Claim 1

A method of treating or reducing the risk of a Pneumocystis infection in a subject comprising administering to the subject in an amount and for a duration sufficient to treat or reduce the risk of the Pneumocystis infection a compound of any of formulas (I)-(III):
wherein,
R1 is O(CH2CH2O)nCH2CH2X1, O(CH2CH2NH)nCH2CH2X1, O(CH2CH2CH2O)nCH2CH2X1, NHCH2CH2X2, NH(CH2CH2O)mCH2CH2X2, NH(CH2CH2CH2O)mCH2CH2X2, NH(CH2CH2O)pCH2CH2X3, NH(CH2CH2CH2O)pCH2CH2X3, NHCH2CH2X4, NH[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, O[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, NH(CH2CH2NH)rCH2CH2X5, NHCH2(CH2)qX6, or OCH2(CH2)qX6;
RT is n-pentyl, sec-pentyl, or iso-pentyl;
X1 is NH2, NHRA1, NRA1RA2, NRA1RA2RA3, or NHCH2(CH2)vZ1;
X2 is OH, ORB1, or OCH2(CH2)vZ1;
X3 is NH2, NHRC1, NRC1RC2, or NRC1RC2RC3, or NHCH2(CH2)vZ1;
X4 is NRD1RD2RD3 or NHCH2(CH2)vZ1;
each X5 is, independently, selected from OH, ORE1, NH2, NHRE1, NRE1RE2, NRE1RE2RE3, OCH2(CH2)vZ1, and NHCH2(CH2)vZ1;
X6 is selected from NRF1RF2RF3 and Z1;
a is an integer from 1 to 2;
b is an integer from 0 to 3;
c is an integer from 1 to 2;
d is an integer from 0 to 3;
n is an integer from 1 to 5;
m is an integer from 1 to 5;
p is an integer from 1 to 5;
r is an integer from 1 to 5;
q is an integer from 1 to 3;
v is an integer from 1 to 3;
each of RA1, RA2, RA3, RB1, RC1, RC2, RC3, RD1, RD2, RD3, RE1, RE2, RE3, RF1, RF2, and RF3 is, independently, selected from CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
Z1 is selected from:
and each of R1A, R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, R10A, R11A, R12A, R13A, R14A, R15A, R16A, R17A, R18A, R19A, R20A, R21A, and R22A is, independently, selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the treating comprises reducing the cyst burden in the lung of the subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the treating comprises inhibiting the reproduction of a Pneumocystis spp. in the subject.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject has Pneumocystis pneumonia.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject is immunocompromised.

### Claim 6 (depends on 5)

The method of claim 5, wherein the subject is HIV positive or has hyper IgM syndrome.

### Claim 7 (depends on 5)

The method of claim 5, wherein the subject has a CD4+ T-cell count of less than 200 cells/μl of blood.

### Claim 8 (depends on 5)

The method of claim 5, wherein the compound of any of formulas (I)-(III), or a pharmaceutically acceptable salt thereof, is administered concurrently or within 7 days, before and/or after, the subject undergoes an immunosuppression therapy, an anti-TNF therapy, a corticosteroid therapy, a chemotherapy, or a transplantation procedure.

### Claim 9 (depends on 1)

The method of claim 1, wherein the subject is a human and the Pneumocystis infection is caused by Pneumocystis jirovecii.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is administered intraorally, intravenously, intramuscularly, intradermally, intraarterially, subcutaneously, orally, or by inhalation.

### Claim 11

A method of inhibiting the replication of a Pneumocystis spp. comprising contacting the Pneumocystis spp., in an amount and for a duration sufficient to inhibit replication of the Pneumocystis spp., with a compound of any of formulas (I)-(III):
wherein,
R1 is O(CH2CH2O)nCH2CH2X1, O(CH2CH2NH)nCH2CH2X1, O(CH2CH2CH2O)nCH2CH2X1, NHCH2CH2X2, NH(CH2CH2O)mCH2CH2X2, NH(CH2CH2CH2O)mCH2CH2X2, NH(CH2CH2O)pCH2CH2X3, NH(CH2CH2CH2O)pCH2CH2X3, NHCH2CH2X4, NH[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, O[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, NH(CH2CH2NH)rCH2CH2X5, NHCH2(CH2)qX6, or OCH2(CH2)qX6;
RT is n-pentyl, sec-pentyl, or iso-pentyl;
X1 is NH2, NHRA1, NRA1RA2, NRA1RA2RA3, or NHCH2(CH2)vZ1;
X2 is OH, ORB1, or OCH2(CH2)vZ1;
X3 is NH2, NHRC1, NRC1RC2, or NRC1RC2RC3, or NHCH2(CH2)vZ1;
X4 is NRD1RD2RD3 or NHCH2(CH2)vZ1;
each X5 is, independently, selected from OH, ORE1, NH2, NHRE1, NRE1RE2, NRE1RE2RE3, OCH2(CH2)vZ1, and NHCH2(CH2)vZ1;
X6 is selected from NRF1RF2RF3 and Z1;
a is an integer from 1 to 2;
b is an integer from 0 to 3;
c is an integer from 1 to 2;
d is an integer from 0 to 3;
n is an integer from 1 to 5;
m is an integer from 1 to 5;
p is an integer from 1 to 5;
r is an integer from 1 to 5;
q is an integer from 1 to 3;
v is an integer from 1 to 3;
each of RA1, RA2, RA3, RB1, RC1, RC2, RC3, RD1, RD2, RD3, RE1, RE2, RE3, RF1, RF2, and RF3 is, independently, selected from CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
Z1 is selected from:
and each of R1A, R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, R10A, R11A, R12A, R13A, R14A, R15A, R16A, R17A, R18A, R19A, R20A, R21A, and R22A is, independently, selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2,
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the Pneumocystis spp. is Pneumocystis jirovecii.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, and neutral forms or pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is administered concurrently with a second antifungal agent.

### Claim 15 (depends on 14)

The method of claim 14, wherein the second antifungal agent is clindamycin, trimethoprim, sulfamethoxazole, cotrimoxazole, atovaquone, pentamidine, primaquine, pyrimethamine, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 14)

The method of claim 14, wherein the second antifungal agent is selected from glucan synthase inhibitors, polyene compounds, azole compounds, and pharmaceutically acceptable salts thereof.

### Claim 17 (depends on 11)

The method of claim 11, wherein the compound is selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, and neutral forms or pharmaceutically acceptable salts thereof.

### Claim 18 (depends on 11)

The method of claim 11, wherein the compound is administered concurrently with a second antifungal agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein the second antifungal agent is clindamycin, trimethoprim, sulfamethoxazole, cotrimoxazole, atovaquone, pentamidine, primaquine, pyrimethamine, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 18)

The method of claim 18, wherein the second antifungal agent is selected from glucan synthase inhibitors, polyene compounds, azole compounds, and pharmaceutically acceptable salts thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein the compound is the compound of formula (I), or pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The method of claim 21, wherein the compound is Compound 1, or a neutral form or pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 10)

The method of claim 10, wherein the compound is administered intravenously.

### Claim 24 (depends on 10)

The method of claim 10, wherein the compound is administered subcutaneously.

### Claim 25 (depends on 11)

The method of claim 11, wherein the compound is the compound of formula (I), or pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 25)

The method of claim 25, wherein the compound is Compound 1, or a neutral form or pharmaceutically acceptable salt thereof.