Granted Patent B2

US 12,344,680 · App. 17/365,188 · Granted Jul 1, 2025

Inventors: Kenneth Duke James, Jr. (Mebane, NC); Christopher Patrick Laudeman (Durham, NC); Navdeep Balkrishna Malkar (Cary, NC); Balasingam Radhakrishnan (Chapel Hill, NC)

Assignee: Napp Pharmaceutical Group Limited

C07K7/64C07K7/00C07K7/56C07K7/60A61K38/00A61K38/04A61K38/08A61K38/12C07K7/50C07K7/54

Abstract

Claims (56)

1. A method of treating or preventing a fungal infection in a subject, the method comprising administering to the subject a compound described by formula (II):

wherein,

R 2 is NH(CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 NH) t CH 2 CH 2 X 9 , NH[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , O[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , NHCH 2 (CH 2 ) u X 10 , or OCH 2 (CH 2 ) u X 10 ;

X 8 is OH, OR G1 , NH 2 , NHR G1 , NR G1 R G2 , NR G1 R G2 R G3 , OCH 2 (CH 2 ) w Z 2 , or NHCH 2 (CH 2 ) v Z 2 ;

each X 9 is, independently, selected from OH, OR H1 , NHR H1 , NR H1 R H2 , NR H1 R H2 R H3 , OCH 2 (CH 2 ) w Z 2 , and NHCH 2 (CH 2 ) v Z 2 ;

X 10 is selected from NR I1 R I2 R I3 or Z 2 ;

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;

s is an integer from 1 to 5;

t is an integer from 1 to 5;

u is an integer from 1 to 3;

each of R G1 , R G2 , R G3 , R H1 , R H2 , R H3 , R I1 , R I2 , and R I3 is, independently, selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ;

w is an integer from 1 to 3;

Z 2 is selected from

and each of R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 13A , R 14A , R 15A , R 16A , R 17A , R 18A , R 19A , R 20A , R 21A , and R 22A is, independently, selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ,

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , further described by formula (IIa):

wherein,

R 2 is NH(CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 NH) t CH 2 CH 2 X 9 , NH[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , O[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , NHCH 2 (CH 2 ) u X 10 , or OCH 2 (CH 2 ) u X 10 ;

X 8 is OH, OR G1 , NH 2 , NHR G1 , NR G1 R G2 , or NR G1 R G2 R G3 ;

each X 9 is, independently, selected from OH, OR H1 , NHR H1 , NR H1 R H2 , and NR H1 R H2 R H3 ;

X 10 is selected from NR I1 R I2 R I3 ;

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;

s is an integer from 1 to 5;

t is an integer from 1 to 5;

u is an integer from 1 to 3; and

each of R G1 , R G2 , R G3 , R H1 , R H2 , R H3 , R I1 , R I2 , and R I3 is, independently, selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ,

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein one of X 8 , X 9 , and X 10 is selected from N(CH 3 ) 3 + and N(CH 2 CH 3 ) 3 + .

4. The method of claim 1 , further described by formula (IIb):

wherein,

R 2 is NH(CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 CH 2 O) s CH 2 CH 2 X 8 , NH(CH 2 CH 2 NH) t CH 2 CH 2 X 9 , NH[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , O[CH 2 (CH 2 ) a O] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 9 } 2 , NHCH 2 (CH 2 ) u X 10 , or OCH 2 (CH 2 ) u X 10 ;

X 8 is OCH 2 (CH 2 ) w Z 2 or NHCH 2 (CH 2 ) v Z 2 ;

each X 9 is, independently, selected from OCH 2 (CH 2 ) w Z 2 and NHCH 2 (CH 2 ) v Z 2 ;

X 10 is Z 2 ;

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;

s is an integer from 1 to 5;

t is an integer from 1 to 5;

u is an integer from 1 to 3;

w is an integer from 1 to 3;

Z 2 is selected from

and each of R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 13A , R 14A , R 15A , R 16A , R 17A , R 18A , R 19A , R 20A , R 21A , and R 22A is, independently, selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ,

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the compound is an acetate salt or chloride salt.

6. The method of claim 1 , wherein the compound is administered to treat a blood stream infection or tissue infection in the subject.

7. The method of claim 1 , wherein the infection is selected from tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, Pityriasis versicolor , oral thrush, vaginal candidosis, respiratory tract candidosis, biliary candidosis, eosophageal candidosis, urinary tract candidosis, systemic candidosis, mucocutaneous candidosis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.

8. The method of claim 1 , wherein the fungal infection is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus , or A. ochraceus.

9. The method of claim 1 , wherein the subject is being prepared for an invasive medical procedure, the subject is immunocompromised, or the subject is undergoing long term antibiotic therapy.

Assignments (6)

Continuity (8)

References Cited (191)