Methods for the synthesis of ceragenins

Patent metadata

Field	Value
Publication number	US-10370403-B2
Application number	US-201615135969-A
Country	US
Kind code	B2
Filing date	Apr 22, 2016
Priority date	Apr 22, 2015
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

Disclosed herein are methods of making ceragnenin compounds for treating, preventing, or diagnosing diseases, disorders, or conditions associated with bacterial or viral infections, cancer, inflammation, and osteogenesis. Ceragenin compounds display broad-spectrum antibacterial activity utilizing a mode of action similar to antimicrobial peptides, but without the high synthesis costs and susceptibility to proteolytic degradation. Ceragenin compounds reproduce the amphiphilic morphology found in many antimicrobial peptides and display potent and diverse biological activities, including anti-bacterial, anti-cancer, anti-inflammatory, bone growth promotion, and wound healing promotion.

First claim

What is claimed is:

1. A method of making a compound of Formula (I) or (III), comprising the steps of:
(a) reacting a compound of Formula (1) and R 1 R 2 —NH

to form a compound of Formula (2):

(b) optionally reducing a compound of Formula (2) to form a compound of Formula (3):

(c1) optionally protecting a compound of Formula (3) with an amine protecting group (PG) to form a compound of Formula (4):

where R 2 is a hydrogen and is replaced with the amine protecting group,
or (c2) optionally protecting a compound of Formula (2) with an amine protecting group (PG) to form a compound of Formula (10):

where R 2 is a hydrogen and is replaced with the amine protecting group;
(d1) reacting a compound of Formula (3) or Formula (4) with a compound of Formula (A)

to form a compound of Formula (5a) or (5b):

or (d2) reacting a compound of Formula (2) or Formula (10) with a compound of Formula (A) to form a compound of Formula (11a) or (11b):

(e1) subjecting a compound of Formula (5a) or (5b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
R 3 —SO 2 Cl  (B)

to form a compound of Formula (6a) or (6b) having three terminal sulfonate groups:

or (e2) subjecting a compound of Formula (11a) or (11b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B) to form a compound of Formula (12a) or (12b) having three terminal sulfonate groups:

(f1) reacting a compound of Formula (6a) or (6b) and R 4 R 5 —NH to thereby directly replace the three terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (I):

or (f2) reacting a compound of Formula (12a) or (12b) and R 4 R 5 —NH too thereby directly replace the three terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (III):

wherein:
X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
n is an integer from 1 to 25;
R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 24 alkyl, optionally substituted C 2 -C 24 alkenyl, optionally substituted C 2 -C 24 alkynyl, optionally substituted C 6 or C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C 7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C 1 -C 6 alkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C 1 -C 6 alkyl, an amine protecting group, and an optionally substituted amide;
R 3 is selected from the group consisting of optionally substituted C 1 -C 24 alkyl, optionally substituted C 2 -C 24 alkenyl, optionally substituted C 2 -C 24 alkynyl, optionally substituted C 6 or C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocyclyl, heterocyclyl, optionally substituted C 7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C 1 -C 6 alkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C 1 -C 6 alkyl,
wherein if substituted, R 1 , R 2 , R 3 , R 4 and/or R 5 include a substitution selected from the group consisting of C 1 -C 24 alkyl, C 1 -C 24 alkenyl, C 1 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 10 carbocyclyl, C 3 -C 10 -carbocyclyl-C 1 -C 6 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 6 -alkyl, aryl, aryl(C 1 -C 6 )alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C 1 -C 6 )alkyl, halo, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy(C 1 -C 6 )alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, C 1 -C 6 alkylthio, arylthio, amino, amino(C 1 -C 6 )alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
wherein if one or more of R 1 , R 2 , R 3 , R 4 , or R 5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

2. The method of claim 1 , comprising the steps of:
(a) reacting a compound of Formula (1) and R 1 R 2 —NH

to form a compound of Formula (2):

(b) optionally reducing a compound of Formula (2) to form a compound of Formula (3):

(c) optionally protecting a compound of Formula (3) with an amine protecting group to form a compound of Formula (4):

wherein R 2 is a hydrogen and is replaced with the amine protecting group;
(d) reacting a compound of Formula (3) or Formula (4) with a compound of Formula (A)

to form a compound of Formula (5a) or (5b):

(e) subjecting a compound of Formula (5a) or (5b) to hydroboration

Assignees

• Savage Paul B
• Jacks Thomas E
• Miller Ross A
• Thompson Andrew S
• Randall Jared Lynn
• Univ Brigham Young

Inventors

• Savage Paul B
• Jacks Thomas E
• Miller Ross A
• Thompson Andrew S
• Randall Jared Lynn

Classifications

• C07J41/0061

  one of the carbon atoms being part of an amide group · CPC title

• C07J41/0055

  the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives · CPC title

• A61P31/22

  for herpes viruses · CPC title

• C07J9/005

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• C07J41/0088 Primary

  containing unsubstituted amino radicals · CPC title