Cationic steroidal antimicrobial compounds and methods of manufacturing such compounds

Patent metadata

Field	Value
Publication number	US-9434759-B1
Application number	US-201514866213-A
Country	US
Kind code	B1
Filing date	Sep 25, 2015
Priority date	May 18, 2015
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

Cationic steroidal antimicrobial (CSA) compounds having amide functionality and methods of manufacturing such CSA compounds. The CSA compound can be a compound of Formula (I), Formula (II), Formula (III), or a salt thereof:

where R 18 has the following structure:

—R 20 —(C═O)—N—R 21 R 22

R 20 is omitted or substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl, and
R 21 and R 22 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl, provided that at least one of R 21 and R 22 is not hydrogen.

First claim

What is claimed is:

1. A cationic steroidal antimicrobial (CSA) compound of Formula (III), or salt thereof:

wherein,
R 3 , R 7 , and R 12 are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, alkylaminoalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, di(alkyl)aminoalkyl, alkylcarboxyalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxamido, guanidinoalkyloxy, guanidinoalkylcarboxy, quaternary ammonium alkylcarboxy, and hydroxyalkyl,
R 18 has the following structure:
—R 20 —(C═O)—N—R 21 R 22

R 20 is a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 1 -C 10 alkenyl, a substituted or unsubstituted C 1 -C 10 alkynyl, or a substituted or unsubstituted C 6 or C 10 aryl, and
R 21 and R 22 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, substituted or unsubstituted C 2 -C 24 alkenyl, substituted or unsubstituted C 2 -C 24 alkynyl, substituted or unsubstituted C 6 or C 10 aryl, substituted or unsubstituted 5 to 10 membered heteroaryl, substituted or unsubstituted 5 to 10 membered heterocyclyl, substituted or unsubstituted C 7 -C 13 aralkyl, substituted or unsubstituted (5 to 10 membered heteroaryl)-C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 carbocyclyl, substituted or unsubstituted C 4 -C 10 (carbocyclyl)alkyl, substituted or unsubstituted (5 to 10 membered heterocyclyl)-C 1 -C 6 alkyl, substituted or unsubstituted substituted amido, and amine protecting group, provided that at least one of R 21 and R 22 is not hydrogen.

2. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of unsubstituted (C 1 -C 6 ) hydroxyalkyl, unsubstituted (C 1 -C 16 ) alkylamino-(C 1 -C 5 )alkyl, unsubstituted (C 1 -C 5 ) aminoalkyloxy, unsubstituted (C 1 -C 5 ) aminoalkylcarboxy, unsubstituted (C 1 -C 5 ) aminoalkylaminocarbonyl, unsubstituted (C 1 -C 5 ) aminoalkylcarboxamido, unsubstituted di(C 1 -C 5 alkyl)amino-(C 1 -C 5 ) alkyl, unsubstituted (C 1 -C 5 ) guanidinoalkyloxy, unsubstituted (C 1 -C 16 ) quaternary ammonium alkylcarboxy, and unsubstituted (C 1 -C 16 ) guanidinoalkylcarboxy.

3. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, alkoxycarbonylalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxamido, guanidinoalkyloxy, guanidinoalkylcarboxy, and quaternary ammonium alkylcarboxy.

4. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are each one of aminoalkyloxy or aminoalkylcarboxy.

5. The CSA compound of claim 1 , wherein R 3 , R 7 , and R 12 are independently selected from the group consisting of amino-C 3 -alkyloxy; amino-C 3 -alkyl-carboxy; C 8 -alkylamino-C 5 -alkyl; C 8 -alkoxy-carbonyl-C 4 -alkyl; C 8 -alkyl-carbonyl-C 4 -alkyl; di-(C 5 -alkyl)amino-C 5 -alkyl; C 13 -alkylamino-C 5 -alkyl; C 6 -alkoxy-carbonyl-C 4 -alkyl; C 6 -alkyl-carboxy-C 4 -alkyl; and C 16 -alkylamino-C 5 -alkyl.

6. A pharmaceutical composition comprising the CSA compound of claim 1 and a pharmaceutically acceptable excipient.

7. A cationic steroidal antimicrobial (CSA) compound selected from the group consisting of:

and salts thereof.

8. The CSA compound of claim 7 , wherein the CSA compound is

or salt thereof.

9. The CSA compound of claim 7 , wherein the CSA compound comprises a salt selected from the group consisting of: (1) salts obtained by reacting a CSA compound with an inorganic acid, a hydrohalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and/or phosphoric acid; (2) salts obtained by reacting a CSA compound with an organic acid, an aliphatic or aromatic carboxylic or sulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, and/or naphthalenesulfonic acid; (3) salts obtained by reacting a CSA compound with a base to form an ammonium salt, an alkali metal salt, a lithium, sodium or a potassium salt, an alkaline earth metal salt, a calcium, magnesium and/or aluminum salt; (4) salts of organic bases, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, and/or tromethamine, and salts with amino acids such as arginine and lysine; and (5) salts of an inorganic base, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and/or sodium hydroxide.

10. The CSA compound of claim 7 , wherein the CSA compound comprises a salt selected from the group consisting of hydrochloride salts, mono-hydrochloride salts, di-hydrochloride salts, tri-hydrochloride salts, tetra-hydrochloride salts, sulfuric acid addition salts, sulfonic acid addition salts, disulfonic acid addition salts, 1,5-naphthalenedisulfonic acid addition salts, sulfate salts, and bisulfate salts.

11. The CSA compound of claim 1 , wherein one of R 21 or R 22 is hydrogen and one is not hydrogen.

12. An antimicrobial composition comprising the CSA compound of claim 1 and a carrier.

13. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable excipient comprises at least one member selected from the group consisting of carriers, solvents, stabilizers, adjuvants, diluents, and combinations thereof.

14. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, solids, emulsions, suspensions, solutions, liquids, powders, syrups, creams, ointments, troches, lozenges, granules, and elixirs.

15. The CSA compound of claim 7 , wherein the CSA compound is

16. A pharmaceutical composition comprising the CSA compound of claim 7 and a pharmaceutically acceptable excipient.

17. An antimicrobial composition comprising the CSA compound of claim 7 and a carrier.

18. A cationic steroidal antimicrobial (CSA) compound of Formula (III), or salt thereof:

wherein,
R 3 , R 7 , and R 12 are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, aminoalkylaminocarbonyl, aminoalkylcarboxamido, and quaternary ammonium alkylcarboxy,
R 18 has the following structure:
—R 20 —(C═O)—N—R 21 R 22

R 20 is a C 4 alkyl, and
R 21 and R 22 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, substituted or unsubstituted C 2 -C 24 alkenyl, substituted or unsubstituted C 2 -

Assignees

• Savage Paul B
• Univ Brigham Young

Inventors

• Savage Paul B

Classifications

• A61P31/04

  Antibacterial agents · 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

• C07J41/0088 Primary

  containing unsubstituted amino radicals · CPC title

• C07C211/00

  Compounds containing amino groups bound to a carbon skeleton · CPC title

• C07J41/0061

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