# US 2014/0155358 A1 · Therapeutic Compounds

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- Number: US 2014/0155358 A1
- Document ID: US20140155358A1
- Status: Published application
- Kind: A1
- Application number: 14/111,013
- Filed: 2012-04-11
- Published: 2014-06-05
- Earliest claimed: 2011-04-11
- Assignees: Akthelia Pharmaceuticals
- Inventors: Rubhana Raqib; Birgitta Agerberth; Gudmundur Hrafn Gudmundsson; Roger Stromberg
- Web page: https://patentgrep.com/patent/US20140155358A1

## CPC

- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/59: Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K 31/592: 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
- A61K 31/593: 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- C07C 57/30: containing six-membered aromatic rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention relates to compounds which are active as drugs for stimulating the innate antimicrobial peptide system and can be used as antimicrobial drugs. Preferred targets are infections selected from infection of the lung, trachea, urinary tract or kidney, upper GI tract and\or blood. Preferred target pathogens are selected from: Mycobacterium tuberculosis; Pseudomonas bacteria; Haemophilus influenzae; Moraxella catarrhalis. “Preferred” compounds of the invention are. Preferred compounds include 4-phenylbutyric acid or a salt of 4-phenylbutyrate, such as sodium 4-phenylbutyrate, Butyric acid or a salt of butyrate, such as sodium butyrate, or gyceryl tributyrate.

## Claims

### Claim 1

A method of treatment or prophylaxis of an infection caused by a pathogen in a patient in need of the same, which method comprises oral or intravenous administration to the patient an effective amount of a compound of formula (I)
wherein
Q represents —COOH, —COOR5, or a pharmaceutically acceptable salt of —COOH;
R1 represents an unsubstituted aryl group, hydrogen, a linear or branched unsubstituted or substituted saturated or unsaturated alkyl group with 1 to 10 carbon atoms, halide, amino, hydroxyl, carbonyl, or a substituted aryl group;
R2a, R2b, R3a, R3b, R4a and R4b, if present, each independently represent hydrogen, halide, amino, hydroxyl, carbonyl, a linear or branched substituted or unsubstituted saturated or unsaturated alkyl group with 1 to 10 carbon atoms, or a substituted or unsubstituted aryl group; and/or R3a, together with an adjacent R4a or R2a, may represent a carbon-carbon π bond; and/or
R3b, together with an adjacent R4b or R2b, may represent a carbon-carbon π bond;
m and n are each independently 0 or 1;
R5, if present, represents a linear or branched substituted or unsubstituted saturated or unsaturated alkyl group with 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, a triglyceride moiety —CH2CH(OC(═O)R6)CH2(OC(═O)R7), or a diglyceride moeity —C(C═O)OCH2CH(OC(═O)R6)CH2OH or a salt thereof; and
R6 and R7, if present, independently represent hydrogen, a linear or branched substituted or unsubstituted saturated or unsaturated alkyl group with 1 to 10 carbon atoms or a substituted or unsubstituted aryl group.
wherein:
(i) said infection is selected from infection of the lung, trachea, urinary tract or kidney, upper GI tract and\or blood
and\or
(ii) said pathogen is selected from: Mycobacterium tuberculosis; Pseudomonas bacteria; Haemophilus influenzae; Moraxella catarrhalis;
and in each case wherein the effective amount is an oral dose of between 500 and 4000 mg/day, or an intravenous dose of between 200 and 1000 mg/day such as to boost innate antimicrobial activity in the patient

### Claim 2 (depends on 1)

A method as claimed in claim 1 wherein the compound is selected from:
(i) 4-phenylbutyric acid or a salt of 4-phenylbutyrate,
(ii) butyric acid or a salt of butyrate, such as sodium butyrate (compound IIb)
(iii) glyceryl tributyrate (TBG)
(iv) 2-methyl-3-phenylpropionic acid or a salt of 2-methyl-3-phenylpropionate.

### Claim 3 (depends on 2)

A method as claimed in claim 2 wherein the compound is sodium 4-phenylbutyrate.

### Claim 4 (depends on 2)

A method as claimed in claim 2 wherein the compound is administered in combination with Vitamin D.

### Claim 5 (depends on 2)

A method as claimed in claim 2 wherein the compound is administered such as to boost the innate antimicrobial activity in the lung, trachea, urinary tract or kidney, jejunum, ileum.

### Claim 6 (depends on 2)

A method as claimed in claim 2 wherein said infection is tuberculosis and\or the pathogen is Mycobacterium tuberculosis.

### Claim 7 (depends on 6)

A method as claimed in claim 6 wherein said patient is immunocompromised, and is optionally HIV positive.

### Claim 8 (depends on 6)

A method as claimed in claim 6 wherein the compound is a salt of 4-phenylbutyrate, and the compound is administered in combination with Vitamin D.

### Claim 9 (depends on 2)

A method as claimed in claim 2 wherein the said infection is an infection of the blood.

### Claim 10 (depends on 9)

A method as claimed in claim 9 wherein the compound is administered such as to boost the innate antimicrobial activity by inducing anti-microbial peptides in white blood cells.

### Claim 11 (depends on 2)

A method as claimed in claim 2 wherein the said infection is a respiratory infection of the respiratory airways or lungs.

### Claim 12 (depends on 11)

A method as claimed in claim 11 wherein said infection is secondary infection which is associated with dysenteric or cholera-like diarrhoea, optionally arising from shigella infection.

### Claim 13 (depends on 12)

A method as claimed in claim 12 wherein said secondary infection is viral or bacterial.

### Claim 14 (depends on 13)

A method as claimed in claim 13 wherein said secondary infection is pneumonia or meningitis.

### Claim 15 (depends on 11)

A method as claimed in claim 11 wherein the said infection is a lung infection and said pathogen is Pseudomonas bacteria.

### Claim 16 (depends on 15)

A method as claimed in claim 15 wherein said pathogen is Pseudomonas aeruginosa and said compound is 4-phenylbutyric acid or a salt of 4-phenylbutyrate which is administered in combination with Vitamin D.

### Claim 17 (depends on 11)

A method as claimed in claim 11 wherein said pathogen is Haemophilus influenzae and Moraxella catarrhalis.

### Claim 18 (depends on 2)

A method as claimed in claim 2 wherein said infection is a kidney or urinary tract infection and said compound is TBG.

### Claim 19 (depends on 2)

A method as claimed in claim 2 wherein the treatment or prophylaxis of the infection comprises:
(1) administration to the patient of an antibiotic for 1 or 2 days with or without a compound of formula (I); followed by
(2) administration to the patient of an effective amount of a compound of formula (I) for a further 2, 3, 4, 5 or more days.

### Claim 20 (depends on 2)

A method as claimed in claim 2 wherein the effective amount is between 500 and 2000 mg/day 4-phenylbutyric acid or a salt of 4-phenylbutyrate given orally.

### Claim 21 (depends on 2)

A method as claimed in claim 2 wherein the effective amount is between 200 and 700 mg of sodium butyrate or 600 and 1000 mg of sodium phenylbutyrate given intravenously.

### Claim 22 (depends on 2)

A method as claimed in claim 2 wherein the effective amount is between 3000 and 4000 mg/day TBG given orally.

### Claim 23 (depends on 2)

A method as claimed in claim 2 wherein the daily dosage of the compound of formula (I) is split into doses given 2 or 3 times daily.

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26

(canceled)

### Claim 27

(canceled)