# US 2013/0157979 A1 · Phosphate esters of gyrase and topoisomerase inhibitors

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- Number: US 2013/0157979 A1
- Document ID: US20130157979A1
- Status: Published application
- Kind: A1
- Application number: 13/527,832
- Filed: 2012-06-20
- Published: 2013-06-20
- Earliest claimed: 2011-06-20
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Youssef Laafiret Bennani; Paul S. Charifson; Anne-Laure Grillot; Arnaud Le Tiran; Hardwin O'Dowd
- Web page: https://patentgrep.com/patent/US20130157979A1

## CPC

- A61K 31/685: one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
- A61K 31/688: both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- C07D 405/14: containing three or more hetero rings
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to phosphate esters of compounds that inhibit bacterial gyrase and/or Topoisomerase IV and pharmaceutical compositions thereof. These phosphate esters are useful for treating bacterial infections.

## Claims

### Claim 1

A compound of the formula (I):
or a pharmaceutically acceptable salt thereof, wherein
X is —PO(OH)O—R1, or —PO(O−M+)O—R1;
M+ is a pharmaceutically acceptable monovalent cation;
R1 is (C1-C20)-alkyl, (C2-C20)-alkenyl, —(CH2CH2O)nCH3, or R2; wherein said alkyl or alkenyl is optionally substituted with R2, —OR9, —N(R9)2, —CN, —C(O)OR9, —C(O)N(R9)2, —N(R9)—C(O)—R9, halogen, —CF3, or —NO2;
each R2 is independently a 5-6 membered carbocyclic or heterocyclic aliphatic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, and N(R9); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from —OH, C1-C4 alkyl, and —O—(C1-C4)-alkyl;
each R9 is independently H or a C1-C4 alkyl group; and
n is an integer 1 to 5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is —PO(O−M+)O—R1; and M+ is selected from a group consisting of Li+, Na+, K+, N-methyl-D-glucamine, and N(R9)4+.

### Claim 3 (depends on 1)

The compound of either claim 1, wherein R1 is (C1-C20)-alkyl, (C2-C20)-alkenyl, or —O(CH2CH2O)nCH3, wherein n is an integer 1, 2 or 3, morpholinoethyl, 4-ethyltetrahydro-2H-pyranyl, piperidinylethyl, piperazinylethyl, or pyrrolidinylethyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R1 is morpholinoethyl, 4-ethyltetrahydro-2H-pyranyl, piperidinylethyl, piperazinylethyl, or pyrrolidinylethyl.

### Claim 5 (depends on 3)

The compound of claim 3, wherein R1 is (C1-C20)-alkyl.

### Claim 6 (depends on 3)

The compound of claim 3, wherein R1 is —O(CH2CH2O)nCH3, wherein n is an integer 1, 2 or 3.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl hydrogen phosphate.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is ammonium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl phosphate.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl hexadecyl hydrogen phosphate.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is ammonium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl hexadecyl phosphate.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is 2-(5-(2-(3-ethylureido)-6-fluoro-7-((R)-tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-morpholinoethyl hydrogen phosphate.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound according to any of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, further comprising a second therapeutic agent selected from an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.

### Claim 14 (depends on 12)

The pharmaceutical composition of claim 12, further comprising an agent that increases the susceptibility of bacterial organisms to antibiotics.

### Claim 15 (depends on 1)

A method of decreasing or inhibiting Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium ulcerans, Chlamydophila pneumoniae, Chlamydia trachomatis, Haemophilus influenzae, Streptococcus pyogenes or β-haemolytic streptococci bacterial quantity in a biological sample comprising contacting said biological sample with the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A method of controlling, treating or reducing the advancement, severity or effects of a nosocomial or a non-nosocomial bacterial infection in a patient, comprising administering to said patient the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein the bacterial infection is characterized by the presence of one or more of Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium ulcerans, Chlamydophila pneumoniae, Chlamydia trachomatis, Haemophilus influenzae Streptococcus pyogenes or β-haemolytic streptococci.

### Claim 18 (depends on 17)

The method of claim 17, wherein the bacterial infection is selected from one or more of the following: upper respiratory infections, lower respiratory infections, ear infections, pleuropulmonary and bronchial infections, complicated urinary tract infections, uncomplicated urinary tract infections, intra-abdominal infections, cardiovascular infections, a blood stream infection, sepsis, bacteremia, CNS infections, skin and soft tissue infections, GI infections, bone and joint infections, genital infections, eye infections, or granulomatous infections, uncomplicated skin and skin structure infections, complicated skin and skin structure infections (cSSSI), catheter infections, pharyngitis, sinusitis, otitis externa, otitis media, bronchitis, empyema, pneumonia, community acquired pneumoniae (CAP), hospitalized acquired pneumonia, hospitalized bacterial pneumonia, diabetic foot infections, vancomycin resistant enterococci infections, cystitis and pyelonephritis, renal calculi, prostatitis, peritonitis and other inter-abdominal infections, dialysis-associated peritonitis, visceral abscesses, endocarditis, myocarditis, pericarditis, transfusion-associated sepsis, meningitis, encephalitis, brain abscess, osteomyelitis, arthritis, genital ulcers, urethritis, vaginitis, cervicitis, gingivitis, conjunctivitis, keratitis, endophthalmitisa, an infection in cystic fibrosis patients or an infection of febrile neutropenic patients.

### Claim 19 (depends on 18)

The method of claim 18, wherein the bacterial infection is selected from one or more of the following: community acquired pneumoniae (CAP), hospitalized acquired pneumonia, hospitalized bacterial pneumonia, bacteremia, diabetic foot infections, catheter infections, uncomplicated skin and skin structure infections, complicated skin and skin structure infections (cSSSI), vancomycin resistant enterococci infections or osteomyelitis.

### Claim 20 (depends on 16)

The method of claim 16, further comprising administering to said patient an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound, either as part of a multiple dosage form together with said compound or salt or as a separate dosage form.