# US 10,370,332 B2 · Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-YL]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof

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- Number: US 10,370,332 B2
- Document ID: US10370332B2
- Status: Granted
- Kind: B2
- Application number: 15/861,586
- Filed: 2018-01-03
- Published: 2018-05-10
- Granted: 2019-08-06
- Earliest claimed: 2012-10-17
- Assignees: Macrophage Pharma Limited
- Applicants: Macrophage Pharma Limited
- Inventors: Stéphane Pintat; Stephen John Davies; David Festus Charles Moffat
- Web page: https://patentgrep.com/patent/US10370332B2

## CPC

- C07D 213/73: Unsubstituted amino or imino radicals
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound which is: tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate or a salt, hydrate or solvate thereof. The present invention also provides a pharmaceutical composition comprising the compound together with one or more pharmaceutically acceptable carriers and/or excipients. The compound and composition are useful for inhibiting the activity of a p38 MAP kinase enzyme. As such they may be used in the treatment of a autoimmune or inflammatory disease, or a cell proliferative disease. In addition, the invention provides an acid produced by hydrolysis of the ester group of the compound of the invention. The acid is N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alanine.

## Claims

### Claim 1

Method for the production of tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate comprising reacting together the following compounds (i) and (ii):
(i) 4-Chlorophenyl 3-(2,4-difluorophenyl)-3-oxopropanimidothioate hydro-chloride;
(ii) 2-(4-Amino-3,5-difluorophenyl)ethanol

### Claim 2 (depends on 1)

A method according to claim 1 wherein tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate is synthesised according to the following scheme wherein compound (ii) is added during Stage 1 to produce 2-(4-{[3-(2,4-Difluorophenyl)-3-oxopropanimidoyl]amino}-3,5-difluorophenyl)ethyl acetate as an intermediate:

### Claim 3 (depends on 2)

A method according to claim 2 wherein in stage 2, propiolic acid is added to form 2-{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl acetate.

### Claim 4 (depends on 2)

A method according to claim 2 wherein tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate is formed in Stage 5, by the addition of tert-butyl L-alaninate hydrochloride to the compound formed after Stage 4.

### Claim 5 (depends on 1)

A method according to claim 1 wherein compound (ii), 2-(4-Amino-3,5-difluorophenyl)ethanol, is prepared according to the following reaction scheme:

### Claim 6 (depends on 1)

A method of forming a pharmaceutical composition comprising producing tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate according to the method of claim 1, and formulating the said tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate with one or more pharmaceutically acceptable carriers and/or excipients.

### Claim 7 (depends on 6)

A method of forming a pharmaceutical composition according to claim 6, wherein the tert-Butyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate is formulated for oral or parenteral administration.

### Claim 8 (depends on 7)

A method of forming a pharmaceutical composition according to claim 7, wherein the parenteral administration is subcutaneous, intravenous, intramuscular, intrasternal, transdermal or by infusion.