# US 11,993,582 B2 · Crystalline forms of a LTA4H inhibitor

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- Number: US 11,993,582 B2
- Document ID: US11993582B2
- Status: Granted
- Kind: B2
- Application number: 17/264,333
- Filed: 2019-07-29
- Published: 2021-09-30
- Granted: 2024-05-28
- Earliest claimed: 2018-07-31
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Andreas Kordikowski; Yanxiang Wu
- Web page: https://patentgrep.com/patent/US11993582B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

This application relates to various crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, as well as compositions, method of making and methods of using the same. In some embodiments the crystalline forms also contain water (“hydrates”). These materials are useful in the treatment of diseases and disorders which are typically ameliorated by the inhibition of LTA4H. Such diseases and disorders may include inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation.

## Claims

### Claim 1

A crystalline form B of the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, characterized by one of the following characteristics:
(i) an x-ray powder diffraction pattern comprising representative peaks in terms of 2θ at 22.6±0.2°2θ, 24.1±0.2°2θ and 26.3±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å;
(ii) an x-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of 11.3±0.2°2θ, 12.8 0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å; and
(iii) an x-ray powder diffraction pattern comprising five or more 2θ values selected from the group consisting of 11.3±0.2°2θ, 12.8 0.2°2θ, 15.2±0.2°2θ, 19.7±0.2°2θ, 20.0±0.2°2θ, 20.3±0.2°2θ, 21.0±0.2°2θ, 22.6±0.2°2θ, 24.1±0.2°2θ, 24.4±0.2°2θ, 25.1±0.2°2θ, 26.3±0.2°2θ, 28.5±0.2°2θ, and 30.0±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å.

### Claim 2 (depends on 1)

The crystalline form according to claim 1 having an x-ray diffraction spectrum substantially the same as the x-ray powder diffraction spectrum shown in FIG. 1.

### Claim 3 (depends on 1)

The crystalline form according to claim 1 having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 2.

### Claim 4 (depends on 1)

The crystalline form according to claim 1 having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 3.

### Claim 5 (depends on 1)

The crystalline form according to claim 1 consisting essentially of Form B.

### Claim 6 (depends on 1)

The crystalline form according to claim 1, wherein Form B is in a substantially phase pure form.

### Claim 7

A crystalline form HB of a hydrate of the compound (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, characterized by one of the following characteristics:
(i) an x-ray powder diffraction pattern comprising representative peaks in terms of 2θ at 22.1±0.2°2θ, 23.8±0.2°2θ, 24.7±0.2°2θ and 28.7±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å;
(ii) an x-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of 13.4±0.2°, 20.8±0.2°, 22.1±0.2°, 23.5±0.2°, 23.5±0.2°, 23.8±0.2, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ and 38.7±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å; and
(iii) an x-ray powder diffraction pattern comprising five or more 2θ values selected from the group consisting of 13.4±0.2°, 20.8±0.2°, 22.1±0.2°, 23.5±0.2°, 23.5±0.2°, 23.8±0.2, 24.7±0.2°2θ, 26.1±0.2°2θ, 26.9±0.2°2θ, 28.7±0.2°2θ, 30.4±0.2°2θ, 31.2±0.2°2θ, 33.8±0.2°2θ and 38.7±0.2°2θ, measured at a temperature of about 25° C. and an x-ray wavelength, λ, of 1.5418 Å.

### Claim 8 (depends on 7)

The crystalline form according to claim 7 having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 4.

### Claim 9 (depends on 7)

The crystalline form according to claim 7 having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 5.

### Claim 10 (depends on 7)

The crystalline form according to claim 7 having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 6.

### Claim 11 (depends on 7)

The crystalline form according to claim 7 wherein said hydrate is a monohydrate.

### Claim 12 (depends on 7)

The crystalline form according to claim 7 consisting essentially of Form HB.

### Claim 13 (depends on 7)

The crystalline form according to claim 7 wherein Form HB is in a substantially phase pure form.

### Claim 14 (depends on 1, 7)

A pharmaceutical composition comprising a crystalline form selected from the group consisting of Form B according to claim 1, Form HB according to claim 7; and combinations of Forms B and HB; and one or more pharmaceutically acceptable excipients.

### Claim 15 (depends on 1, 7)

A pharmaceutical composition comprising a crystalline form selected from the group consisting of Form B according to claim 1, Form HB according to claim 7; and combinations of Forms B and HB; in combination with one or more therapeutic agents, wherein the therapeutic agent is independently selected from the group consisting of a COX inhibitor, a Cysteinyl-Leukotriene Receptor antagonist, a leukotriene C4 synthase (LTC4S) inhibitor, a statin, sulfasalazine, Mesalamine, a calcineurin inhibitor; a mTOR inhibitor; an ascomycin having immunosuppressive properties; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; IL-1beta inhibitor.

### Claim 16 (depends on 1, 7)

A method of treating an inflammatory or autoimmune disease or a disorder, in a subject in need thereof, comprising administering to the mammal a therapeutically-effective amount of a crystalline form selected from the group consisting of Form B according to claim 1, Form HB according to claim 7; and combinations of Forms B and HB.