# US 2021/0277064 A1 · Cyclosporine compositions and methods of use

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- Number: US 2021/0277064 A1
- Document ID: US20210277064A1
- Status: Published application
- Kind: A1
- Application number: 17/269,614
- Filed: 2019-08-20
- Published: 2021-09-09
- Earliest claimed: 2018-08-22
- Assignees: Bacainn Biotherapeutics, Ltd.
- Applicants: Bacainn Biotherapeutics, Ltd.
- Inventors: Chris Murphy; Ronald Farquhar; Roland E. Dolle
- Web page: https://patentgrep.com/patent/US20210277064A1

## CPC

- C07K 7/645: {Cyclosporins; Related peptides}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 38/13: Cyclosporins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are cyclosporine compounds and methods for use in the treatment or prevention of neutrophil-mediated inflammation, wherein the compounds inhibit the activity of MRP2 and FPR1.

## Claims

### Claim 1

A compound having the structure of Formula I,
a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing;
wherein
L1 is a C0 to C4 alkyl group optionally substituted with one or more F;
R is selected from the group consisting of —OH and a PEG, wherein the PEG optionally comprises a linker group, L2.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is selected from —OH or —NH(CH2)2-6(CH2CH2O)42-46—O(CH2)0-5CH3.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R is selected from the group consisting of CH3O—(CH2CH2O)44—CH2CH2CH2NH— (BT051), CH3O—(CH2CH2O)44—CH2CH2NH— (BT090), and HO— (BT070).

### Claim 4 (depends on 1)

The compound of claim 1, wherein L1 is an ethylene group or a propylene group.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R is a PEG having from 40 to 50 ethylene oxide units.

### Claim 6 (depends on 1)

The compound of claim 1, wherein L2 is a substituted or unsubstituted heteroalkylene group.

### Claim 7 (depends on 6)

The compound of claim 6 wherein L2 is a C1-6 unsubstituted heteroalkylene having one or two nitrogen atoms.

### Claim 8 (depends on 1)

The compound of claim 1 having the structure of Formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing:

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.

### Claim 10

A method for treating or preventing a disease associated with neutrophil-mediated inflammation in a target tissue of a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I:
a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing;
wherein
L1 is a C0 to C4 alkyl group optionally substituted with one or more F;
R is selected from the group consisting of —OH and a PEG, wherein the PEG optionally comprises a linker group, L2.

### Claim 11 (depends on 10)

The method of claim 10, wherein R is selected from the group consisting of —OH, —NH(CH2)2-6(CH2CH2O)42-46—O(CH2)0-5CH3, CH3O—(CH2CH2O)44—CH2CH2CH2NH— (BT051), CH3O—(CH2CH2O)44—CH2CH2NH— (BT090), and HO— (BT070).

### Claim 12

(canceled)

### Claim 13 (depends on 10)

The method of claim 10, wherein L1 is an ethylene group or a propylene group.

### Claim 14 (depends on 10)

The method of claim 10, wherein R is a PEG having from 40 to 50 ethylene oxide units.

### Claim 15 (depends on 10)

The method of claim 10, wherein L2 is a substituted or unsubstituted heteroalkylene group.

### Claim 16 (depends on 10)

The method of claim 10 having the structure of Formula IA or a pharmaceutically acceptable salt thereof:

### Claim 17 (depends on 10)

The method of claim 10, wherein the compound is formulated as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 10)

The method of claim 10, wherein the disease is selected from the group consisting of intestinal disease, colitis, inflammatory lung disease, inflammatory skin disease, ocular disease, urogenital disease, and sexually transmitted diseases.

### Claim 19 (depends on 18)

The method of claim 18, wherein;
the intestinal disease is selected from the group consisting of proctitis, orchitis, Crohn's disease, and celiac disease;
the colitis is selected from the group consisting of ulcerative colitis, also known as colitis ulcerosa, infectious/non-infectious enterocolitis, and inflammatory bowel disease (IBD);
the inflammatory lung disease is selected from the group consisting of pneumococcal infection, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis;
the inflammatory skin disease is selected from the group consisting of dermatitis (eczema), rosacea, seborrheic dermatitis, and psoriasis;
the ocular disease is selected from the group consisting of uveitis, retinitis, keratitis, and macular degeneration;
the urogenital disease comprises a urinary tract infection; and
the sexually transmitted disease is selected from the group consisting of pelvic inflammatory disease, gonorrhea infection, chlamydia infection, herpes, and urethritis.

### Claim at position 20

20-25. (canceled)

### Claim 26 (depends on 10)

The method of claim 10, wherein the administering step is selected from the group consisting of topical administration and administration at a luminal surface of the target tissue.

### Claim 27 (depends on 10)

The method of claim 10, wherein the inflammation is non-infectious inflammation or infectious inflammation.

### Claim 28

(canceled)

### Claim 29 (depends on 10)

The method of claim 10, wherein the method further comprises:
administering to the subject a therapeutically effective amount of one or more second compound that inhibits one or more of multidrug resistance protein 2 (MRP2) and hepoxilin A3 (HXA3) synthase, wherein the therapeutic amount of the second compound reduces migration of neutrophils into the target tissue; and/or
administering to the subject a therapeutically effective amount of one or more compounds that increases multidrug resistance protein 1 (MRP1), wherein the therapeutic amount of the one or more compounds that increases MRP1 reduces migration of neutrophils into the target tissue; and/or
administering to the subject a therapeutically effective amount of one or more compounds that increases one or more N-acylethanolamines (NAEs), wherein the therapeutic amount of the one or more compounds that increases NAEs reduces migration of neutrophils into the target tissue.

### Claim at position 25

30-32. (canceled)

### Claim 33 (depends on 10)

The method of claim 10, wherein the inflammation is associated with:
Crohn's disease and the treatment or prevention further comprises administering one or more mesalamine products, corticosteroid formulations, ileal-release budesonide, glucocorticosteroids/EEN immunomodulatives, including azathioprine, 6-mercaptopurine, and methotrexate, anti-tumor necrosis factor (TNF) drugs, including infliximab, adalimumab, and certolizumab, pegol, anti-alpha-4 beta-7 integrin antibody vedolizumab, ABT-494, and filgotinib; and/or
ulcerative colitis and the treatment or prevention further comprises administering one or more of 5-aminosalycylates, mesalamine, corticosteroids, multimatrix budesonide, azathioprine, 6-mercaptopurine, anti-TNF drugs, including infliximab, adalimumab, and golimumab, vedolizumab, tofacitinib, ABT-494, and filgotinib.

### Claim 34

(canceled)

### Claim 35 (depends on 10)

The method of claim 10, further comprising administering one or more antibiotic and/or anti-inflammatory agents selected from the group consisting of: Dalbavancin, Oritavancin, Cubicin, Tedizolid, Ceftobiprole, Ceftobiprole, Ceftolozane-tazobactam, mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin, clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, steroidal agents such as corticosteroids such as hydrocortisone, hydroxyltriamcinolone alphamethyl dexamethasone, dexamethasonephosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclarolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenalone acetonide, medrysone, amciafel, amcinafide, betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, non-steroidal agents such as COX inhibitors, LOX inhibitors, p38 kinase inhibitors, immunosuppresant agents such as cyclosporin, and cytokine synthesis inhibitors, tetracycline, minocycline, and doxycycline, or any combination thereof.

### Claim 36 (depends on 10)

The method of claim 10 further comprising administering one or more antibodies selected from the group consisting of: antibodies targeting Clostridium difficile toxins, antibodies targeting tumor necrosis factor (TNF), antibodies targeting interleukins, and antibodies targeting metalloproteinase-9.

### Claim 37 (depends on 10)

The method of claim 10, wherein the compound of Formula I reduces migration of neutrophils into the target tissue as compared to untreated control tissue.