# US 10,370,400 B2 · 4-methylumbelliferone derivatives for treatment for immune modulation

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- Number: US 10,370,400 B2
- Document ID: US10370400B2
- Status: Granted
- Kind: B2
- Application number: 15/870,755
- Filed: 2018-01-12
- Published: 2018-07-19
- Granted: 2019-08-06
- Earliest claimed: 2017-01-13
- Assignees: The Board of Trustees of the Leland Stanford Junior University
- Applicants: The Board of Trustees of the Leland Stanford Junior University
- Inventors: Nadine Nagy; Jayakumar Rajadas; Paul Bollyky
- Web page: https://patentgrep.com/patent/US10370400B2

## CPC

- C07H 17/075: Benzo[b]pyran-2-ones
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure presents 4-MUG derivatives (e.g., 4-MUG ester prodrugs) that reduce or prevent HA synthesis. In some embodiments, the 4-MUG derivatives of the present disclosure can be used to suppress HA synthesis and curtail inflammation.

## Claims

### Claim 1

A compound of Formula (I):
wherein
R1 and R2 are each independently selected from H, C(O)—C1-10 alkyl, and C(O)—C1-10 haloalkyl;
R3 is selected from H, C(O)—C1-10 alkyl, C(O)—C1-10 haloalkyl, C(O)—C6-10 aryl, and C(O)—C5-10 heteroaryl, wherein the C(O)—C1-10 haloalkyl, C(O)—C6-10 aryl, and C(O)—C5-10 heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, and nitro; and
R4 is selected from C2-10 alkyl and C2-10 haloalkyl, or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein OR1 is in a down position.

### Claim 3 (depends on 1)

The compound of claim 1, wherein OR2 is in an up position.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 and R2 are each independently selected from H and C(O)—C1-10 alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 and R2 are each independently selected from H, C(O)-ethyl, and C(O)-methyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 and R2 are each independently selected from H and C(O)-methyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein OR3 is in a down position.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 is selected from H and C(O)—C1-10 alkyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R3 is selected from H, C(O)-ethyl, and C(O)-methyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R3 is selected from H and C(O)-methyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein C(O)OR4 is in a up position.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R4 is C2-10 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R4 is selected from ethyl, propyl, and butyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R4 is selected from ethyl and butyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound of Formula (I) is a β-glucoside.

### Claim 16 (depends on 1)

A compound of claim 1, selected from
a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method for intracellular delivery of a compound of claim 1, comprising contacting a cell with a compound of claim 1.

### Claim 19 (depends on 1)

A method of inducing a regulatory T-cell response, inhibiting hyaluronan synthesis in a subject, or increasing FoxP3+ regulatory T-cells, comprising administering to a subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A method of treating inflammatory, autoimmune, allergic, or atopic disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the inflammatory, autoimmune, allergic, or atopic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, multiple sclerosis, Sjögrens disease, autoimmune thyroiditis, primary sclerosing cholangitis, rheumatoid arthritis, psoriasis, colitis, lichen planus, psoriasis, eczema, and asthma.

### Claim 21 (depends on 1)

A method for treating insulitis and/or reversing progression of diabetes in a subject suffering from or at risk of developing diabetes, the method comprising:
administering to the subject a composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit hyaluronan synthesis in the subject.

### Claim 22 (depends on 1)

A method for treating multiple sclerosis and/or autoimmune demyelination in a subject suffering from or at risk of developing multiple sclerosis, the method comprising:
administering to the subject a composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit hyaluronan synthesis in the subject.