# US 10,945,976 B2 · Autoimmune disorder treatment using RXR agonists

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- Number: US 10,945,976 B2
- Document ID: US10945976B2
- Status: Granted
- Kind: B2
- Application number: 16/228,217
- Filed: 2018-12-20
- Published: 2019-05-02
- Granted: 2021-03-16
- Earliest claimed: 2011-12-13
- Assignees: Io Therapeutics, Inc.; Trustees of Dartmouth College
- Applicants: IO Therapeutics, Inc.; Trustees of Dartmouth College
- Inventors: Roshantha A. Chandraratna; Ethan Dmitrovsky; Elizabeth Nowak; Randolph Noelle
- Web page: https://patentgrep.com/patent/US10945976B2

## CPC

- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61K 31/201: having one or two double bonds, e.g. oleic, linoleic acids
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/353: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4704: 2-Quinolinones, e.g. carbostyril
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 37/00: Drugs for immunological or allergic disorders
- 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
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present specification provides RXR agonist compounds, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection as well as use of such RXR agonists to manufacture a medicament and use of such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection.

## Claims

### Claim 1

A method of treating schizophrenia, the method comprising elevating Treg cell numbers and suppressing Th17 cell numbers in an individual having schizophrenia by administering a therapeutically effective amount of a retinoid X receptor (RXR) agonist having the structure of formula XII:
or a pharmaceutically acceptable salt thereof;
wherein R is H or lower alkyl of 1 to 6 carbons,
wherein the therapeutically effective amount is about 0.001 mg/kg/day to about 100 mg/kg/day;
whereby the balance between Treg and Th17 cell development is modulated to restrain autoimmunity.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula XXIX:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the therapeutically effective amount is about 0.001 mg/kg/day to about 0.2 mg/kg/day.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the therapeutically effective amount is about 0.1 mg/kg/day to about 3.0 mg/kg/day.

### Claim 5 (depends on 1)

The method according to claim 1, wherein R is H.

### Claim 6 (depends on 2)

The method according to claim 2, wherein the RXR agonist is a salt of the compound of formula XXIX.

### Claim 7

A method of treating an autoimmune aspect of schizophrenia, the method comprising concurrently promoting differentiation of Treg cells and inhibiting differentiation of Th17 cells using a single agent by administering to an individual having schizophrenia a therapeutically effective amount of a retinoid X receptor (RXR) agonist having the structure of formula XII:
or a pharmaceutically acceptable salt thereof;
wherein R is H or lower alkyl of 1 to 6 carbons,
wherein the therapeutically effective amount is about 0.001 mg/kg/day to about 100 mg/kg/day;
wherein the autoimmune aspect comprises inflammation or Th17 to Treg cell ratio;
whereby the autoimmune aspect of schizophrenia is reduced.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula XXIX:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 7)

The method according to claim 7, wherein the therapeutically effective amount is about 0.001 mg/kg/day to about 0.2 mg/kg/day.

### Claim 10 (depends on 7)

The method according to claim 7, wherein the therapeutically effective amount is about 0.1 mg/kg/day to about 3.0 mg/kg/day.

### Claim 11 (depends on 7)

The method according to claim 7, wherein R is H.

### Claim 12 (depends on 8)

The method according to claim 8, wherein the RXR agonist is a salt of the compound of formula XXIX.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the RXR agonist is administered by inhalation.

### Claim 14 (depends on 7)

The method according to claim 7, wherein the RXR agonist is administered by inhalation.

### Claim 15 (depends on 1)

The method of claim according to claim 1, wherein the therapeutically effective amount is about 0.01 mg/kg/day to about 0.1 mg/kg/day.

### Claim 16 (depends on 7)

The method of claim according to claim 7, wherein the therapeutically effective amount is about 0.01 mg/kg/day to about 0.1 mg/kg/day.

### Claim 17 (depends on 1)

The method according to claim 1, wherein elevating Treg cell numbers comprises promoting differentiation of Treg cells.

### Claim 18 (depends on 1)

The method according to claim 1, wherein suppressing Th17 cell numbers comprises inhibiting Th17 cell differentiation.

### Claim 19 (depends on 7)

The method according to claim 7, wherein the ratio of Th17 cells to Treg cells is decreased.