# US 8,772,273 B2 · Formulations and uses of retinoic acid receptor selective agonists

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- Number: US 8,772,273 B2
- Document ID: US8772273B2
- Status: Granted
- Kind: B2
- Application number: 13/253,014
- Filed: 2011-10-04
- Published: 2013-04-04
- Granted: 2014-07-08
- Earliest claimed: 2011-10-04
- Assignees: QuRetino Therapeutics, Inc.
- Applicants: Ferenc Makra
- Inventors: Ferenc Makra
- Web page: https://patentgrep.com/patent/US8772273B2

## CPC

- A61K 31/215: of carboxylic acids
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/48: of the pancreatic hormones
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/10: for osteoporosis
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- 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

## Abstract

The invention provides retinoic acid receptor (RAR) selective agonists and formulations thereof for the treatment of disease or for inducing a medically beneficial effect.

## Claims

### Claim 1

A method of treating acne vulgaris, the method comprising: administering to a subject a topical formulation comprising a single active ingredient, wherein the active ingredient consists of a RAR selective agonist, wherein the RAR selective agonist is not more than 0.005% of the formulation, and wherein the RAR selective agonist has the structure:
wherein the dotted bond is either present and forms a double bond, or is absent;
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 1, 2 or 3;
X is —C(R8)(R9)— for n=1, 2 or 3; or X is oxygen for n=1;
wherein R8 and R9 are independently hydrogen or alkyl;
R5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR10—, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
wherein R10 is hydrogen or alkyl;
m is 0 when the dotted bond is present; or m is 1 when the dotted bond is absent;
wherein Ar is phenyl or a heteroarylic ring;
R6 is hydrogen, halogen, alkoxy or hydroxy;
R7 is hydrogen or alkyl; and
Y
is —COO—, —OCO—, —CONR10—, —NR10CO—, —CH═CH—, —C≡C—, —COCH═CH—, —CHOHCH═CH—, —CH2O—, —CH2S—, —CH2SO—, —CH2SO2—, —CH2NR10—, —OC H2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—,
with the proviso that when Y
is —OCO—, —NR10CO—, —OCH2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—, R5 is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloaslkyl-alkyl or phenyl-alkyl;
or a pharmaceutically active salt of carboxylic acids of formula I.

### Claim 2 (depends on 1)

The method of claim 1 wherein the RAR selective agonist is administered by applying a cream, ointment, lotion or liquid comprising the RAR selective agonist.

### Claim 3 (depends on 1)

The method of claim 1 wherein R8 and R9 are H.

### Claim 4 (depends on 1)

The method of claim 1 wherein R1, R2, R3 and R4 are alkyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein
R1, R2, R3, and R4 are each methyl,
Xn is —CH2—CH2—,
R5 is —CH2—CH2—CH2—CH2—CH3,
Y is —COO—, and
R6 and R7 are each is H.

### Claim 6 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 1 or 2;
X is —C(R8)(R9)— for n=1 or 2; or X is oxygen for n=1;
wherein R8 and R9 are independently hydrogen or alkyl; and
R5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR10—, alkenyl, alkenyloxy, alkynyl;
wherein R10 is hydrogen or alkyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 1 or 2;
X is —C(R8)(R9)— for n=1 or 2; or X is oxygen for n=1;
wherein R8 and R9 are independently hydrogen or alkyl; and
R5 is hydrogen, alkyl, alkylthio, alkyl-NR10—, alkenyl, alkynyl;
wherein R10 is hydrogen or alkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 2;
X is —C(R8)(R9)— for n=2;
wherein R8 and R9 are independently hydrogen or alkyl; and
R5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR10—, alkenyl, alkenyloxy, alkynyl;
wherein R10 is hydrogen or alkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 2;
X is —C(R8)(R9)— for n=2;
wherein R8 and R9 are independently hydrogen or alkyl; and
R5 is hydrogen, alkyl, alkylthio, alkyl-NR10—, alkenyl, alkynyl;
wherein R10 is hydrogen or alkyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 2;
X is —C(R8)(R9)— for n=2;
wherein R8 and R9 are independently hydrogen or alkyl;
R5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR10—, alkenyl, alkenyloxy, alkynyl;
wherein R10 is hydrogen or alkyl; and
Y
is —COO—, —OCO—, —CONR10—, —NR10CO—, —CH═CH—, —C≡C—, —CH2O—, —CH2S—, —CH2SO—, —CH2SO2—, —CH2NR10—, —OCH2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—,
with the proviso that when Y
is —OCO—, —NR10CO—, —OCH2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—, R5 is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein
R1, R2, R3 and R4 are independently hydrogen or alkyl;
n is 2;
X is —C(R8)(R9)— for n=2;
wherein R8 and R9 are independently hydrogen or alkyl; and
R5 is hydrogen, alkyl, alkylthio, alkyl-NR10—, alkenyl, alkynyl;
wherein R10 is hydrogen or alkyl; and
Y
is —COO—, —OCO—, —CONR10—, —NR10CO—, —CH═CH—, —C≡C—, —CH2O—, —CH2S—, —CH2SO—, —CH2SO2—, —CH2NR10—, —OCH2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—,
with the proviso that when Y
is —OCO—, —NR10CO—, —OCH2—, —SCH2—, —SOCH2—, —SO2CH2— or —NR10CH2—, R5 is hydrogen, alkyl, alkenyl, alkynyl.