# US 9,434,718 B2 · TOFA analogs useful in treating dermatological disorders or conditions

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- Number: US 9,434,718 B2
- Document ID: US9434718B2
- Status: Granted
- Kind: B2
- Application number: 14/506,074
- Filed: 2014-10-03
- Published: 2015-01-22
- Granted: 2016-09-06
- Earliest claimed: 2009-07-08
- Assignees: Dermira (Canada), Inc.
- Applicants: Dermira (Canada), Inc.
- Inventors: Timothy Scott Daynard; Geoffrey C. Winters; David W. C. Hunt
- Web page: https://patentgrep.com/patent/US9434718B2

## CPC

- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/351: not condensed with another ring
- A61K 31/365: Lactones
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/4525: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 307/58: One oxygen atom, e.g. butenolide
- C07D 307/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention is directed to analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their use in the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne and oily skin, and other dermatological disorders and conditions. This invention is also directed to pharmaceutical compositions comprising analogs of TOFA and a pharmaceutically acceptable excipient for dermatological or oral administration.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is —O—R3—OR2, —O—R3—OC(O)—N(R5)R6, —O—R3—N(R4)C(O)OR5, —O—R3—C(O)OR5, —O—R3—C(O)N(R5)R6 or —N(R5)S(O)2—R4;
each R2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
each R3 is independently an optionally substituted alkylene chain; and
R4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
each R5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
each R6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or —R3—C(O)OR4;
or any R5 and R6, together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;
wherein, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted alkylene chain; optionally substituted cycloalkyl, optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl may comprise one or more substituents selected from the group consisting of alkyl, akenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl, heteroarylalkyl,
—R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)S(O)tR16 (where t is 1 to 2), —R15—N═C(OR14)R14, —R15S(O)tOR16 (where t is 1 to 2), —R15—S(O)pR16 (where p is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl,
as a single stereoisomer or as a mixture thereof;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein:
R1 is —O—R3—OR2;
R2 is optionally substituted heterocyclylalkyl; and
R3 is an optionally substituted alkylene chain.

### Claim 3 (depends on 2)

The compound of claim 2 which is 3-(tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylate.

### Claim 4 (depends on 1)

The compound of claim 1 wherein:
R1 is —O—R3—OC(O)—N(R5)R6;
each R2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted substituted heteroarylalkyl;
R3 is an optionally substituted alkylene chain; and
R5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
R6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or —R3—C(O)OR3; and
or any R5 and R6, together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.

### Claim 5 (depends on 4)

The compound of claim 4 selected from:
1-(benzyl(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate;
1-((2-ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate;
4 (2S)-2-benzyl 1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl) pyrrolidine-1,2-dicarboxylate;
1-(4-phenylcyclohexanecarbonyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate;
1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl 3-phenylpyrrolidine-1-carboxylate;
1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl 3,4-dihydroisoquinoline-2(1H)-carboxylate;
1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl piperidine-1-carboxylate;
1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl morpholine-4-carboxylate;
1-tert-butyl 4-(1-(5-(tetradeclyoxy)furan-2-carbonyloxy)ethyl)piperazine-1,4-dicarboxylate; and
1-(dicyclohexylcarbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate.

### Claim 6 (depends on 1)

The compound of claim 1 wherein:
R1 is —O—R3—N(R4)C(O)OR5
R3 is an optionally substituted alkylene chain; and
R4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
R5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.

### Claim 7 (depends on 1)

The compound of claim 1 wherein:
R1 is —O—R3—C(O)OR5
R3 is an optionally substituted alkylene chain; and
R5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.

### Claim 8 (depends on 1)

The compound of claim 1 wherein:
R1 is —N(R5)S(O)2—R4;
R4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
R5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.

### Claim 9 (depends on 8)

The compound of claim 8 which is 5-(tetradecyloxy)-N-tosylfuran-2-carboxamide.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising: a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically or dermatologically acceptable excipient.