# US 7,612,108 B2 · 2-phenylthiophene derivative

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- Number: US 7,612,108 B2
- Document ID: US7612108B2
- Status: Granted
- Kind: B2
- Application number: 11/661,294
- Filed: 2005-08-26
- Published: 2008-01-31
- Granted: 2009-11-03
- Earliest claimed: 2004-08-27
- Assignees: Astellas Pharma Inc.
- Inventors: Junji Miyata; Masaki Yokota; Ryo Naito; Akio Kamikawa; Masakatsu Kawakami; Kazuyuki Hattori
- Web page: https://patentgrep.com/patent/US7612108B2

## CPC

- C07D 333/40: Thiophene-2-carboxylic acid
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/12: of the kidneys
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a 2-phenylthiophene derivative or a salt thereof, wherein the thiophene ring is substituted with a carboxyl group or the like and the benzene ring has an electron-withdrawing group such as a cyano group and an electron-donating group such as a substituted alkoxy group at the same time. Since the compound of the invention has good xanthine oxidase-inhibitory action and uric acid-lowering action and does not have a structure derived from nucleic acid, the compound has advantages of high safety and excellent effects as compared with conventional compounds and is useful as a therapeutic or preventive agent for hyperuricemia, gout, inflammatory bowel diseases, diabetic kidney diseases, diabetic retinopathy, or the like.

## Claims

### Claim 1

A compound represented by the following general formula (I) or a salt thereof:
wherein the symbols have the following meanings:
R1: —CO2H, —CO2-lower alkyl, or a tetrazolyl group,
R2: H, halogen, lower alkyl, or —O-lower alkyl,
R3: H, lower alkyl, or halogen,
R4: —CN, —NO2, —Br, halogeno-lower alkyl, or —(CO)-lower alkyl,
R5: H, lower alkyl, —O-lower alkyl, halogen, —NO2, or —CN,
X: —O—, —N(R7)—, or —S—,
wherein the group represented by R4 is bonded to the phenyl group at the meta- or para- position relative to the thienyl group and the group represented by —X—R6 is bonded to the phenyl group at the meta- or para- position relative to the thienyl group,
R7: H or lower alkyl,
R6: linear or branched alkyl having 1 to 8 carbon atoms, linear or branched alkenyl having 3 to 8 carbon atoms, —Y-(cycloalkyl which may contain an oxygen atom), —Y-phenyl, or —Y-heteroaryl,
where the linear or branched alkyl having 1 to 8 carbon atoms, linear or branched alkenyl having 3 to 8 carbon atoms, cycloalkyl which may contain an oxygen atom, phenyl, and heteroaryl may be substituted with a group selected from the group consisting of hydroxy, —CN, —O-lower alkyl, —S-lower alkyl, —NR9(R9), and —(CO)NR9(R9),
Y: a bond, lower alkylene, or lower alkenylene,
R8 and R9: the same or different from each other, H or lower alkyl,
where, when X is a group represented by —N(R7)—, R7 and R6 may be combined together with the nitrogen atom to form a nitrogen-containing saturated heterocycle and the nitrogen-containing saturated heterocycle may be substituted with an lower alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1 represented by the following general formula (IA) or a salt thereof:
wherein the symbols represented by R1 to R6 and X have the following meanings:
R1: —CO2H or a tetrazolyl group,
R2 and R3: the same or different from each other, H, F, or Cl,
R4: —CN, —NO2, or —(CO)-lower alkyl,
R5: H or halogen,
X: —O—, —N(R7)—, or —S—,
R7: H or lower alkyl
R6: linear or branched alkyl having 1 to 8 carbon atoms, linear or branched alkenyl having 3 to 8 carbon atoms, —Y-cycloalkyl, —Y-phenyl, or —Y-monocyclic heteroaryl,
where the linear or branched alkyl having 1 to 8 carbon atoms, linear or branched alkenyl having 3 to 8 carbon atoms, cycloalkyl, phenyl, and monocyclic heteroaryl may be substituted with —CN,
Y: a bond, lower alkylene, or lower alkenylene,
where, when X is a group represented by —N(R7)—, R7 and R6 may be combined together with the nitrogen atom to form a nitrogen-containing saturated heterocycle and the nitrogen-containing saturated heterocycle may be substituted with an lower alkyl.

### Claim 3 (depends on 2)

The compound according to claim 2 or a salt thereof, wherein R1 is —CO2H.

### Claim 4 (depends on 3)

The compound according to claim 3 or a salt thereof, wherein R4 is —CN.

### Claim 5 (depends on 4)

The compound according to claim 4 or a salt thereof, wherein X is —O—.

### Claim 6 (depends on 4)

The compound according to claim 4 or a salt thereof, wherein X is —N(R7)—.

### Claim 7 (depends on 5)

The compound according to claim 5 or a salt thereof, wherein R6 is a linear or branched alkyl group having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or -lower alkylene-(cycloalkyl having 3 to 6 carbon atoms).

### Claim 8 (depends on 6)

The compound according to claim 6 or a salt thereof, wherein R7 and R6 may be combined together with the nitrogen atom to form a nitrogen-containing saturated heterocycle which may be substituted with lower alkyl.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A therapeutic method of hyperuricemia, gout, inflammatory bowel diseases, diabetic kidney diseases, or diabetic retinopathy, which comprises administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient.

### Claim 11 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-(3-cyano-4-n-propoxyphenyl)thiophene-2-carboxylic acid.

### Claim 12 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-(3-cyano-4-isobutoxyphenyl)thiophene-2-carboxylic acid.

### Claim 13 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-(4-isobutoxy-3-nitrophenyl)thiophene-2-carboxylic acid.

### Claim 14 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-{4-[butyl(methyl)amino]-3-cyanophenyl}thiophene-2-carboxylic acid.

### Claim 15 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-(3-cyano-4piperidin-1-ylphenyl)thiophene-2-carboxylic acid.

### Claim 16 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid.

### Claim 17 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound is 5-[3-cyano-4(cyclopentyloxy)phenyl]-3-fluorothiophene-2-carboxylic acid.