# US 8,772,297 B2 · TGF-β signal transduction inhibitor

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- Number: US 8,772,297 B2
- Document ID: US8772297B2
- Status: Granted
- Kind: B2
- Application number: 13/579,843
- Filed: 2011-02-17
- Published: 2013-02-21
- Granted: 2014-07-08
- Earliest claimed: 2010-02-17
- Assignees: Kyoto University
- Applicants: Hideaki Kakeya; Akira Hattori; Yasuaki Takasu; Nobutaka Fujii; Shinya Oishi; Soichi Kojima; Mitsuko Hara
- Inventors: Hideaki Kakeya; Akira Hattori; Yasuaki Takasu; Nobutaka Fujii; Shinya Oishi; Soichi Kojima; Mitsuko Hara
- Web page: https://patentgrep.com/patent/US8772297B2

## CPC

- C07D 295/104: with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/28: to which a second hetero atom is attached
- C07D 295/18: by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 405/12: 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 provides a compound represented by the following formula (I) or a physiologically acceptable salt thereof, and use thereof for the prophylaxis or treatment of TGF-β-related diseases: wherein Y is a hydrogen atom and the like; R2 is and the like; R3 is —NR8—R9— and the like; R4, R5, R6 and R7 are the same or different and each is a hydrogen atom and the like; and X is and the like.

## Claims

### Claim 1

A compound represented by the following formula (I):
wherein
Y is a hydrogen atom, a carboxyl group or
wherein
L is an oxygen atom or a bond, and R1 is optionally substituted C1-6 alkyl;
R2 is
R3 is —NR8—R9— or a bond, wherein R8 is a hydrogen atom or C1-6 alkyl, and R9 is C1-6 alkylene;
R4, R5, R6 and R7 are the same or different and each is a hydrogen atom or C1-6 alkyl; and
X is
wherein R10 is a hydrogen atom or C1-6 alkyl; and
R11 is optionally substituted phenyl, optionally substituted C1-6 alkyl or a hydrogen atom, or
R10 and R11 form, together with the nitrogen atom bonded thereto, an optionally substituted 5- to 7-membered cyclic amino group,
or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound or a physiologically acceptable salt thereof according to claim 1, wherein Y is

### Claim 3 (depends on 1)

The compound or a physiologically acceptable salt thereof according to claim 1, wherein R11 is a group represented by the following formula:
wherein
R12 is a hydrogen atom, furyl or thienyl; and
R13 is optionally substituted amino, optionally substituted C1-6 alkyl, hydroxy, optionally substituted C1-6 alkoxy, C1-6 alkanoyl, C6-10 aroyl or N3.

### Claim 4 (depends on 3)

The compound or a physiologically acceptable salt thereof according to claim 3, wherein R13 is an amino group optionally mono- or di-substituted by C1-6 alkyl or C1-6 alkanoyl, or an optionally substituted 5- to 7-membered cyclic amino group.

### Claim 5

A compound which is
4-[3-(piperidine-1-sulfonyl)benzenesulfonyl]piperazine-1-carboxylic acid tert-butyl ester,
4-{[3-(piperidine-1-sulfonyl)benzenesulfonylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester,
4-({methyl-[3-(methyl-p-tolylsulfamoyl)benzenesulfonyl]amino}methyl)piperidine-1-carboxylic acid tert-butyl ester,
4-[({3-[(4-tort-butylphenyl)methylsulfamoyl]benzenesulfonyl}methylamino)-methyl]piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-tert-butylphenylsulfamoyl)-2,4,5,6-tetramethylbenzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(piperidine-1-sulfonyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-[(3-diethylsulfamoylbenzenesulfonylamino)methyl]piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(morpholine-4-sulfonyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-[(3-sulfamoylbenzenesulfonylamino)methyl]piperidine-1-carboxylic acid tert-butyl ester,
4-(benzenesulfonylaminomethyl)piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(cyclohexylmethylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-[(3-phenylsulfamoylbenzenesulfonylamino)methyl]piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-methoxyphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(3-methoxyphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(2-methoxyphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-trifluoromethylphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(2-acetylaminophenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-[(3-p-tolylsulfamoylbenzenesulfonylamino)methyl]piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-tert-butylphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-piperidin-1-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-diethylaminophenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-dimethylaminophenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-morpholin-4-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-acetylphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-({3-[4-(1-hydroxyethyl)phenylsulfamoyl]benzenesulfonylamino}methyl)piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-hydroxyphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylicacid tert-butyl ester,
4-{[3-(4-oxanylmethoxyphenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-azidophenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-(4-{3-[(1-tert-butoxycarbonylpiperidin-4-ylmethyl)sulfamoyl]benzenesulfonylamino}phenyl)piperazine-1-carboxylic acid tert-butyl ester,
4-({3-[4-(4-benzoylpiperazin-1-yl)phenylsulfamoyl]benzenesulfonylamino}methyl)piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(4-dimethylamino-3-furan-2-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(3-furan-2-yl-4-piperidin-1-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(3-furan-2-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
4-{[3-(3-thiophen-2-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester,
or a physiologically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound or a physiologically acceptable salt thereof according to claim 1, which is 4-{[3-(4-dimethylamino-3-furan-2-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}piperidine, 4-{[3-(4-dimethylamino-3-furan-2-yl-phenylsulfamoyl)benzenesulfonylamino]methyl}-1-butyryl-piperidine or a physiologically acceptable salt thereof.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 1 to said mammal.

### Claim 9 (depends on 2)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 2 to said mammal.

### Claim 10 (depends on 3)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 3 to said mammal.

### Claim 11 (depends on 4)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 4 to said mammal.

### Claim 12 (depends on 5)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 5 to said mammal.

### Claim 13 (depends on 6)

A method for treatment of tissue fibrillization induced by TGF-β in a sclerotic disease or cancer in a mammal, comprising administering a therapeutically effective amount of the compound or a physiologically acceptable salt thereof according to claim 6 to said mammal.

### Claim 14 (depends on 2)

A pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof according to claim 2.

### Claim 15 (depends on 3)

A pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof according to claim 3.

### Claim 16 (depends on 4)

A pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof according to claim 4.

### Claim 17 (depends on 5)

A pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof according to claim 5.

### Claim 18 (depends on 6)

A pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof according to claim 6.