# US 8,569,327 B2 · Phenanthroindolizidine derivative and NFκB inhibitor containing same as active ingredient

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- Number: US 8,569,327 B2
- Document ID: US8569327B2
- Status: Granted
- Kind: B2
- Application number: 13/124,554
- Filed: 2009-10-23
- Published: 2011-08-18
- Granted: 2013-10-29
- Earliest claimed: 2008-10-23
- Assignees: Kabushiki Kaisha Yakult Honsha
- Applicants: Takashi Ikeda; Seigo Sawada; Takashi Yaegashi; Takeshi Matsuzaki; Shusuke Hashimoto; Ryuta Yamazaki
- Inventors: Takashi Ikeda; Seigo Sawada; Takashi Yaegashi; Takeshi Matsuzaki; Shusuke Hashimoto; Ryuta Yamazaki
- Web page: https://patentgrep.com/patent/US8569327B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/08: Vasodilators for multiple indications
- 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 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A novel compound having an excellent NFκB inhibitory effect is provided. Specifically disclosed is a compound represented by the following formula (1) or a salt thereof: wherein, R1 represents a hydrogen atom, a lower alkyl group, or the like; R2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or the like; R3 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, or a halogen atom; R4 represents a hydrogen atom or a lower alkyloxy group; R5 represents a hydrogen atom, a lower alkyloxy group, a halogen atom, a hydroxyl group, or a methylenedioxy group formed together with R6 or an isopropylidenedioxy group formed together with R6; R6 represents a hydrogen atom, a lower alkyloxy group, or a methylenedioxy group formed together with R5 or an isopropylidenedioxy group formed together with R5; R7 represents a hydrogen atom or a lower alkyl group; and R8 represents a hydrogen atom, a hydroxyl group, an amino group, a lower alkylcarbonyloxy group, or a halogen atom.

## Claims

### Claim 1

A compound represented by formula (1) or a salt thereof:
wherein:
R1 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkyloxy group, or a halogen atom;
R2 represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkylcarbonyloxy group optionally having a substituent, a heterocyclic carbonyloxy group, a lower alkyloxycarbonyloxy group, a lower alkyl-substituted aminocarbonyloxy group, an amino group optionally having a substituent, a lower alkyl-substituted amino group optionally having a substituent, a heterocyclic group, a lower alkyloxycarbonylamino group optionally having a substituent, a lower alkylcarbonylamino group, a formamide group, or a hydroxy lower alkyl group;
R3 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, or a halogen atom;
R4 represents a hydrogen atom or a lower alkyloxy group;
R5 represents a lower alkyloxy group, a halogen atom, a hydroxyl group, or a methylenedioxy group formed together with R6 or an isopropylidenedioxy group formed together with R6;
R6 represents a lower alkyloxy group, a methylenedioxy group formed together with R5 or an isopropylidenedioxy group formed together with R5;
R7 represents a hydrogen atom or a lower alkyl group; and
R8 represents a hydrogen atom, a hydroxyl group, an amino group, a lower alkylcarbonyloxy group, or a halogen atom.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R1 represents a hydrogen atom, an alkyl group with a carbon number of 1 to 6, a hydroxyl group, an alkyloxy group with a carbon number of 1 to 6, or a halogen atom;
R2 represents a hydrogen atom, an alkyl group with a carbon number of 1 to 6, a halogen atom, an alkylcarbonyloxy group with a carbon number of 1 to 6 optionally having a substituent, a heterocyclic carbonyloxy group, an alkyloxycarbonyloxy group with a carbon number of 1 to 6, an alkyl-substituted aminocarbonyloxy group with a carbon number of 1 to 6, an amino group optionally having a substituent, an alkyl-substituted amino group with a carbon number of 1 to 6 optionally having a substituent, an alkyl-substituted amino group with a carbon number of 1 to 6 optionally having an aromatic group, a heterocyclic group, an alkyloxycarbonylamino group with a carbon number of 1 to 6 optionally having a substituent, an alkyloxycarbonylamino group with a carbon number of 1 to 6 optionally having an aromatic group, an alkylcarbonylamino group with a carbon number of 1 to 6, a formamide group, or a hydroxyalkyl group with a carbon number of 1 to 6;
R3 represents a hydrogen atom, an alkyl group with a carbon number of 1 to 6, a hydroxyl group, or a halogen atom;
R4 represents a hydrogen atom or an alkyloxy group with a carbon number of 1 to 6;
R5 represents an alkyloxy group with a carbon number of 1 to 6, a halogen atom, a hydroxyl group, or a methylenedioxy group formed together with R6 or an isopropylidenedioxy group formed together with R6;
R6 represents an alkyloxy group with a carbon number of 1 to 6, or a methylenedioxy group formed together with R5 or an isopropylidenedioxy group formed by together with R5;
R7 represents a hydrogen atom or an alkyl group with a carbon number of 1 to 6; and
R8 represents a hydrogen atom, a hydroxyl group, an amino group, an alkylcarbonyloxy group with a carbon number of 1 to 6, or a halogen atom.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein R1 represents a hydrogen atom, a methyl group, a hydroxyl group, a methoxy group, a chlorine atom, or a fluorine atom;
R2 represents a hydrogen atom, an ethyl group, a fluorine atom, an acetoxy group, a propionyloxy group, an isobutyryloxy group, a valeroyloxy group, a 3-methoxycarbonylpropionyloxy group, a pivaloyloxy group, a butyryloxy group, a 6-carbo[(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yloxy]heptanoyloxy group, a nicotinoyloxy group, an isonicotinoyloxy group, a piperidinopiperidinylcarbonyloxy group, a 2-thiophenecarbonyloxy group, a 3-thiophenecarbonyloxy group, a 2-furoyloxy group, a 3-furoyloxy group, a methoxycarbonyloxy group, a 2-propynyloxycarbonyloxy group, an ethoxycarbonyloxy group, a dimethylaminocarbonyloxy group, an amino group, a methanesulfonamide group, a diphenylmethylamino group, an ethylamino group, a pyrrolidinyl group, an isobutyloxycarbonylamino group, a benzyloxycarbonylamino group, a methoxycarbonylamino group, an acetamide group, a trifluoroacetamide group, a benzamide group, a formamide group, or a hydroxymethyl group;
R3 represents a hydrogen atom, a methyl group, a hydroxyl group, a fluorine atom, or a chlorine atom;
R4 represents a hydrogen atom or a methoxy group;
R5 represents a methoxy group, an ethoxy group, a fluorine atom, a hydroxyl group, or a methylenedioxy group formed together with R6 or an isopropylidenedioxy group formed together with R6;
R6 represents a methoxy group, an ethoxy group, or a methylenedioxy group formed together with R5 or an isopropylidenedioxy group formed together with R5;
R7 represents a hydrogen atom or a methyl group; and
R8 represents a hydrogen atom, a hydroxyl group, an amino group, an acetoxy group, or a fluorine atom.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein the compound represented by the formula (1) has a conformation represented by formula (2):

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein the compound represented by formula (1) is a compound represented by formula (3):

### Claim 6

A compound or a salt thereof selected from the group consisting of:
(12aS,13S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
(12aR,13R)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
(12aS,13S)-3-ethyl-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
(12aR,13R)-3-ethyl-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
(12aS,13S)-3-fluoro-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
(12aR,13R)-3-fluoro-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
acetic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
acetic acid(12aS,13S)-3-acetoxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-yl ester;
isobutyric acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
2,2-dimethyl-propionic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
nicotinic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
isonicotinic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
1,4]bipiperidinyl-1′-carboxylic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
acetic acid(S)-13-fluoro-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
propionic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
succinic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester methyl ester;
carbonic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester methyl ester;
((12aS,13S)-13 -hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-carbamic acid isobutyl ester;
thiophene-2-carboxylic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
furan-2-carboxylic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
dimethyl-carbamic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
furan-3-carboxylic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
thiophene-3-carboxylic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy- 9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
octanedionic acid(9S,12S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
(12aS,13S)-3-amino-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-13-ol;
((12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-carbamic acid benzyl ester;
carbonic acid(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester-propyn-2-yl ester;
carbonic acid ethyl ester(12aS,13S)-13-hydroxy-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
(12aS,13S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-2,13-diol;
(12aS,13S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-4,13-diol;
(S)-3-fluoro-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene;
(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene;
(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-2-ol;
acetic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
2,2-dimethyl-propionic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
succinic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester methyl ester;
carbonic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester methyl ester;
furan-2-carboxylic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
nicotinic acid(S)-6,7-dimethoxy-9,10,11,12,12 a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-4-ol;
(S)-3-ethyl-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene;
((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-carbamic acid isobutyl ester;
pentanoic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
butyric acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
propionic acid(S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl ester;
(S)-3-amino-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene;
N-((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-acetamide;
(S)-6,7-dimethoxy-3-pyrrolidine-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene;
benzhydryl-((S)-6,7-dimethoxy-3 -pyrrolidine-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-amine;
((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-methanol;
N-((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-2,2,2-trifluoro-acetamide;
((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-ethylamine;
((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-carbamic acid methyl ester;
N-((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-methanesulfonamide;
N-((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-formamide; and
N-((S)-6,7-dimethoxy-9,10,11,12,12a,13-hexahydro-9a-aza-cyclopenta[b]triphenylene-3-yl)-benzamide.

### Claim 7 (depends on 1)

A medicine, comprising the compound or salt of claim 1 as an active ingredient.

### Claim 8 (depends on 1)

An NFκB inhibitor, comprising the compound or salt of claim 1 as an active ingredient.

### Claim 9 (depends on 1)

A therapeutic agent, comprising the compound or salt of claim 1 as an active ingredient, wherein the agent is suitable to treat colon cancer.

### Claim 10 (depends on 1)

An agent for treating lung cancer, comprising the compound or salt of claim 1 as an active ingredient.

### Claim 11 (depends on 1)

A pharmaceutical composition, comprising:
the compound or salt of claim 1; and
a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method for treating colon cancer in a subject in need thereof, comprising administering to said subject in need thereof, an effective amount of the compound or salt of claim 1.

### Claim 13 (depends on 1)

A method for treating lung cancer in a subject in need thereof, comprising administering to said subject in need thereof, an effective amount of the compound or salt of claim 1.

### Claim 14 (depends on 6)

A medicine, comprising the compound or salt of claim 6 as an active ingredient.

### Claim 15 (depends on 6)

An NFκB inhibitor, comprising the compound or salt of claim 6 as an active ingredient.

### Claim 16 (depends on 6)

A therapeutic agent, comprising the compound or salt of claim 6 as an active ingredient, wherein the agent is suitable to treat colon cancer.

### Claim 17 (depends on 6)

An agent for treating lung cancer, comprising the compound or salt of claim 6 as an active ingredient.

### Claim 18 (depends on 6)

A pharmaceutical composition, comprising:
compound or salt of claim 6; and
a pharmaceutically acceptable carrier.

### Claim 19 (depends on 6)

A method for treating colon cancer in a subject in need thereof, comprising administering to said subject in need thereof, an effective amount of the compound or salt of claim 6.

### Claim 20 (depends on 6)

A method for treating lung cancer in a subject in need thereof, comprising administering to said subject in need thereof, an effective amount of the compound or salt of claim 6.