# US 8,541,442 B2 · Indole derivatives as anticancer agents

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- Number: US 8,541,442 B2
- Document ID: US8541442B2
- Status: Granted
- Kind: B2
- Application number: 13/147,707
- Filed: 2010-02-03
- Published: 2011-12-01
- Granted: 2013-09-24
- Earliest claimed: 2009-02-04
- Assignees: Janssen Pharmaceutica NV
- Applicants: Bruno Schoentjes; Sophie Descamps; Nathalie Claudie Isabelle Amblard
- Inventors: Bruno Schoentjes; Sophie Descamps; Nathalie Claudie Isabelle Amblard
- Web page: https://patentgrep.com/patent/US8541442B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/06: Antianaemics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 27/12: for cataracts
- 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 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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

The present invention provides compounds of formula (I), their use for the treatment of cancer as well as pharmaceutical compositions comprising said compounds of formula (I).

## Claims

### Claim 1

A compound of formula (I)
including any stereochemically isomeric form thereof, wherein
R1 is hydroxyC1-6alkyl or C2-6alkenyl; provided that the R1 substituent is placed in position 6 or 7 of the indole moiety;
R2 is hydrogen or C1-4alkyl;
Z is a radical selected from
R3 is hydrogen or hydroxyC1-4alkyl;
R4 is hydroxy or C1-4alkyloxy;
R5 is hydrogen or C1-4alkyl; or
R4 and R5 are taken together to form oxo;
a pharmaceutically acceptable salt thereof or a solvate thereof.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein the compound has the following formula

### Claim 3 (depends on 2)

A compound as claimed in claim 2 wherein R1 is hydroxyC1-6alkyl.

### Claim 4 (depends on 3)

A compound as claimed in claim 3 wherein R2 is C1-4alkyl.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein Z is a radical of formula (z-1).

### Claim 6 (depends on 4)

A compound as claimed in claim 4 wherein Z is a radical of formula (z-2).

### Claim 7 (depends on 6)

A compound as claimed in claim 6 wherein R4 is hydroxyl and R5 is hydrogen.

### Claim 8 (depends on 6)

A compound as claimed in claim 6 wherein R4 is hydroxyl and R5 is C1-4alkyl.

### Claim 9 (depends on 1)

A compound as claimed in claim 1 wherein the compound is an enantiomer having the formula
and having a levorotatory rotation measured with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20° C. and a cell pathlength of 1 dm in chloroform at a concentration of 8.59 mg/ml; or
a pharmaceutically acceptable salt thereof or a solvate thereof.

### Claim 10 (depends on 1)

A compound as claimed in claim 1 wherein the compound is an enantiomer having the formula
and having a dextrorotatory rotation measured with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20° C. and a cell pathlength of 1 dm in methanol at a concentration of 10.33 mg/ml; or
a pharmaceutically acceptable salt thereof or a solvate thereof.

### Claim 11 (depends on 10)

A compound according to claim 10 for use as a medicine.

### Claim 12 (depends on 10)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 10.

### Claim 13 (depends on 10)

A combination of one or more anti-cancer agents and a compound as claimed in claim 10.

### Claim 14 (depends on 1)

A process for preparing a compound as claimed in claim 1, comprising
a) reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W1 is a suitable leaving group, in a reaction-inert solvent optionally in the presence of an appropriate base or reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W1 is a suitable leaving group in the presence of a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent
with R1, R2 and Z as defined in claim 1;
b) reducing the corresponding carbonyl derivative of formula (IV) in the presence of a suitable reducing agent and a suitable solvent,
with R2 and Z as defined in claim 1;
c) reducing the corresponding ester derivative of formula (V) wherein Rx represents —C1-3alkylC(═O)OC1-4alkyl, in the presence of a suitable reducing agent and a suitable solvent,
with R2 and Z as defined in claim 1;
d) hydrolysing an intermediate of formula (VI) with a suitable base in the presence of a suitable solvent,
with R2 and Z as defined in claim 1;
or, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; or, if desired, preparing stereochemically isomeric forms or solvates thereof.