# US 8,785,424 B2 · ngCycloartanone derivatives with anticancer activity

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- Number: US 8,785,424 B2
- Document ID: US8785424B2
- Status: Granted
- Kind: B2
- Application number: 13/321,440
- Filed: 2010-05-20
- Published: 2012-03-29
- Granted: 2014-07-22
- Earliest claimed: 2009-05-20
- Assignees: Pierre Fabre Medicament; Centre National de la Recherche Scientifique (CNRS)
- Applicants: Christophe Long; Yves Guminski; Fadila Derguini; Joséphine Beck; Frédéric Cantagrel
- Inventors: Christophe Long; Yves Guminski; Fadila Derguini; Joséphine Beck; Frédéric Cantagrel
- Web page: https://patentgrep.com/patent/US8785424B2

## CPC

- C07J 53/004: {3 membered carbocyclic rings}
- A61P 35/00: Antineoplastic agents
- C07J 71/0005: {Oxygen-containing hetero ring}
- C07J: STEROIDS (seco-steroids C07C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a compound of following formula (I): or to a pharmaceutically acceptable salt thereof, as well as to pharmaceutical compositions including same and to the use thereof as a drug, in particular for treating a proliferative disease such as cancer.

## Claims

### Claim 1

The compound of following formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
indicates a single bond or a double bond,
X1 and X2 represent, independently of each other, an oxygen or sulfur atom,
R1 represents an oxygen atom, a sulfur atom or an N—OR11 or N—NHCO—NH2 group,
R2 represents a hydrogen atom or an OR12 or SR12 group,
R3 represents a hydrogen atom, —SO2R55, —CH2OCH2CH2SiR61R62R63, a —CO—(C1-C6)alkyl, or —CO—(C2-C6)alkenyl group, wherein said group is optionally substituted by a halogen atom or a COOH or NR56R57 group,
R4 represents a group selected from:
a hydrogen atom,
a saturated or unsaturated linear or branched hydrocarbon chain comprising 1 to 15 carbon atoms, one or more non-consecutive carbon atoms may be replaced by an oxygen atom, wherein said chain is optionally substituted by one or more groups selected from a halogen atom, ═O, —OH, —OSO2R13, —N3, (C1-C6)alkoxy, —Z1C(X)R14, —C(X)Z2R15, —Z3C(X)Z4R16, —NH—OR17, ═N—OR18, ═N—NR53R54, —OSiR19R20R21, —SiR58R59R60, —OP(O)(OR22)(OR23), —NR24R25, a heterocycle with 5 or 6 members, an epoxide, a sugar residue and an inositol residue, one or more hydroxy groups of said sugar and inositol residues are optionally substituted by an acetyl group or —P(O)(OH)2, and
a heterocycle with 5 or 6 members or a polycycle with 10 to 15 members, wherein said heterocycle or polycycle comprises at least one oxygen atom and is optionally substituted by one or more groups selected from —OH, ═O, —NH2, —N3, ═CH2, —COOR26, (C2-C6)alkenyl, (C1-C6)alkoxy, and a (C1-C6)alkyl group optionally substituted by a halogen atom or an —N3, —OH, (C1-C6)alkoxy, —NHCOR27 or —NR28—OC(O)R29 group,
R5 and R6 each represent a hydrogen atom when represents a double bond, or R5 and R6 each represent, independently of each other, a hydrogen atom or an OR48 group, or R5 and R6 together form, with the carbon atoms that carry them, an epoxide ring, when represents a single bond,
R7 represents a hydrogen atom or a OR49 group,
R8 represents a hydrogen atom, or
R7 and R8 together form, with the carbon atoms that carry them, an epoxide ring,
R9 represents a —CO—(C1-C6)alkyl or —CO—(C2-C6)alkenyl group, or
R9 and R4 together form a bond, or R9 forms a bond with the carbon atom of the R4 group located in the a position relative to carbon atom 22,
R10 represents a hydrogen atom, or
R10 and R3 together form a bond, or
R10 and R9 together form a bond,
with:
R11, R26, R28, R30, R31, R36, R37, R41, R42, R43, R48, R49 and R50 representing, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R12 representing a hydrogen atom or a (C1-C6)alkyl or (C2-C6)alkenyl group,
R13 and R55 represent, independently of each other, an —OH, (C1-C6)alkoxy, aryl, —NR30R31 or (C1-C6)alkyl-aryl group, or a (C1-C6)alkyl group optionally substituted by an —NR30R31 group,
R14 representing a (C1-C6)alkyl, (C2-C6)alkenyl, aryl, (C1-C6)alkyl-aryl or aryl -(C1-C6)alkyl group, wherein said group is optionally substituted by a group selected from a halogen atom, an —NR32—[(CH2)a—NR33]d—[(CH2)b—NR34—(CH2)c—N—R35]e—R52, —P(O)(OH)2 or —COOH group, with a, b and c representing an integer between 1 and 5 and d and e each representing 0 or 1,
R15 and R16 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl, (C1-C6)alkyl-aryl or aryl-(C1-C6)alkyl group, wherein said group is optionally substituted by a group selected from a halogen atom, an —NR32—[(CH2)a—NR33]d—[(CH2)b—NR34—(CH2)c—N—R35]e—R52 or —COOH group, with a, b, c, d and e as defined above,
R17 and R18 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R19, R20, R21, R58, R59, R60, R61, R62 and R63 representing, independently of one another, a (C1-C6)alkyl, (C2-C6)alkenyl or aryl group,
R22 and R23, identical or different, representing a hydrogen atom or a (C1-C6)alkyl or (C2-C6)alkenyl group, wherein said group is optionally substituted by an —OC(O)—(C1-C6)alkyl, NR36R37 and —N+R38R39R40 group, or R22 and R23 together form, with the oxygen atoms that carry them and the phosphorous atom, a ring,
R24 and R25, representing, independently of each other, a hydrogen atom or a —CO—(C1-C6)alkyl, —CO—(C2-C6)alkenyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl or (C1-C6)alkyl group optionally substituted by an NR41R42 group, or R24 and R25 together form, with the nitrogen atom that carries them, a heterocycle with 5 or 6 members, wherein said heterocycle may comprise, in addition to the nitrogen atom carrying R24 and R25, one or more heteroatoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by a (C1-C6)alkyl group,
R27 representing an aryl, (C1-C6)alkyl or (C2-C6)alkenyl group, wherein said group is optionally substituted by one or more halogen atoms,
R29 representing a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R32, R33, R34, R35, R52, R53, R54, R56 and R57 representing, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl,—CO—(C1-C6)alkyl, —CO—(C2-C6)alkenyl, —CO2—(C1-C6)alkyl or —CO2—(C2-C6)alkenyl group,
R38, R39 and R40 representing, independently of one another, a (C1-C6)alkyl or (C2-C6)alkenyl group,
X representing O, S or NR50,
Z1, Z2, Z3 and Z4 representing, independently of one another, O or NR43, or Z2R15 and/or Z4R16 representing, independently of each other, a heterocycle with 5 or 6 members optionally substituted by a (C1-C6)alkyl group, wherein the heterocycle comprises at least one nitrogen atom by which it is linked to the rest of the molecule.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein that R1 is selected from an oxygen atom, an N—OH, —N—OMe, —N—OBn and —N—NHCO—NH2 group.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 represents a hydrogen atom.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R5 and R6 each represent a hydrogen atom and represents a double bond.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R7 and R8 each represent a hydrogen atom.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R9 represents a —CO—(C1-C6)alkyl group.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein X2-R3 represents an OH or OC(O)CH3 group and R10 represents a hydrogen atom or R3 and R10 together form a bond.

### Claim 8 (depends on 1)

The compound according to claim 1 of the following formula (Ia) or (Ib):
with R2, R3, R4, R5, R6 and R10 as defined in claim 1.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R4 represents a chain:
wherein:
represents a single bond or a double bond,
R44 represents a hydrogen atom and R45 represents an OH group, or R44 and R45 together form an ═O or ═N—OR48 group,
R46 represents a hydrogen atom and R47 represents a hydrogen atom, a (C1-C6)alkoxy group, —NH—OR49 or a heterocycle with 5 or 6 members linked to the rest of the molecule via a nitrogen atom, when represents a single bond, or R46 is absent and R47 represents a hydrogen atom when represents a double bond, and
A represents a —CHO, —COOH, —CH2A1 or —CH2OCH2A1 group with
Al representing a hydrogen atom, a halogen atom, —OH, —OSO2R13, —N3, (C1-C6)alkoxy optionally substituted by one or more —OH groups; (C2-C6)alkenoxy, —OCH2OR66, —Z1C(X)R14, —Z3C(X)Z4R16, —NH—OR17, —OSiR19R20R21, —OP(O)(OR22)(OR23), —NR24R25, a heterocycle with 5 or 6 members or a sugar residue, wherein one or more hydroxy groups of said sugar residue are optionally substituted by an acetyl or —P(O)(OH)2 group,
R48 and R49 representing, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group,
R66 representing a —CO—((C1-C6)alkyl) or (C1-C6)alkyl group optionally substituted by an SiR67R68R69 group, and
R67, R68 and R69 representing, independently of one another, a (C1-C6)alkyl group.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R4 represents the ring:
linked to the rest of the molecule via the carbon atom marked with an asterisk (*) and wherein,
represents a single bond or a double bond,
R64 represents a (C1-C6)alkyl group, optionally substituted by a halogen atom or an —N3, —OH, (C1-C6)alkoxy, —NHCOR27 or —NR28—OC(O)R29 group; or a ═CH2 group, wherein this ═CH2 group is present only when represents a single bond, and
R65 is not present when represents a double bond, or R65 represents a hydrogen atom or a (C1-C6)alkoxy group when represents a single bond, or
R64 and R65 together form, with the carbon atoms that carry them, when represents a single bond, a cyclic system comprising 1 or 2 fused saturated, unsaturated or aromatic rings, each with 5 to 7 members,
wherein said cyclic system comprises at least one oxygen atom linked to the carbon atom marked with an asterisk and optionally comprises one or more additional heteroatoms selected from O, S and N, and
wherein said cyclic system is optionally substituted by one or more groups selected from ═O, —OH, —COOR26, and (C1-C6)alkyl optionally substituted by an —OH group.

### Claim 11 (depends on 1)

The compound according to claim 1, selected from:

### Claim 12 (depends on 1)

A compound according to claim 1, wherein X1 and X2 represent an oxygen atom.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein R2 represents a hydrogen atom or an OH or SH group.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein R7 represents a hydrogen atom or a OH group.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein X represents O.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein R1 is an oxygen atom.

### Claim 17 (depends on 1)

A compound according to claim 1, wherein R9 represents a —CO—CH3 group.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 19 (depends on 18)

The pharmaceutical composition according to claim 18, further comprising at least one other active ingredient.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising:
(i) at least one compound according to claim 1, and
(ii) at least one other active ingredient,
as combination products for simultaneous, separate or sequential use.

### Claim 21 (depends on 19, 20)

The pharmaceutical composition according to claim 19 or 20, wherein the other active ingredient is an anticancer agent.

### Claim 22 (depends on 18, 20)

A method to treat colon cancer, comprising the administration of an effective amount for treatment of a subject in need thereof of a compound according to the following formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
indicates a single bond or a double bond,
X1 and X2 represent, independently of each other, an oxygen or sulfur atom,
R1 represents an oxygen atom, a sulfur atom or an N—OR11 or N—NHCO—NH2 group,
R2 represents a hydrogen atom or an OR12 or SR12 group,
R3 represents a hydrogen atom, —SO2R55, —CH2OCH2CH2SiR61R62R63, a —CO—(C1-C6)alkyl, or —CO—(C2-C6)alkenyl group, wherein said group is optionally substituted by a halogen atom or a COOH or NR56R57 group,
R4 represents a group selected from:
a hydrogen atom,
a saturated or unsaturated linear or branched hydrocarbon chain comprising 1 to 15 carbon atoms, one or more non—consecutive carbon atoms may be replaced by an oxygen atom, wherein said chain is optionally substituted by one or more groups selected from a halogen atom, ═O, —OH, —OSO2R13, —N3, (C1-C6)alkoxy, —Z1C(X)R14, —C(X)Z2R15, —Z3C(X)Z4R16, —NH—OR17, ═N—OR18, ═N—NR53R54, —OSiR19R20R21, —SiR58R59R60, —OP(O)(OR22)(OR23), —NR24R25, a heterocycle with 5 or 6 members, an epoxide, a sugar residue and an inositol residue, one or more hydroxy groups of said sugar and inositol residues are optionally substituted by an acetyl group or —P(O)(OH)2, and
a heterocycle with 5 or 6 members or a polycycle with 10 to 15 members, wherein said heterocycle or polycycle comprises at least one oxygen atom and is optionally substituted by one or more groups selected from -OH, ═O, —NH2, —N3, ═CH2, —COOR26, (C2-C6)alkenyl, (C1-C6)alkoxy, and a (C1-C6)alkyl group optionally substituted by a halogen atom or an —N3, —OH, (C1-C6)alkoxy, —NHCOR27 or —NR28—OC(O)R29 group,
R5 and R6 each represent a hydrogen atom when represents a double bond, or R5 and R6 each represent, independently of each other, a hydrogen atom or an OR48 group, or R5 and R6 together form, with the carbon atoms that carry them, an epoxide ring, when represents a single bond,
R7 represents a hydrogen atom or a OR49 group,
R8 represents a hydrogen atom, or
R7 and R8 together form, with the carbon atoms that carry them, an epoxide ring,
R9 represents a —CO—(C1-C6)alkyl or —CO—(C2-C6)alkenyl group, or
R9 and R4 together form a bond, or
R9 forms a bond with the carbon atom of the R4 group located in the α position relative to carbon atom 22,
R10 represents a hydrogen atom, or
R10 and R3 together form a bond, or
R10 and R9 together form a bond,
with:
R11, R26, R28, R30, R31, R36, R37, R41, R42, R43, R48, R49 and R50 representing, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R12 representing a hydrogen atom or a (C1-C6)alkyl or (C2-C6)alkenyl group,
R13 and R55 represent, independently of each other, an —OH, (C1-C6)alkoxy, aryl, —NR30R31 or (C1-C6)alkyl-aryl group, or a (C1-C6)alkyl group optionally substituted by an —NR30R31 group,
R14 representing a (C1-C6)alkyl, (C2-C6)alkenyl, aryl, (C1-C6)alkyl-aryl or aryl -(C1-C6)alkyl group, wherein said group is optionally substituted by a group selected from a halogen atom, an —NR32—[(CH2)a—NR33]d—[(CH2)b—NR34—(CH2)c—N—R35]e—R52, —P(O)(OH)2 or —COOH group, with a, b and c representing an integer between 1 and 5 and d and e each representing 0 or 1,
R15 and R16 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl, (C1-C6)alkyl-aryl or aryl-(C1-C6)alkyl group, wherein said group is optionally substituted by a group selected from a halogen atom, an —NR32—[(CH2)a—NR33]d—[(CH2)b—NR34—(CH2)c—N—R35]e-R52 or —COOH group, with a, b, c, d and e as defined above,
R17 and R18 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R19, R20, R21, R58, R59, R60, R61, R62 and R63 representing, independently of one another, a (C1-C6)alkyl, (C2-C6)alkenyl or aryl group,
R22 and R23, identical or different, representing a hydrogen atom or a (C1-C6)alkyl or (C2-C6)alkenyl group, wherein said group is optionally substituted by an —OC(O)—(C1-C6)alkyl, NR36R37 and —N+R38R39R40 group,
or R22 and R23 together form, with the oxygen atoms that carry them and the phosphorous atom, a ring,
R24 and R25, representing, independently of each other, a hydrogen atom or a —CO—(C1-C6)alkyl, —CO—(C2-C6)alkenyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl or (C1-C6)alkyl group optionally substituted by an NR41R42 group, or
R24 and R25 together form, with the nitrogen atom that carries them, a heterocycle with 5 or 6 members, wherein said heterocycle may comprise, in addition to the nitrogen atom carrying R24 and R25, one or more heteroatoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by a (C1-C6)alkyl group,
R27 representing an aryl, (C1-C6)alkyl or (C2-C6)alkenyl group, wherein said group is optionally substituted by one or more halogen atoms,
R29 representing a (C1-C6)alkyl, (C2-C6)alkenyl, aryl or aryl-(C1-C6)alkyl group,
R32, R33, R34, R35, R52, R53, R54, R56 and R57 representing, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C2-C6)alkenyl, —CO—(C1-C6)alkyl, —CO—(C2-C6)alkenyl, —CO2—(C1-C6)alkyl or —CO2—(C2-C6)alkenyl group,
R38, R39 and R40 representing, independently of one another, a (C1-C6)alkyl or (C2-C6)alkenyl group,
X representing O, S or NR50,
Z1, Z2, Z3 and Z4 representing, independently of one another, O or NR43, or Z2R15 and/or Z4R16 representing, independently of each other, a heterocycle with 5 or 6 members optionally substituted by a (C1-C6)alkyl group, wherein the heterocycle comprises at least one nitrogen atom by which it is linked to the rest of the molecule;
or a pharmaceutical composition according to claim 18 or 20 to a person in need thereof.