INHIBITORS OF THE INTERACTION BETWEEN MDM2 AND P53

• US 20090149493A1
• Filed: 03/19/2007
• Published: 06/11/2009
• Est. Priority Date: 03/22/2006
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Van Hijfte, Luc, Meyer, Christophe, Lacrampe, Jean Fernand Armand, Schoentjes, Bruno, Poncelet, Alain Philippe, Lardeau, Delphine Yvonne Raymonde
• Granted Patent: US 8,232,298 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds of formula (I) wherein n, m, p, s, t, R¹, R², A and Z have defined meanings.

Claims

1. A compound of formula (I),

a N-oxide form, an addition salt or a stereochemically isomeric form thereof, wherein

m is 0, 1, or 2 and when m is 0 then a direct bond is intended;

n is 0, 1, 2, 3 or 4 and when n is 0 then a direct bond is intended;

p is 0, or 1 and when p is 0 then a direct bond is intended;

s is 0, or 1 and when s is 0 then a direct bond is intended;

t is 0 or I and when t is 0 then a direct bond is intended;

R¹ and R² are each independently hydrogen, halo, C_1-6alkyl, C_1-6alkyloxy, arylC_1-6alkyloxy, heteroarylC_1-6alkyloxy, phenylthio, hydroxyC_1-6alkylcarbonyl, C_1-6alkyl substituted with a substituent selected from amino, aryl and heteroaryl;

or C_3-7cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl;

A is a radical selected from

wherein

R⁴ and R⁵ are each independently selected from hydrogen, halo, C_1-6alkyl, polyhaloC_1-6alkyl, cyano, cyanoC_1-6alkyl, hydroxyC_1-6alkyl, hydroxy, amino, C_1-6alkyloxy,

C_1-6alkylcarbonyl, methylsulfonylamino, aryl or heteroaryl;

Z is a radical selected from

wherein

R⁶ or R⁷ are each independently selected from hydrogen, halo, hydroxy, amino, C_1-6alkyl, nitro, polyhaloC_1-6alkyl, cyano, cyanoC_1-6alkyl, tetrazoloC_1-6alkyl, aryl, heteroaryl, arylC_1-6alkyl, heteroarylC_1-6alkyl, aryl(hydroxy)C_1-6alkyl, heteroaryl(hydroxy)C_1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C_1-6alkylcarbonyl, arylC_1-6alkylcarbonyl, heteroarylC_1-6alkylcarbonyl, C_1-6alkyloxy, C_3-7cycloalkylcarbonyl, C_3-7cycloalkyl(hydroxy)C_1-6alkyl, arylC_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyloxyC_1-6alkyl, C_1-6alkylcarbonyloxyC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyloxyC_1-6alkyl, hydroxyC_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonylC_2-6alkenyl C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, hydroxycarbonyl, hydroxycarbonylC_1-6alkyl and —

(CH₂)_v—

(C(═

O)_r)—

(CHR¹⁰)_u—

NR⁸R⁹;

wherein

v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bond is intended;

r is 0, or 1 and when r is 0 then a direct bond is intended;

u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond is intended;

R¹⁰ is hydrogen or C_1-6alkyl;

R⁸ and R⁹ are each independently selected from hydrogen, C_1-12alkyl, C_1-6alkylcarbonyl, C_1-6alkylsulfonyl, arylC_1-6alkylcarbonyl, C_3-7cycloalkyl, C_3-7cycloalkylcarbonyl, —

(CH₂)_k—

NR¹¹R¹², C_1-2alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C_1-6alkyloxycarbonyl, C_1-6alkyloxy, aryl or heteroaryl;

or C_3-7cycloalkyl substituted with a substituent selected from hydroxy, C_1-6alkyloxy, aryl, amino, arylC_1-6alkyl, heteroaryl or heteroarylC_1-6alkyl;

or

R⁸ and R⁹ together with the nitrogen to which they are attached can optionally form a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or piperazinyl substituted with a substituent selected from C_1-6alkyl, arylC_1-6alkyl, arylC_1-6alkyloxycarbonyl, heteroarylC_1-6alkyl, C_3-7cycloalkyl and C_3-7cycloalkylC_1-6alkyl;

wherein

k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended;

R¹¹ and R¹² are each independently selected from hydrogen, C_1-6alkyl, arylC_1-6alkyloxycarbonyl, C_3-7cycloalkyl, C_1-2alkyl substituted with a substituent selected from hydroxy, C_1-6alkyloxy, aryl, and heteroaryl; and

C_3-7cycloalkyl substituted with a substituent selected from hydroxy, C_1-6alkyloxy, aryl, arylC_1-6alkyl, heteroaryl, and heteroarylC_1-6alkyl;

or

R¹¹ and R¹² together with the nitrogen to which they are attached can optionally form a morpholinyl, a piperazinyl or a piperazinyl substituted with C_1-6alkyloxycarbonyl;

aryl is phenyl or naphthalenyl;

each phenyl or naphthalenyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxyC_1-6alkyl, C_1-6alkyl, amino, polyhaloC_1-6alkyl and C_1-6alkyloxy; and

each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from methylenedioxy and ethylenedioxy;

heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;

each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C_1-6alkyl, amino, polyhaloC_1-6alkyl, aryl, arylC_1-6alkyl or C_1-6alkyloxy; and

each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy.

2. A compound according to claim 1 wherein;

m is 0;

n is 0 or 2;

p is 1;

s is 0;

t is 0;

R¹ and R² are each independently hydrogen;

A is a radical selected from (a-15), (a-21), (a-30), (a-39) or (a-40);

R⁴ and R⁵ are each independently selected from hydrogen or C_1-6alkyloxy;

Z is the radical (b-2);

or R⁶ and R⁷ are each independently selected from hydrogen.

3. A compound according to claim 1 wherein

m is 0;

n is 2;

p is 1;

s is 0;

t is 0;

R¹ and R² are each independently hydrogen;

A is a radical selected from (a-21), (a-39) or (a-40);

R⁴ and R⁵ are each independently selected from hydrogen or C_1-6alkyloxy;

Z is the radical (b-2);

or R⁶ and R⁷ are each independently selected from hydrogen.

6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.

7. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 are intimately mixed.

8. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A combination of an anti-cancer agent and a compound according to claim 1.

10. A process for preparing a compound as claimed in claim 1, said process comprising the steps of:

a) reacting an intermediate of formula (II) with an intermediate of formula (ITT) wherein W is an appropriate leaving group,

b) converting an intermediate of formula (IV) into compounds of formula (I), wherein p is 1, herein referred to as compounds of formula (I-a), in the presence of lithium aluminium hydride in a suitable solvent,

c) reacting an appropriate carboxaldehyde of formula (VI), with an intermediate of formula (V), in the presence of an appropriate reagent, in a suitable solvent,

d) reacting an intermediate of formula (II) with an appropriate carboxaldehyde of formula (VII) with the formation of a compound of formula (I), wherein t is 1, herein referred to as compounds of formula (I-b), or

e) reacting an intermediate of formula (VIII) with lithium aluminium hydride in a suitable solvent, with the formation of a compound of formula (I), wherein s is 1, herein referred to as compounds of formula (I-c).

15. A compound according to claim 2 wherein

m is 0;

n is 2;

p is 1;

s is 0;

t is 0;

R¹ and R² are each independently hydrogen;

A is a radical selected from (a-21), (a-39) or (a-40);

R⁴ and R⁵ are each independently selected from hydrogen or C_1-6alkyloxy;

Z is the radical (b-2);

or R⁶ and R⁷ are each independently selected from hydrogen.

16. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 15.

17. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 15 are intimately mixed.

18. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier.

4. A compound selected from the group consisting of:

11. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 4.

12. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 4 are intimately mixed.

13. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

14. A combination of an anti-cancer agent and a compound according to claim 4.

5. (canceled)