Imidazo[4,5-c]quinolines as DNA-PK inhibitors

• US 20130172337A1
• Filed: 07/26/2011
• Published: 07/04/2013
• Est. Priority Date: 08/28/2010
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Fuchss, Thomas, Mederski, Werner, Zenke, Frank
• Granted Patent: US 9,000,153 B2
• Time in Patent Office: Days
• US Class Current: 514/232.8
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 215/42 attached in position 4
• CPC Class Codes: C07D 215/44 with aryl radicals attached to said nitrogen atoms
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/11001 Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase

Abstract

The invention relates to compounds of the formulae (I) and (II) in which R1, R2, R3, R4, R5, R8, X and m have the meaning indicated in the claims, and/or physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. The compounds of the formula (I) can be used for the inhibition of serine/threonine protein kinases and for the sensitisation of cancer cells to anticancer agents and/or ionising radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumours, metastases or angiogenesis disorders, in combination with radiotherapy and/or an anticancer agent. The invention furthermore relates to a process for the preparation of the compounds of the formula (I).

Claims

1. Compounds of the formula (I)

2. Compounds according to claim 1 having the sub-formula (IA)

3. Compounds according to claim 1 having the sub-formula (IB)

4. Compounds according to claim 3 having the sub-formula (IB-1)

5. Compounds according to claim 1, selected from the group:

6. Intermediate compounds of the formula (II)

7. Intermediate compounds according to claim 6 in which

R1 denotes A,

R2 denotes A or —

(CH₂)_p—

(CH₂)_s—

Ar,

R3 denotes CN,

R5 denotes Hal,

R8 denotes NH₂,

A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, where 1, 2 or 3 H atoms may be replaced, independently of one another, by Hal,

Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal,

Hal denotes F, Cl, Br or I, and

m, p, s, independently of one another, denote 0, 1 or 2,

and/or salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios.

8. Process for the preparation of compounds of the formula (I) under claim 1, sub-formulae thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, having the following steps:

(a) reaction of a compound of the formula (II)

9. Process for the preparation of intermediate compounds of the formula (II) according to claim 6 and/or salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, having the following steps:

(a) reaction of a compound of the formula (III)

10. A method for the inhibition of serine/threonine protein kinases in vitro comprising introducing a compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios to a sample containing serine/threonine protein kinases.

11. A method for sensitizing cancer cells to an anticancer agent and/or ionizing radiation comprising introducing a compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, to cancer cells with the proviso that the sensitisation does not take place in vivo on the human or animal body.

12. Medicaments comprising at least one compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios.

13. Pharmaceutical composition comprising, as active compound, an effective amount of at least one compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, together with pharmaceutically tolerated assistants, in combination with at least one anticancer agent.

14. Compounds according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, for use in the prophylaxis, therapy and/or progress control of cancer, tumours, metastases and/or angiogenesis disorders, in combination with radiotherapy and/or with at least one anticancer agent.

15. Compounds according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, for use for the sensitisation of cancer cells to an anticancer agent and/or ionising radiation.