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

• US 9,000,153 B2
• Filed: 07/26/2011
• Issued: 04/07/2015
• 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
• Primary Examiner(s): Grazier, Nyeemah A
• Application Number:
  US13/819,488
• Publication Number:
  US 20130172337A1
• Time in Patent Office: 1,351 Days
• Field of Search: None
• US Class Current: 544/126
• 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 sensitization of cancer cells to anticancer agents and/or ionizing radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumors, 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. A compound of formula (I)

2. The compound according to claim 1 having sub-formula (IA)

3. The compound according to claim 1 having sub-formula (IB)

4. The compound according to claim 3 having sub-formula (IB-1)

5. The compound according to claim 1, of the formula:

6. A process for the preparation of compounds of formula (i) according to claim 1, sub-formulae thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, comprising:

(a) reacting a compound of formula (II)

7. A method for the inhibition of DNA-PK in vitro, comprising bringing together an effective amount of a compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof and a sample containing DNA-PK.

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

9. A pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, and a pharmaceutically acceptable carrier.

10. A 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, and a pharmaceutically acceptable carrier, in combination with at least one additional anticancer agent.

11. A method for therapy and/or progress control of cancer, a tumour, metastases and/or an angiogenesis disorder, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a physiologically acceptable salt, tautomer and/or stereoisomer thereof in combination with radiotherapy and/or with at least one anticancer agent, other than a compound of formula I.

12. A method for sensitizing cancer cells to an anticancer agent and/or ionising radiation, comprising bringing together said cancer cells and an effective amount of a compound of claim 1 or a physiologically acceptable salt, tautomer and/or stereoisomer thereof.