2-Benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments

• US 20060004014A1
• Filed: 06/21/2005
• Published: 01/05/2006
• Est. Priority Date: 06/21/2004
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Solca, Flavio, Grauert, Matthias, Hoffmann, Matthias, Steegmaier, Martin, Lehmann-Lintz, Thorsten, Redemann, Norbert
• Application Number:
  US11/157,883
• Publication Number:
  US 20060004014A1
• Time in Patent Office: Days
• US Class Current: 514/251
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07D 475/00 : Heterocyclic compounds containing pteridine ring systems

Abstract

The present invention relates to new 2-benzylaminodihydropteridinones of general formula (I)
wherein the groups R¹ to R⁷, R¹⁰ and R¹¹ have the meanings given in the claims and specification, the isomers thereof, methods of preparing these dihydropteridinones and their use as medicaments.

Claims

1. ) A compound of formula (I),

wherein

R¹, R² which may be identical or different, denote a group selected from among optionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl, heteroaryl, C₃-C₈-cycloalkyl, C₃-C₈-heterocycloalkyl, —

X-aryl, —

X-heteroaryl, —

X-cycloalkyl, —

X-heterocycloalkyl, —

NR⁸-aryl, —

NR⁸-heteroaryl, —

NR⁸-cycloalkyl, and —

NR⁸-heterocycloalkyl, or

a group selected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸ and XR⁸, or

R¹ and R² together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,

R³ denotes hydrogen or a group selected from among optionally substituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, aryl, heteroaryl, C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl and C₅-C₁₂-spirocycloalkyl or

R¹ and R³ or R² and R³ together denote a saturated or unsaturated C₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms,

R⁴ denotes optionally substituted aryl or heteroaryl,

R⁵ denotes a group selected from among hydrogen, CHO, XH, —

X—

C₁-C₂-alkyl and an optionally substituted C₁-C₃-alkyl group,

R⁶ denotes a group selected from among hydrogen, NH₂, XH, halogen and a C₁-C₃-alkyl group optionally substituted by one or more halogen atoms,

R⁷ denotes hydrogen or —

CO—

C₁-C₄-alkyl, —

CO—

NH—

C₁-C₄-alkyl, —

CO—

X—

C₁-C₄-alkyl, and

X in each case independently of one another denote O or S,

R⁸ in each case independently of one another denote hydrogen or a group selected from among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, benzyl and phenyl,

R¹⁰ and R¹¹ in each case independently of one another denote hydrogen or a group selected from among optionally substituted C₁-C₄-alkyl,

or R¹⁰ and R¹¹ together denote a 2-5 membered alkyl bridge,

or the pharmacologically acceptable acid addition salt, solvate or hydrate thereof.

2. ) The compound according to claim 1,

wherein

R¹ to R⁴ have the meanings specified,

R⁵ denotes methyl, and

R⁶ and R⁷ denote hydrogen,

R¹⁰ and R¹¹ in each case independently of one another denote hydrogen or methyl, or

R¹⁰ and R¹¹ together denote cyclopropyl.

3. ) The compound according to claim 2,

wherein

R³ to R⁷, R¹⁰ and R¹¹ have the meanings specified and

R¹, R² which may be identical or different, denote hydrogen or a group selected from among optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, and C₂-C₆-alkynyl, or

R¹ and R² together denote a 2- to 5-membered alkyl bridge.

4. ) The compound according to claim 1,

wherein

R¹, R³ to R⁷ , R¹⁰ and R¹¹ have the meanings specified, and

R³ is hydrogen or contains a group selected from among optionally substituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl and C₆-C₁₄-aryl, or a group selected from among optionally substituted and/or bridged C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl and C₅-C₁₂-spirocycloalkyl.

5. ) The compound according to claim 4,

wherein

R¹ to R³, R⁵ to R⁷, R¹⁰ and R¹¹ have the meanings specified, and

R⁴ denotes a group of formula

R⁹ which may be identical or different, denotes a group selected from among optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, —

O—

C₁-C₆-alkyl, —

O—

C₂-C₆-alkenyl, —

O—

C₂-C₆-alkynyl, C₃-C₆-heterocycloalkyl, C₃-C₆-cycloalkyl, aryl, heteroaryl, —

O-aryl, —

O-heteroaryl, —

O-cycloalkyl, and —

O-heterocycloalkyl or

a group selected from among hydrogen, —

CONH₂, —

COOR⁸, —

OCON(R⁸)₂, —

N(R⁸)₂, —

NHCOR⁸, —

NHCON(R⁸)₂, —

NO₂, CF₃, halogen, —

O—

C₁-C₆-alkyl-Q¹, —

CONR⁸—

C₁-C₁₀-alkyl-Q¹, —

CONR⁸—

C₂-C₁₀-alkenyl-Q¹, —

CONR⁸-Q², halogen, OH, —

SO₂R⁸, —

SO₂N(R⁸)₂, —

COR⁸, —

COOR⁸, —

N(R⁸)₂, —

NHCOR⁸, —

CONR⁸OC₁—

C₁₀-alkyl-Q¹ and CONR⁸O-Q²,

R⁸ in each case independently of one another denote hydrogen or a group selected from among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and phenyl,

Q¹ denotes hydrogen, —

NHCOR⁸, or a group selected from among an optionally substituted —

NH-aryl, —

NH-heteroaryl, aryl, heteroaryl, C₃-C₈-cycloalkyl and heterocycloalkyl group,

Q² denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl and C₃-C₈-cycloalkyl group, and

n denotes 0,1, 2, 3, 4 or 5.

6. ) The compound according to claim 1,

wherein

Q¹, Q², n, R⁴ to R⁸ have the meanings specified,

R¹, R² which may be identical or different, denote hydrogen or a group selected from among methyl, ethyl, propyl, allyl and propargyl or

R¹ and R² together represent cyclopropyl

R³ denotes hydrogen, or denotes optionally substituted C₁-C₆-alkyl or optionally substituted and/or bridged C₃-C₁₂-cycloalkyl, and

R¹⁰ and R¹¹ denote hydrogen.

7. ) The compound according to claim 5,

wherein

Q¹, Q², n, R¹ to R⁴, R⁶ to R⁸, R¹⁰ and R¹¹ have the meanings specified, and

R⁹ which may be identical or different, denote hydrogen or a group selected from among halogen, (C₁-C₆-alkyl)₂N—

, CF₃, NH₂SO₂—

, —

CONH—

C₆-C₁₄-aryl, —

CONH—

C₁-C₄-alkyl-C₆-C₁₄-aryl and —

O—

C₁-C₄-alkyl.

8. ) A method for the treatment and/or prevention of diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, characterised in that an effective amount of a compound of formula I according to claim 1 is administered to a patient.

9. ) A pharmaceutical preparation comprising as active substance one or more compounds of formula (I) according to claim 1 combined with one or more conventional excipients or carriers or both.