CA2517020A1 - Dihydropteridinones, method for the production and use thereof in the form of drugs - Google Patents

Dihydropteridinones, method for the production and use thereof in the form of drugs

Info

Publication number
CA2517020A1
CA2517020A1 CA 2517020 CA2517020A CA2517020A1 CA 2517020 A1 CA2517020 A1 CA 2517020A1 CA 2517020 CA2517020 CA 2517020 CA 2517020 A CA2517020 A CA 2517020A CA 2517020 A1 CA2517020 A1 CA 2517020A1
Authority
CA
Grant status
Application
Patent type
Prior art keywords
c6
c1
c14
c4
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA 2517020
Other languages
French (fr)
Other versions
CA2517020C (en )
Inventor
Matthias Hoffmann
Matthias Grauert
Trixi Brandl
Steffen Breitfelder
Christian Eickmeier
Martin Steegmaier
Gisela Schnapp
Anke Baum
Jens Juergen Quant
Flavio Solca
Florian Colbatzky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma Gmbh & Co. Kg
Matthias Hoffmann
Matthias Grauert
Trixi Brandl
Steffen Breitfelder
Christian Eickmeier
Martin Steegmaier
Gisela Schnapp
Anke Baum
Jens Juergen Quant
Flavio Solca
Florian Colbatzky
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D475/00Heterocyclic compounds containing pteridine ring systems

Abstract

The invention relates to novel dihydropteridinones of general formula (I), wherein rests L, R1-R5 have the significance indicated in claims and a specification, in the isomers thereof, in a method for producing and using said dihydropteridinones in the form of drugs.

Claims (12)

1) Compounds of general formula (I), wherein R1, R2 which may be identical or different, denote hydrogen or optionally substituted C1-C6-alkyl, 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 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, C5-C12-spirocycloalkyl, C3-C12-heterocycloalkyl which contains 1 to 2 heteroatoms, and C3-C12-heterocycloalkenyl which contains 1 to 2 heteroatoms, or R1 and R3 or R2 and R3 together denote a saturated or unsaturated C3-C4-alkyl bridge which may contain 1 heteroatom, R4 denotes a group selected from among hydrogen, -CN, hydroxy, -NR6R7 and halogen, or a group selected from among optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkyloxy, C2-C5-alkenyloxy, C2-C5-alkynyloxy, C1-C6-alkylthio, C1-C6-alkylsulphoxo and C1-C6-alkylsulphonyl, L denotes a linker selected from among optionally substituted C2-C10-alkyl, C2-C10-alkenyl, C6-C14-aryl, -C2-C4-alkyl-C6-C14-aryl, -C6-C14-aryl-C1-C4-alkyl, optionally bridged C3-C12-cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms, n denotes 0 or 1 m denotes 1 or 2 R5 denotes a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, R8-diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, -NR8R9 and azacycloheptyl, R6, R7 which may be identical or different, denote hydrogen or C1-C4-alkyl, and R8, R9 denote unsubstituted nitrogen substituents at R5, which may be identical or different, denote either hydrogen or a group selected from among C1-C6-alkyl, -C1-C4-alkyl-C3-C10-cycloalkyl, C3-C10-cycloalkyl, C6-C14-aryl, -C1-C4-alkyl-C6-C14-aryl, pyranyl, pyridinyl, pyrimidinyl, C1-C4-alkyloxycarbonyl, C6-C14-arylcarbonyl, C1-C4-alkylcarbonyl, C6-C14-arylmethyloxycarbonyl, C6-C14-arylsulphonyl, C1-C4-alkylsulphonyl and C6-C14-aryl-C1-C4-alkylsulphonyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
2) Compounds of general formula (I), wherein R1 to R4, R6 and R7 are as hereinbefore defined, and L denotes a linker selected from among optionally substituted C2-C10-alkyl, C2-C10-alkenyl, C6-C14-aryl, -C2-C4-alkyl-C6-C14-aryl, -C6-C14-aryl-C1-C4-alkyl, optionally bridged C3-C12-cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms n denotes 1 m denotes 1 or 2 R5 denotes a group which is bound to L via a nitrogen atom, selected from among optionally substituted morpholinyl, piperidinyl, R8-piperazinyl, pyrrolidinyl, tropenyl, R8-diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, -NR8R9 and azacycloheptyl, R8, R9 denote unsubstituted nitrogen substituents at R5, which may be identical or different, hydrogen or a group selected from among C1-C6-alkyl, -C1-C4-alkyl-C3-C10-cycloalkyl, C3-C10-cycloalkyl, C6-C14-aryl, -C1-C4-alkyl-C6-C14-aryl, pyranyl, pyridinyl, pyrimidinyl, C1-C4-alkyloxycarbonyl, C6-C14-arylcarbonyl, C1-C4-alkylcarbonyl, C6-C14-arylmethyloxycarbonyl, C6-C14-arylsulphonyl, C1-C4-alkylsulphonyl and C6-C14-aryl-C1-C4-alkylsulphonyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
3) Compounds according to claim 1, wherein R1 to R4, R6 and R7 are as hereinbefore defined, L denotes a linker selected from among optionally substituted C2-C10-alkyl, C2-C10-alkenyl, C6-C14-aryl, -C2-C4-alkyl-C6-C14-aryl, -C6-C14-aryl-C1-C4-alkyl, optionally bridged C3-C12-cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms n denotes 0 or 1 m denotes 1 or 2 R5 denotes a group which is bound to L via a carbon atom, selected from among R8 - piperidinyl, R8R9-piperazinyl, R8-pyrrolidinyl, R8-piperazinylcarbonyl, R8-tropenyl, R8-morpholinyl and R8-azacycloheptyl, and R8, R9 denote unsubstituted nitrogen substituents at R5, which may be identical or different, hydrogen or a group selected from among C1-C6-alkyl, -C1-C4-alkyl-C3-C10-cycloalkyl, C3-C10-cycloalkyl, C6-C14-aryl, -C1-C4-alkyl-C6-C14-aryl, pyranyl, pyridinyl, pyrimidinyl, C1-C4-alkyloxycarbonyl, C6-C14-arylcarbonyl, C1-C4-alkylcarbonyl, C6-C14-arylmethyloxycarbonyl, C6-C14-arylsulphonyl, C1-C4-alkylsulphonyl and C6-C14-aryl-C1-C4-alkylsulphonyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
4) Compounds according to one of claims 1 to 3, wherein L, m, n and R3 to R9 are as hereinbefore defined, and R1, R2 which may be identical or different, denote a group selected from among hydrogen, Me, Et, Pr, or R1 and R2 together form a C2-C4-alkyl bridge, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
5) Compounds according to one of claims 1 to 4, wherein R1, R2, m, n and R5 to R8 are as hereinbefore defined, and R3 denotes a group selected from among optionally substituted C1-C10-alkyl, C3-C7-cycloalkyl, C3-C6-heterocycloalkyl and C6-C14-aryl 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 a group selected from among hydrogen, OMe, OH, Me, Et, Pr, OEt, NHMe, NH2, F, CL, Br, O-propargyl, O-butynyl, CN, SMe, NMe2, CONH2, ethynyl, propynyl, butynyl and allyl, and L denotes a linker selected from among optionally substituted phenyl, phenylmethyl, cyclohexyl and branched C1-C6-alkyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
6) Compound of formula I according to one of claims 1 to 5 for use as a pharmaceutical composition.
7) Compound of formula I according to one of claims 1 to 5 for use as a pharmaceutical composition with an antiproliferative activity.
8) Use of a compound of formula I according to one of claims 1 to 5 for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
9) Method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective quantity of a compound of formula I according to claims 1 to 4.
10) Pharmaceutical preparations, containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 4 or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
11) Process for preparing a compound of general formula (I), wherein R1-R5,m ,n and L have the meanings given in claims 1 to 5, characterised in that a compound of general formula (II) wherein R1-R3 have the meanings given in claims 1 to 4 and A is a leaving group, is reacted with an optionally substituted compound of general formula (III), wherein R4 has the meanings given in claims 1 to 5 and R10 denotes OH, NH-L-R5, -O-methyl, -O-ethyl, and then optionally the product of general formula (IV) wherein R1 to R4 has the meanings given in claims 1 to 5 and R10 denotes OH, -NH-L-R5, -O-methyl or -O-ethyl, optionally after previous hydrolysis of the ester group -COR10, is reacted with an amine of general formula (V) NH2-L-R5m (V) wherein R5 has the meanings given in claims 1 to 5.
12) Compound of formula (II), wherein R1-R3 have the meanings given in claims 1 to 5 and A is a leaving group.
CA 2517020 2003-02-26 2003-02-26 Dihydropteridinones, method for the production and use thereof in the form of drugs Active CA2517020C (en)

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CA2517020C CA2517020C (en) 2012-06-26

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EP (1) EP1599478B1 (en)
JP (1) JP3876265B2 (en)
KR (1) KR100983462B1 (en)
CN (2) CN100537570C (en)
CA (1) CA2517020C (en)
DE (1) DE50307267D1 (en)
DK (1) DK1599478T3 (en)
ES (1) ES2287583T3 (en)
WO (1) WO2004076454A1 (en)

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