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US 2003/0199691 A1Published application
2-(2,6-dichlorophenyl)-diarylimidazoles
AssigneeHoffmann-La Roche Inc.
InventorsMichael Brandt, Georg Fertig, Hans-Willi Krell, Thomas von Hirschheydt, Edgar Voss
Life of this patent
Estimating the term…
Abstract
1 The invention is directed to compounds of formula (I), which are valuable therapeutics for the treatment of cancer and related diseases.
Claims49
A compound of formula (I)
- 7
- wherein
- X is hydrogen;
- OR1;
- SR2;
- (SO)R2;
- (SO2)R2, or a group A1—Q;
- A1 represents a C1-C3-alkylen group;
- Q is OR1;
- SR2;
- SOR2;
- SO2R2;
- NR3R4;
- NHCH2CH2NR3R4 or halogen;
- R1 is selected from the group consisting of hydrogen;
- C1-C3-alkyl;
- allyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- (R)-2,3-dihydroxy-1-propyl;
- (S)-2,3-dihydroxy-1-propyl;
- 1,3-dihydroxy-2-propyl;
- 3-hydroxy-2-hydroxymethyl-1-propyl;
- 2-methoxyethoxymethyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A1—Q1;
- Q1 represents C1-C2-alkoxy;
- cyano;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- carboxamide;
- —CO—NR3R4;
- C1-C6-alkylsulfanyl;
- C1-C6-alkylsulfenyl;
- C1-C6-alkylsulfonyl and with the proviso that if A1 represents an 1,2-ethylen- or 1,3-propylen group, then Q1 is hydroxy or NR3R4;
- R2 is C1-C6-alkyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- 2,3-dihydroxy-1-propyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A1—Q1;
- R3 and R4 are independently selected from the group consisting of hydrogen;
- C1-C6-alkyl or together form a 5 to 7 membered, saturated or unsaturated, unsubstituted or substituted ring, substituted by a methyl group and containing one or two heteroatoms, independently selected from N or O;
- Y is hydrogen or a group A2—R;
- A2 is an unsubstituted C1-C5-alkylen or substituted C1-C5-alkylen, substituted by C1-C6-alkyl;
- phenyl or by hydroxy;
- R represents hydroxy;
- linear or branched C1-C6-alkoxy;
- amino;
- dimethylamino;
- diethylamino;
- t-butyloxycarbonylamino;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- triazolyl;
- cyano;
- piperidino;
- 1-pyrrolidinyl;
- morpholino;
- 4-methylpiperazin-1-yl;
- O—A1—NR3R4;
- S—A1—NR3R4;
- 4-carboxyphenyl;
- furan-3-yl;
- thiophen-2-yl or 3-methylthiophen-2-yl;
- z represents one or two substituents independently selected from the group consisting of halogen;
- hydroxy;
- allyloxy;
- methyl;
- C1-C5-alkoxy;
- methoxymethoxy;
- (2-methoxyethoxy)methyloxy;
- methylthio;
- ethoxymethoxy;
- methylendioxy;
- ethynyl;
- trimethylsilylethynyl and unsubstituted benzyloxy or substituted benzyloxy substituted by halogen;
- methoxy;
- cyano;
- nitro;
- methylendioxy;
- carboxy or ethoxy;
- or its pharmaceutically acceptable salt thereof.
78 more elements
A compound of formula (II),
- 8
- wherein
- X is OR1;
- SR2;
- (SO)R2;
- (SO2)R2 or CH2—Q;
- Q is OR1;
- SR2;
- SOR2;
- SO2R2;
- NR3R4;
- NH—CH2—CH2NR3R4 or halogen;
- R1 is selected from the group consisting of hydrogen;
- C1-C3-alkyl;
- allyl;
- dimethylphosphonylmethyl;
- (R)-2,3-dihydroxy-1-propyl;
- (S)-2,3-dihydroxy-1-propyl;
- 1,3-dihydroxy-2-propyl;
- 3-hydroxy-2-hydroxymethyl-1-propyl;
- 2-methoxyethoxymethyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl;
- trifluoromethylsulfonyl;
- trimethylsilanyl;
- triisopropylsilanyl;
- t-butyldimethylsilanyl;
- phenyldimethylsilanyl;
- 1,3-di-t-butyldimethylsilanyloxy-2-propyl;
- 3-t-butyldimethylsilanyloxy-2-t-butyldimethylsilanyloxymethyl-1-propyl or a group A1—Q1;
- A1 represents a methylene, ethylene or propylene group;
- Q1 means cyano;
- carboxyl;
- COOCH3;
- or COOCH2CH3;
- R2 is C1-C6-alkyl;
- CH2—COO—CH2—CH3;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- 2,3-dihydroxy-1-propyl;
- 2-hydroxy-1-ethyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A1—Q1;
- R3 and R4 are independently selected from the group consisting of hydrogen;
- methyl;
- ethyl;
- 2-morpholinoethyl, or together form a 5 to 7 membered, saturated or unsaturated, unsubstituted or substituted ring substituted by a methyl group and containing one or two heteroatoms, independently selected from N or O, with the proviso that if X=OR1, then OR1 is not OH or O-allyl.
42 more elements
A process for the manufacture of a compound of formula (VI)
- 9
- characterized by oxidation of the sulfide group of the thioethers, described by formula (V)
- 10
- which are obtained by N-deoxygenation of compounds of formula (IV)
- 11
- whereby the compounds of formula (IV) are obtained by reacting a compound of formula (II)
- 12
- with a compound of formula (III)
- 13
- wherein
- X is hydrogen;
- OR1;
- SR2;
- (SO)R2;
- (SO2)R2;
- or a group A1—Q;
- A1 represents a C1-C3-alkylen group;
- Q is OR1;
- SR2;
- SOR2;
- SO2R2;
- NR3R4;
- NHCH2CH2NR3R4 or halogen;
- R1 is selected from the group consisting of hydrogen;
- C1-C3-alkyl;
- allyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- (R)-2,3-dihydroxy-1-propyl;
- (S)-2,3-dihydroxy-1-propyl;
- 1,3-dihydroxy-2-propyl;
- 3-hydroxy-2-hydroxymethyl-1-propyl;
- 2-methoxyethoxymethyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A1—Q1;
- Q1 represents C1-C2-alkoxy;
- cyano;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- carboxamide;
- —CO—NR3R4;
- C1-C6-alkylsulfanyl;
- C1-C6-alkylsulfenyl;
- C1-C6-alkylsulfonyl and with the proviso that if A1 represents an 1,2-ethylen- or 1,3-propylen group, then Q1 is hydroxy or NR3R4;
- R2 is C1-C6-alkyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- 2,3-dihydroxy-1-propyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A1—Q1;
- R3, R4 are independently selected from the group consisting of hydrogen;
- C1-C6-alkyl or together form a 5 to 7 membered, saturated or unsaturated, unsubstituted or substituted ring, substituted by a methyl group and containing one or two heteroatoms, independently selected from N or O;
- Y is hydrogen or a group A2—R;
- A2 is unsubstituted C1-C5-alkylen or substituted C1-C5-alkylen, substituted by C1-C6-alkyl;
- phenyl or hydroxy;
- R represents hydroxy;
- linear or branched C1-C6-alkoxy;
- amino;
- dimethylamino;
- diethylamino;
- t-butyloxycarbonylamino;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- triazolyl;
- cyano;
- piperidino;
- 1-pyrrolidinyl;
- morpholino;
- 4-methylpiperazin-1-yl;
- O—A1—NR3R4;
- S—A1—NR3R4;
- 4-carboxyphenyl;
- furan-3-yl;
- thiophen-2-yl or 3-methylthiophen-2-yl;
- Z represents one or two substituents independently selected from the group consisting of halogen;
- hydroxy;
- allyloxy;
- methyl;
- C1-C5-alkoxy;
- methoxymethoxy;
- (2-methoxyethoxy)methyloxy;
- methylthio;
- ethoxymethoxy;
- methylendioxy;
- ethynyl;
- trimethylsilylethynyl and unsubstituted benzyloxy or substituted benzyloxy substituted by halogen;
- methoxy;
- cyano;
- nitro;
- methylendioxy;
- carboxy or ethoxy;
- or its pharmaceutically acceptable salt thereof
87 more elements
A process for the manufacture of a compound of formula (VII)
- 14
- characterized by oxidation of the sulfide group of the thioethers, described by formula (V)
- 15
- which are obtained by N-deoxygenation of compounds of formula (IV)
- 16
- whereby the compounds of formula (IV) are obtained by reacting a compound of formula (II)
- 17
- with a compound of formula (III)
- 18
- wherein
- X is hydrogen;
- OR1;
- SR2;
- (SO)R2;
- (SO2)R2;
- or a group A1—Q;
- A1 represents a C1-C3-alkylen group;
- Q is OR1;
- SR2;
- SOR2;
- SO2R2;
- NR3R4;
- NHCH2CH2NR3R4 or halogen;
- R1 is selected from the group consisting of hydrogen;
- C1-C3-alkyl;
- allyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- (R)-2,3-dihydroxy-1-propyl;
- (S)-2,3-dihydroxy-1-propyl;
- 1,3-dihydroxy-2-propyl;
- 3-hydroxy-2-hydroxymethyl-1-propyl;
- 2-methoxyethoxymethyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A1—Q1;
- Q1 represents C1-C2-alkoxy;
- cyano;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- carboxamide;
- —CO—NR3R4;
- C1-C6-alkylsulfanyl;
- C1-C6-alkylsulfenyl;
- C1-C6-alkylsulfonyl and with the proviso that if A1 represents an 1,2-ethylen- or 1,3-propylen group, then Q1 is hydroxy or NR3R4;
- R2 is C1-C6-alkyl;
- dimethylphosphonylmethyl;
- 2,3-epoxy-1-propyl;
- 2,3-dihydroxy-1-propyl;
- 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A1—Q1;
- R3, R4 are independently selected from the group consisting of hydrogen;
- C1-C6-alkyl or together form a 5 to 7 membered, saturated or unsaturated, unsubstituted or substituted ring, substituted by a methyl group and containing one or two heteroatoms, independently selected from N or O;
- Y is hydrogen or a group A2—R;
- A2 is unsubstituted C1-C5-alkylen or substituted C1-C5-alkylen, substituted by C1-C6-alkyl;
- phenyl or hydroxy;
- R represents hydroxy;
- linear or branched C1-C6-alkoxy;
- amino;
- dimethylamino;
- diethylamino;
- t-butyloxycarbonylamino;
- carboxyl;
- C1-C6-alkoxycarbonyl;
- triazolyl;
- cyano;
- piperidino;
- 1-pyrrolidinyl;
- morpholino;
- 4-methylpiperazin-1-yl;
- O—A1—NR3R4;
- S—A1—NR3R4;
- 4-carboxyphenyl;
- furan-3-yl;
- thiophen-2-yl or 3-methylthiophen-2-yl;
- Z represents one or two substituents independently selected from the group consisting of halogen;
- hydroxy;
- allyloxy;
- methyl;
- C1-C5-alkoxy;
- methoxymethoxy;
- (2-methoxyethoxy)methyloxy;
- methylthio;
- ethoxymethoxy;
- methylendioxy;
- ethynyl;
- trimethylsilylethynyl and unsubstituted benzyloxy or substituted benzyloxy substituted by halogen;
- methoxy;
- cyano;
- nitro;
- methylendioxy;
- carboxy or ethoxy;
- or its pharmaceutically acceptable salt thereof
87 more elements
A process for the manufacture of 2,6-dichloro-3-hydroxybenzaldehyde and 2,6-dichloro-4-hydroxybenzaldehyde, the process comprises metallating protected 2,4-dichlorophenol or 3,5-dichlorophenol with a lithium base, followed by reacting with an ester or amide of formic acid, deprotecting and isolating the compounds.
A process for the manufacture of 2,6-dichloro-3-hydroxymethylbenzaldehyde and 2,6-dichloro-4-hydroxymethylbenzaldehyde, the process comprises metallating protected 2,4-dichlorobenzyl alcohol or 3,5-dichlorobenzyl alcohol with a lithium base, followed by reacting with an ester or amide of formic acid, deprotecting with an acid or a fluorine salt and the isolating the compounds.
Dependencies are inferred from the claim text.