4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents
First Claim
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1. A compound of Formula I ##STR13## and the pharmaceutically acceptable salts and stereoisomers thereof whereinZ is ##STR14## X is --N(H)--;
- R1 for each occurrence is substituted independently in the 6 and/or 7 position;
R1 for each occurrence is independently hydroxy, (C1 -C4)alkoxy, hydroxy(C2 -C4)alkoxy, amino(C2 -C4)alkyl, amino(C2 -C4)alkoxy, (C1 -C4)alkoxy(C2 -C4)alkoxy, (C1 -C4)alkylenedioxy, hydroxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, (C1 -C4)alkoxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, mono-N- or di-N,N-(C1 -C4)alkylamino(C2 -C4)alkoxy, 3- or 4-(C1 -C4)alkoxy-(2-hydroxy)-(C3 -C4)alkoxy, carboxy(C1 -C4)alkoxy, morpholino(C2 -C4)alkoxy, imidazol-1-yl(C2 -C4)alkoxy, 4(C1 -C4)alkylpiperazin-1-yl-(C2 -C4)alkoxy, (C1 -C4)alkoxy(C1 -C4)alkanoyloxy, nitro, hydroxylamino, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, (C1 -C4)alkanoylamino, hydroxy(C2 -C4)alkylamino, (C1 -C4)alkoxy(C2 -C4)alkylamino, (C1 -C4)alkylsulfonamido, morpholino, (C1 -C4)alkyl-piperazin-1-yl, bis(C1 -C4)alkanesulfonamido, di(C1 -C4)alkylamino(C2 -C4)alkylamino, (C1 -C4)alkylamino(C2 -C4)alkylamino, imidazol-1-yl, piperidin-1-yl, pyrrolidin-1-yl, (C1 -C4)alkoxy(C1 -C4)alkylcarbonylamino, N-(C1 -C4)alkyl-N-(C1 -C4)alkanoyl-amino, carboxy, (C1 -C4)alkoxycarbonyl, (C1 -C4)alkoxycarbonyl(C1 -C4)alkoxy, amido, mono-N- or di-N,N-(C1 -C4)alkylaminocarbonyl, mono-N- or di-N,N-(hydroxy (C2 -C4)alkyl)aminocarbonyl, (C1 -C4)alkyl, hydroxy(C1 -C4)alkyl, mono-N- or di-N,N-((C1 -C4)alkoxy(C1 -C4)alkyl)amino(C1 -C4)alkyl, mono-N- or di-N,N-(C1 -C4)alkylamino(C1 -C4)alkyl, (C1 -C4)alkanoylamino(C1 -C4)alkyl, (C1 -C4)alkoxy(C2 -C4)alkoxy(C1 -C4)alkyl, (C1 -C4)alkylthio, (C1 -C4)alkoxy(C2 -C4)alkylthio or hydroxy (C2 -C4)alkylthio; and
m is 0, 1 or 2.
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Abstract
This invention relates to certain 4-aminoquinazolines and the pharmaceutically acceptable salts and stereoisomers thereof, the formula whereof are described herein. The compounds are useful for the treatment of hyperproliferative diseases, particularly as anti-cancer agents.
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Citations
20 Claims
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1. A compound of Formula I ##STR13## and the pharmaceutically acceptable salts and stereoisomers thereof wherein
Z is ##STR14## X is --N(H)--; - R1 for each occurrence is substituted independently in the 6 and/or 7 position;
R1 for each occurrence is independently hydroxy, (C1 -C4)alkoxy, hydroxy(C2 -C4)alkoxy, amino(C2 -C4)alkyl, amino(C2 -C4)alkoxy, (C1 -C4)alkoxy(C2 -C4)alkoxy, (C1 -C4)alkylenedioxy, hydroxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, (C1 -C4)alkoxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, mono-N- or di-N,N-(C1 -C4)alkylamino(C2 -C4)alkoxy, 3- or 4-(C1 -C4)alkoxy-(2-hydroxy)-(C3 -C4)alkoxy, carboxy(C1 -C4)alkoxy, morpholino(C2 -C4)alkoxy, imidazol-1-yl(C2 -C4)alkoxy, 4(C1 -C4)alkylpiperazin-1-yl-(C2 -C4)alkoxy, (C1 -C4)alkoxy(C1 -C4)alkanoyloxy, nitro, hydroxylamino, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, (C1 -C4)alkanoylamino, hydroxy(C2 -C4)alkylamino, (C1 -C4)alkoxy(C2 -C4)alkylamino, (C1 -C4)alkylsulfonamido, morpholino, (C1 -C4)alkyl-piperazin-1-yl, bis(C1 -C4)alkanesulfonamido, di(C1 -C4)alkylamino(C2 -C4)alkylamino, (C1 -C4)alkylamino(C2 -C4)alkylamino, imidazol-1-yl, piperidin-1-yl, pyrrolidin-1-yl, (C1 -C4)alkoxy(C1 -C4)alkylcarbonylamino, N-(C1 -C4)alkyl-N-(C1 -C4)alkanoyl-amino, carboxy, (C1 -C4)alkoxycarbonyl, (C1 -C4)alkoxycarbonyl(C1 -C4)alkoxy, amido, mono-N- or di-N,N-(C1 -C4)alkylaminocarbonyl, mono-N- or di-N,N-(hydroxy (C2 -C4)alkyl)aminocarbonyl, (C1 -C4)alkyl, hydroxy(C1 -C4)alkyl, mono-N- or di-N,N-((C1 -C4)alkoxy(C1 -C4)alkyl)amino(C1 -C4)alkyl, mono-N- or di-N,N-(C1 -C4)alkylamino(C1 -C4)alkyl, (C1 -C4)alkanoylamino(C1 -C4)alkyl, (C1 -C4)alkoxy(C2 -C4)alkoxy(C1 -C4)alkyl, (C1 -C4)alkylthio, (C1 -C4)alkoxy(C2 -C4)alkylthio or hydroxy (C2 -C4)alkylthio; and m is 0, 1 or 2. - View Dependent Claims (5, 17, 18, 19, 20)
- R1 for each occurrence is substituted independently in the 6 and/or 7 position;
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2. A compound of Formula I ##STR15## and the pharmaceutically acceptable salts and stereoisomers thereof wherein
Z is ##STR16## R1 for each occurrence is independently substituted in the 6 and/or 7 position; -
R1 for each occurrence is independently hydroxy, (C1 -C4)alkoxy, hydroxy(C2 -C4)alkoxy, amino(C2 -C4)alkyl, amino(C2 -C4)alkoxy, (C1 -C4)alkoxy(C2 -C4)alkoxy, (C1 -C4)alkylenedioxy, hydroxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, (C1 -C4)alkoxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, mono-N- or di-N,N-(C1 -C4)alkylamino(C2 -C4)alkoxy, 3- or 4-(C1 -C4)alkoxy-(2-hydroxy)-(C3 -C4)alkoxy, carboxy (C1 -C4)alkoxy, morpholino (C2 -C4)alkoxy, imidazol-1-yl(C2 -C4)alkoxy, 4(C1 -C4)alkylpiperazin-1-yl-(C2 -C4)alkoxy, (C1 -C4)alkoxy(C1 -C4)alkanoyloxy, nitro, hydroxylamino, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, (C1 -C4)alkanoylamino, hydroxy(C2 -C4)alkylamino, (C1 -C4)alkoxy(C2 -C4)alkylamino, (C1 -C4)alkylsulfonamido, morpholino, (C1 -C4)alkyl-piperazin-1-yl, bis(C1 -C4)alkanesulfonamido, di(C1 -C4)alkylamino(C2 -C4)alkylamino, (C1 -C4)alkylamino(C2 -C4)alkylamino, imidazol-1-yl, piperidin-1-yl, pyrrolidin-1-yl, (C1 -C4)alkoxy(C1 -C4)alkylcarbonylamino, N-(C1 -C4)alkyl-N-(C1 -C4)alkanoyl-amino, carboxy, (C1 -C4)alkoxycarbonyl, (C1 -C4)alkoxycarbonyl(C1 -C4)alkoxy, amido, mono-N- or di-N,N-(C1 -C4)alkylaminocarbonyl, mono-N- or di-N,N-(hydroxy(C2 -C4)alkyl)aminocarbonyl, (C1 -C4)alkyl, hydroxy(C1 -C4)alkyl, mono-N- or di-N,N-((C1 -C4)alkoxy(C1 -C4)alkyl)amino(C1 -C4)alkyl, mono-N- or di-N,N-(C1 -C4)alkylamino(C1 -C4)alkyl, (C1 -C4)alkanoylamino(C1 -C4)alkyl, (C1 -C4)alkoxy(C2 -C4)alkoxy(C1 -C4)alkyl, (C1 -C4)alkylthio, (C1 -C4)alkoxy(C2 -C4)alkylthio or hydroxy(C2 -C4)alkylthio; m is 0, 1 or 2; Y completes a 5 or 6 membered aromatic, or partially saturated ring which may incorporate an oxygen or sulfur atom; and T is methylene, --N(H)--, thio or oxy.
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3. A compound of Formula I ##STR17## and the pharmaceutically acceptable salts and stereoisomers thereof wherein
Z is ##STR18## n is 1, 2 or 3; - m is 1 or 2;
R1 for each occurrence is independently hydroxy, (C1 -C4)alkoxy, hydroxy(C2 -C4)alkoxy, amino(C2 -C4)alkyl, amino(C2 -C4)alkoxy, (C1 -C4)alkoxy(C2 -C4)alkoxy, (C1 -C4)alkylenedioxy, hydroxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, (C1 -C4)alkoxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, mono-N- or di-N,N-(C1 -C4)alkylamino(C2 -C4)alkoxy, 3- or 4-(C1 -C4)alkoxy-(2-hydroxy)-(C3 -C4)alkoxy, carboxy (C1 -C4)alkoxy, morpholino(C2 -C4)alkoxy, imidazol-1-yl(C2 -C4)alkoxy, 4(C1 -C4)alkylpiperazin-1-yl-(C2 -C4)alkoxy, (C1 -C4)alkoxy(C1 -C4)alkanoyloxy, nitro, hydroxylamino, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, (C1 -C4)alkanoylamino, hydroxy(C2 -C4)alkylamino, (C1 -C4)alkoxy(C2 -C4)alkylamino, (C1 -C4)alkylsulfonamido, morpholino, (C1 -C4)alkyl-piperazin-1-yl, bis(C1 -C4)alkanesulfonamido, di(C1 -C4)alkylamino(C2 -C4)alkylamino, (C1 -C4)alkylamino(C2 -C4)alkylamino, imidazol-1-yl, piperidin-1-yl, pyrrolidin-1-yl, (C1 -C4)alkoxy(C1 -C4)alkylcarbonylamino, N-(C1 -C4)alkyl-N-(C1 -C4)alkanoyl-amino, carboxy, (C1 -C4)alkoxycarbonyl, (C1 -C4)alkoxycarbonyl(C1 -C4)alkoxy, amido, mono-N- or di-N,N-(C1 -C4)alkylaminocarbonyl, mono-N- or di-N,N-(hydroxy(C2 -C4)alkyl)aminocarbonyl, (C1 -C4)alkyl, hydroxy(C1 -C4)alkyl, mono-N- or di-N,N-((C1 -C4)alkoxy(C1 -C4)alkyl)amino(C1 -C4)alkyl, mono-N- or di-N,N-(C1 -C4)alkylamino(C1 -C4)alkyl, (C1 -C4)alkanoylamino(C1 -C4)alkyl, (C1 -C4)alkoxy(C2 -C4)alkoxy(C1 -C4)alkyl, (C1 -C4)alkylthio, (C1 -C4)alkoxy(C2 -C4)alkylthio or hydroxy(C2 -C4)alkylthio; and R2 for each occurrence is independently nitro, halo, (C1 -C4)alkyl, pyrrol-1-yl, hydroxyl, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, amino(C1 -C4)alkyl, azido, ethenyl, ethynyl, (C1 -C4)alkylenedioxy, phenyl or (C1 -C4)alkylthio. - View Dependent Claims (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
- m is 1 or 2;
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4. A compound of Formula I ##STR19## and the pharmaceutically acceptable salts and stereoisomers thereof wherein
Z is ##STR20## the B six membered ring has 0, 1 or 2 double bonds in the dotted line region; -
n is 0-2; R2 for each occurrence is independently halo, hydroxy or (C1 -C4)alkyl; m is 0, 1 or 2; and R1 for each occurrence is substituted independently in the 6 and/or 7 positions and is hydroxy, (C1 -C4)alkoxy, hydroxy(C2 -C4)alkoxy, amino(C2 -C4)alkyl, amino(C2 -C4)alkoxy, (C1 -C4)alkoxy(C2 -C4)alkoxy, (C1 -C4)alkylenedioxy, hydroxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, (C1 -C4)alkoxy(C1 -C4)alkyl(C1 -C4)alkylenedioxy, mono-N- or di-N,N-(C1 -C4)alkylamino(C2 -C4)alkoxy, 3- or 4-(C1 -C4)alkoxy-(2-hydroxy)-(C3 -C4)alkoxy, carboxy (C1 -C4)alkoxy, morpholino (C2 -C4)alkoxy, imidazol-1-yl(C2 -C4)alkoxy, 4(C1 -C4)alkylpiperazin-1-yl-(C2 -C4)alkoxy, (C1 -C4)alkoxy(C1 -C4)alkanoyloxy, nitro, hydroxylamino, amino, mono-N- or di-N,N-(C1 -C4)alkylamino, (C1 -C4)alkanoylamino, hydroxy(C2 -C4)alkylamino, (C1 -C4)alkoxy(C2 -C4)alkylamino, (C1 -C4)alkylsulfonamido, morpholino, (C1 -C4)alkyl-piperazin-1-yl, bis(C1 -C4)alkanesulfonamido, di-N,N-(C1 -C4)alkylamino(C2 -C4)alkylamino, (C1 -C4)alkylamino(C2 -C4)alkylamino, piperidin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, (C1 -C4)alkoxy(C1 -C4)alkylcarbonylamino, N-(C1 -C4)alkyl-N-(C1 -C4)alkanoyl-amino, carboxy, (C1 -C4)alkoxycarbonyl, (C1 -C4)alkoxycarbonyl(C1 -C4)alkoxy, amido, mono-N- or di-N,N-(C1 -C4)alkylaminocarbonyl, mono-N- or di-N,N-(hydroxy(C2 -C4)alkyl)aminocarbonyl, (C1 -C4)alkyl, hydroxy(C1 -C4)alkyl, mono-N- or di-N,N-((C1 -C4)alkoxy(C1 -C4)alkyl)amino(C1 -C4)alkyl, mono-N- or di-N,N-(C1 -C4)alkylamino(C1 -C4)alkyl, (C1 -C4)alkanoylamino(C1 -C4)alkyl, (C1 -C4)alkoxy(C2 -C4)alkoxy(C1 -C4)alkyl, (C1 -C4)alkylthio, (C1 -C4)alkoxy(C2 -C4)alkylthio or hydroxy(C2 -C4)alkylthio.
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Specification
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Current AssigneePfizer Inc.
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Original AssigneePfizer Inc.
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InventorsArnold, Lee D.
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Primary Examiner(s)Grumbling, Matthew V.
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Application NumberUS08/682,565Time in Patent Office617 DaysField of Search544/284, 544/293, 544/116, 514/259, 514/260, 514/63, 514/213, 514/234.5, 540/594US Class Current514/63CPC Class CodesA61P 35/00 Antineoplastic agentsA61P 35/04 specific for metastasisC07D 231/12 with only hydrogen atoms, h...C07D 233/56 with only hydrogen atoms or...C07D 249/08 1,2,4-Triazoles; Hydrogenat...C07D 401/04 directly linked by a ring-m...C07D 403/04 directly linked by a ring-m...C07D 403/14 containing three or more he...C07D 487/04 Ortho-condensed systemsC07D 491/04 Ortho-condensed systemsC07F 7/0812 comprising a heterocyclic ring
