WO2003055866A1 - Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux - Google Patents

Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux Download PDF

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WO2003055866A1
WO2003055866A1 PCT/US2002/041176 US0241176W WO03055866A1 WO 2003055866 A1 WO2003055866 A1 WO 2003055866A1 US 0241176 W US0241176 W US 0241176W WO 03055866 A1 WO03055866 A1 WO 03055866A1
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optionally substituted
halogen
group
linear
branched alkyl
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PCT/US2002/041176
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English (en)
Inventor
Jacques Dumas
Robert Sibley
Roger Smith
Ning Su
Yuanwei Chen
Jill Wood
Leatte Guernon
Julie Dixon
Catherine Brennan
Stephen Boyer
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Bayer Pharmaceuticals Corporation
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Priority to AU2002361846A priority Critical patent/AU2002361846A1/en
Publication of WO2003055866A1 publication Critical patent/WO2003055866A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to:
  • compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
  • Z is CH orN; Y is O or S; X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy and nitro,
  • R 3 is selected from the group consisting of: (a) hydrogen, and (b) -(C Cio) linear or branched alkyl;
  • R4 is -(CH ⁇ y -R wherein: j' is selected from the group consisting of:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
  • R 3 /R(. or R 5 /R 6 contain an unsubstituted -(CH 2 ) n -C 6 -C 10 -aryl substiruent, or (2) Rs ⁇ or R 5 /R 6 form a heterocyclic ring;
  • R 8 and R 9 are independently selected from the group consisting of: (a) hydrogen, (b) -(Ci-C 5 ) linear or branched alkyl which is optionally substituted with a substiruent selected from the group consisting of halogen and -(Ci- Cs) alkoxy,
  • R 8 and R 9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -( -C 5 ) linear or branched alkyl;
  • R 10 is hydrogen, -NR 8 R 9 , -ORn, -(C 1 -C 5 ) linear or branched alkyl, or phenyl;
  • each occurrence of Rn is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • Z is CH or N
  • Y is O or S
  • X is OR 5 orNR 5 R6;
  • Ri and R 2 are hydrogen;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH ⁇ y R , wherein
  • R 4 ' is:
  • R 5 has the formula -(CHRn) m -A or -(CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-Cs) linear or branched alkyl,
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with -(C 1 -C 5 ) alkyl;
  • R 9 are independently selected from the group consisting of: (a) hydrogen,
  • R is a saturated or fully unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy- and -(C JL -C S ) linear or branched alkyl optionally substituted by halogen;
  • R 10 is hydrogen, -NR 8 R 9 , -OR ⁇ , -(Ci-C 5 ) linear or branched alkyl, or phenyl;
  • each occurrence of R ⁇ is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
  • R 12 is -R 13 , -OR 13 , or - R 14 R 15 ;
  • R 14 and R 15 are independently selected from the group consisting of: (a) hydrogen, (b) -(C Cs) linear or branched alkyl optionally substituted with halogen, and
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • Embodiment 3 Also described are compounds with the formula (I) and (II) wherein: Z is CH orN; Y is O or S; X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and -OCH 3 wherein at least one of Ri and R 2 is -OCH 3 ;
  • R 3 is hydrogen; j is -(CH 2 ) y -R 4 wherein:
  • R is selected from the group consisting of:
  • A is selected from the group consisting of: (a) hydrogen,
  • (al7) contains at least one carbon atom; (bl7) is directly linked to the -(C 6 -C 10 )-aryl or is linked to the -(C 6 -C ⁇ o)-aryl via an -O- linkage, and (cl7) is optionally substituted with -(Ci-Cs)-alkyl,
  • A is selected from the group consisting of: (a) hydrogen, (b) -(Ci-C 5 ) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-Cs) alkoxy or -NR 8 R ,
  • a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to tliree heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or fully unsaturated five to eight membered carbocycle;
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) amino, (b) cyano,
  • (ql) a four to eight membered saturated or fully unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C 6 -C 10 -aryl optionally substituted with halogen or -( -Cs) alkyl;
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, four to eight membered heterocyclic ring, wherein said ring has one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-C 5 ) linear or branched alkyl;
  • R 10 is hydrogen, -NR 8 R 9 , -OR ⁇ , -(C ⁇ Cs) linear or branched alkyl, or phenyl;
  • R u is hydrogen, -( -Cs) linear or branched alkyl, or phenyl; n, m and p are independently an integer from 0 - 3; and
  • y is an integer from 0 - 2
  • the preferred compounds of embodiment 1 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
  • X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, cyano, halogen, and hydroxy, and wherein Ri and R 2 are both not hydrogen;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH 2 )y-R 4 l wherein: R t ' is selected from the group consisting of:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C 5 ) linear or branched alkyl,
  • R 5 and R 6 are not both hydrogen;
  • R 5 /R 6 contain an unsubstituted -(CH 2 ) n -C 6 -C ⁇ 0 -aryl substituent, or
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy, and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
  • R 8 and R 9 are independently selected from the group consisting of:
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated five or six membered heterocyclic ring, optionally containing one to two additional heteroatoms selected from the group consisting of nitrogen and oxygen;
  • R 10 is hydrogen, -NR 8 R 9 , -OR l l5 -(Ci-C 5 ) linear or branched alkyl, or phenyl;
  • each occunence of R ⁇ is independently selected from the group consisting of hydrogen and -(C 1 -C 5 ) linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • Embodiment 1 more preferred compounds
  • the more prefened compounds of embodiment 1 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
  • X is NR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and halogen, wherein Ri and R are both not hydrogen;
  • R 3 is hydrogen
  • R 4 ' is selected from the group consisting of:
  • R 3 and R 4 form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a fully saturated five or six membered heterocyclic ring, which optionally contains one additional nitrogen atom, and wherein said ring is optionally substituted with one to two substituents selected from the group consisting of:
  • R is selected from the group consisting of hydrogen, -( -C 5 ) linear or branched alkyl and phenyl, which are optionally substituted with one halogen,
  • R 8 and R 9 are independently selected from the group consisting of:
  • R ⁇ o is -NR 8 R 9 or -ORii ,
  • each occunence of Rn is hydrogen
  • n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
  • the prefened compounds of embodiment 2 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other.
  • the prefened compounds of embodiment 2 have the formula (I)
  • X is OR 5 orNR 5 R 6 ;
  • R] and R are hydrogen
  • R 3 is selected from the group consisting of:
  • R is -(CH 2 ) y R ' 5 wherein
  • R is:
  • R 5 has the formula -(CHRu) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of: (a) hydrogen,
  • (9) -S( O) 2 R 10 ; and (10) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (alO) contains at least one carbon atom; (blO) is directly linked to the -(C 6 -Ci 0 )-aryl or is linked to the -(C 6 -do)-aryl via an -O- linkage; and (clO) is optionally substituted with -(Ci-C 5 )-alkyl, -(CH 2 ) n COOR 7 or -(CH 2 ) conflictCONR 8 R 9 , and
  • R 6 is selected from the group consisting of:
  • R 5 and R 6 are not both hydrogen;
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen wherein said heterocyclic ring is optionally substituted with -(C ⁇ -Cs)-alkyl;
  • R 7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy-, and -( -C 5 ) linear or branched alkyl optionally substituted by halogen;
  • R 8 and R 9 are independently selected from the group consisting of:
  • (c) -(C ⁇ -Cio) aryl, and wherein (c) is optionally substituted with one to three substituents selected from the group consisting of halogen,-(C 1 -Cs) alkoxy and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
  • R 10 is hydrogen, -NR 8 R 9 , -ORn, -(C ⁇ -C 5 ) linear or branched alkyl, or phenyl; each occunence of R ⁇ is independently selected from the group consisting of hydrogen and -(Ci-Cs) linear or branched alkyl and phenyl;
  • R12 is -R 13 , -OR 13 , or -NR ⁇ 4 R 15 ;
  • R 13 is
  • R 1 and R 15 are independently selected from the group consisting of:
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • the more prefened compounds of embodiment 2 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other.
  • the more prefened compounds of embodiment 2 have the formula (I)
  • X is NR 5 R 6 ;
  • Ri and R 2 are hydrogen;
  • R 3 is hydrogen
  • R4 is -(CH 2 )yR ', wherein
  • R t ' is:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 6 is hydrogen
  • R 6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen, wherein said heterocyclic ring is optionally substituted with-(Ci-Cs)-alkyl;
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one halogen substituent,
  • R 8 and R 9 are independently selected from the group consisting of:
  • R 10 is -NR 8 R 9 or -OR ⁇ ,
  • each occunence of R ⁇ is hydrogen
  • R12 is -OR13, or -NR 14 R ⁇ 5 ;
  • R 13 is (a) hydrogen, or
  • R 14 and R 15 are independently selected from the group consisting of:
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • the prefened compounds of embodiment 3 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
  • the prefened compounds of embodiment 3 have the fonnula (I)
  • X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and -OCH 3 wherein at least one of Ri and R 2 is -OCH 3 ;
  • R 3 is hydrogen;
  • R 4 is -(CH 2 ) y -R 4 ' wherein:
  • R ' is selected from the group consisting of:
  • Rs has the formula: -(CH 2 ) p -O-A where A is selected from the group consisting of:
  • A is selected from the group consisting of: (a) -(C 1 -C 5 ) linear or branched alkyl optionally substituted with halogen, - (C 1 -C 5 ) alkoxy or -NR 8 R 9 ,
  • R 6 is selected from the group consisting of: (a) hydrogen, and
  • R 5 and Re form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) halogen,
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo,
  • R 8 and R are independently selected from the group consisting of hydrogen, -(Ci-C 5 ) linear or branched alkyl, and -(Ce-C 10 ) aryl which is optionally substituted with one to three substituents selected from the group consisting of halogen and -( - C 5 ) alkoxy, or
  • R 8 and R 9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, five or six membered heterocyclic ring, wherein said ring has one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
  • Rio is hydrogen, -NR 8 R 9 , -OR ⁇ , -(Ci-Cs) linear or branched alkyl, or phenyl;
  • R ⁇ is hydrogen, -(C Cs) linear or branched alkyl, or phenyl
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2
  • the more prefened compounds of embodiment 3 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
  • X is NR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and
  • R 4 ' is selected from the group consisting of:
  • R 3 and t form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is unsubstituted;
  • R 5 has the formula:
  • A is selected from the group consisting of:
  • R 6 is hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring is optionally substituted with one or two substituents selected from the group consisting of:
  • R 7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three halogen substituents;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, -(Ci-C 5 ) linear or branched alkyl, and phenyl which is optionally substituted with one substituent selected from the group consisting of halogen and -(C Cs) alkoxy,
  • R 10 is -NR 8 R 9 or -OR ⁇ , Rii is hydrogen, or -( -Cs) linear or branched alkyl
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2
  • Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II).
  • Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid.
  • Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, ⁇ -aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine,
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N- dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
  • prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include N- dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), wliich is hereby incorporated by reference).
  • halogen refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention.
  • the alkyl may be fully substituted, up to perhalo.
  • fused bicyclo ring refers to a substituent which is a two ring structure which share two carbon atoms.
  • the bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.
  • Z is CH or N; Y is O or S; X is OR 5 or NR 5 Re;
  • Ri, Ri ' , R 2 and R 2' are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy, methoxy and nitro;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH 2 )y-R 4 ! wherein:
  • R 4 ' is selected from the group consisting of:
  • R 5 has the formula (CHR ⁇ ) m -A or (CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • a fused bicyclo ring wherein one ring is a saturated or unsaturated five to six membered saturated or unsaturated heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or unsaturated five to eight membered carbocyclic ring,
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C 5 ) linear or branched alkyl;
  • R 5 and R 6 are not both hydrogen
  • (ql) a four to eight membered saturated or unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C 6 -C 10 -aryl optionally substituted with halogen or -(Ci-C 5 )- alkyl;
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen, wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-Cs) linear or branched alkyl;
  • Rio is hydrogen, -NR 8 R 9 , -OR ⁇ , -(C 1 -C 5 ) linear or branched alkyl, or phenyl;
  • each occunence of R ⁇ is independently selected from the group consisting of hydrogen, -C ⁇ -C 5 linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
  • Lacefield et al. (U.S. Patent No. 3,956,495) describes 2,4-diaminoquinazoline compounds which are used as antithrombotic agents.
  • Pfizer, Inc. (GB 1,156,973) describes 2,4-diaminoquinazoline compounds which are used to reduce blood pressure in hypertensive subjects.
  • Singhal et al. J Indian Chem Soc, vol. LXI, pages 690-693, August 1984
  • 2,4- diaminoquinazoline compounds and their use as antimalarial agents.
  • Abou-Zeid et al. (Egypt. J. Pharm. Sci., vol. 32, no. 1-2, pages 165-174, (1991)) described 1,4-disubstituted piperazines (which happen to also be 2,4-diaminoquinazoline compounds) and their use as antihypertensive agents.
  • the invention also includes pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
  • compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition),
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1 2 F 2 , F 2 C1C- CC1F 2 and CC1F 3 ) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylpara
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerin, propylene glycol and sorbitol
  • levigating agents include but are not limited
  • compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.
  • the compositions of the invention can also have an additional apoptosis inducers as an active ingredient. Examples of known apoptosis inducers (see e.g.
  • Calbiochem's 2001 Signal Transduction Catalog, pages 702-704, the contents of which are incorporated by reference) which can be added to the described invention include but are not limited to A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydroclor
  • Optional cancer treatment agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, ral
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ.
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of formulae (la) or (Ila) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
  • Thin-layer chromatography was performed on Whatman pre-coated glass-backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was perfonned using 230-400 mesh EM Science ® silica gel
  • Melting points were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are unconected.
  • Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si ( ⁇ 0.00) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • Carbon ( 13 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA.
  • Step 1 Chloral hydrate (14.5 g, 87.7 mmol) was dissolved in water (190 mL) and then added to sodium sulfate (92.26 g, 650 mmol) in water (170 mL).
  • m-Anisidine (10 g, 81.2 mmol) was dissolved in water (50 mL) with cone.
  • HCl (7.0 mL) was added to the first mixture, a layer of brown oil formed on the top.
  • Hydroxylamine hydrochloride 17.86 g, 256 mmol was dissolved in water (80 mL) and added to the reaction mixture. The mixture was heated at 40 °C then warmed to 50 °C.
  • Step 1 2-Amino-5-iodobenzoate acid (3 g, 11.4 mmol) was dissolved in THF and then 1,1'- carbonyldiimidazole (1.85 g, 11.4 mmol) was added. The mixture was heated at 60 °C for 2 days. The reaction was monitored by TLC. After starting material was consumed, MeOH (2 mL) was added and the mixture was heated at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (100% CH 2 C1 2 ) to obtain 2.4 g of methyl 2-amino-5-iodobenzoate (76%). MS (GC/MS) 277.
  • Step 2 Methyl 2-amino-5-iodobenzoate (2.4 g, 8.66 mmol) was dissolved in AcOH (7.5 mL). Potassium cyanate was dissolved in water (1.5 mL) and added to the reaction mixture slowly. A precipitate fonned immediately. The mixture was heated to 100 °C for 20 min and then mixture was added water and filtered by suction to afford a white solid. This white solid was dried under vacuum oven for 2 h. To this white solid was added MeOH (27 mL) to form a suspension. To this suspension, a solution of NaOH (406 mg) in water (5.4 mL) was added and the mixture was brought to reflux for 1 h.
  • Step 1 To 2-amino-5-methoxylbenzoic acid (3 g, 17.9 5 mmol) was added 2N HCl (15 mL). After a precipitate formed, water (30 mL) was added to the mixture to form a suspension. A solution of sodium cyanate (1.75 g, 26.92 mmol) in water (20 mL) was added dropwise at rt over 15 min. Froth formed and after vigorously stirring, a pink suspension formed. After stirring for 4 h, the suspension was filtered and washed with water and ether and dried under reduced pressure. The solid was added to concentrated HCl (20 mL), and heated to 105 °C for 1 h.
  • Step 1 To a suspension of 2-amino-5-chlorobenzoic acid (102. lg, 0.58 mol) in water (1.6 L) was added 5 M NaOH (160 mL). To the resulting solution was charged sodium cyanate (43.4 g, 0.64 mol) followed by glacial acetic acid (36.7 mL, 0.641 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the brown solution was added 1 M HCl (1.5 L). The resulting precipitate was stined rt for a period of 2-2.5 h then filtered and washed with water (2 x 666 mL).
  • Step 2 A suspension of 2-[(aminocarbonyl)amino]-5-chlorobenzoic acid (35.0 g, 0.16 mol) and p-toluene sulfonic acid monohydrate (4.66 g, 0.024 mol) in a mixture of toluene (350 mL) and DMF (87.5 mL) was heated to reflux with an attached Dean stark apparatus for a period of 4-4.5 h. The reaction was judged complete by 1H NMR. The suspension was cooled to rt, filtered and the solid washed with toluene (150 mL). The damp solid was pulped in water (250 mL) for a period of 15-20 min.
  • Step 3 A mixture of 6-chloro-2,4(lH,3H)-quinazolinedione (24.0 g, 0.122 mol), POCl 3 (114 mL, 1.22 mol) and PC1 5 (56.2 g, 0.26 mol) was heated to reflux for a period of 3.5-4.0 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes). The reaction mixture was concentrated under vacuum to remove most of the POCl 3 . The resulting solid was poured slowly into ice/water (1000/200 mL) and stined vigorously for a period of one hour. The precipitate was filtered and the damp solid was pulped in water for 15-20 min.
  • Step 1 To a suspension of 2-amino-4-chlorobenzoic acid (15.3 g, 0.087 mol) in water (245 mL) was added 5 M NaOH (24 mL, 0.12 mol). To the resulting solution was charged sodium cyanate (6.50 g, 0.096 mol) followed by glacial acetic acid (5.5 mL, 0.096 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the yellow solution was added 1M HCl (225 mL). The resulting precipitate was stined at rt for a period of 2-2.5 h then filtered and washed with water (2 x 100 mL).
  • Step 2 A suspension of 2-[(aminocarbonyl)amino]-4-chlorobenzoic acid (14.0 g, 0.065 mol) and p-toluene sulfonic acid monohydrate (1.86 g, 0.01 mol) in a mixture of toluene (140 mL) and DMF (35 mL) was heated to reflux with an attached Dean stark apparatus for a period of 3.0 h. The reaction was judged complete by TLC (Eluent- 5:4:1 Hexanes/ethyl acetate/methanol). The suspension was cooled to rt, filtered and the solid washed with toluene (20 mL).
  • Step 3 A mixture of 7-chloro-2,4(lH,3H)-quinazolinedione (7.5 g, 0.04 mol), POCl 3 (35.5 mL, 0.38 mol) and PCls (17.5 g, 0.08 mol) was heated to reflux for a period of 3.0-3.5 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes).
  • Step 1 l-(3-Chloropropoxy)-4-fluorobenzene (1 eq) and phthalimide, potassium salt (1.2 eq) in a solution of DMF (1.0 M were magnetically stined at 80 °C over a period of 18 h. The reaction was cooled, dissolved in CH 2 C1 2 and water and poured into a separatory funnel. The layers were separated and the aqueous was extracted with CH 2 C1 2 (3x). The combined organics were washed with IN NaOH (2x), dried (MgSO ), filtered and concentrated under reduced pressure. The 2-[3-(4-fluorophenoxy)propyl]-lH-isoindole-l,3(2H)-dione was used without purification.
  • Step 1 A slurry of 4-nifrophenol (1 eq) and NaOH pellets (1 eq) in H 2 O (6.8 M) was stined for 10 min after which time -xylene (1.4 M), K 2 CO 3 (1.5 eq) and 2- diethylaminoethylchlorideliydrochloride (1 eq) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in /?-xylene and washed with IN NaOH (2x) and H 2 O (lx). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to yield N,N-diethyl-2-(4-nitrophenoxy)ethanamine as a solid which was carried on without further purification.
  • Step 2 A solution of N,N-diethyl-2-(4-nitrophenoxy)ethanamine (1 eq) in ethanol (0.2 M) was added via syringe to a flask containing Palladium on carbon (10% wt).
  • the reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H 2 atmosphere.
  • the reaction was allowed to stir overnight and then purged with Ar and evacuated tliree times until an Ar atmosphere had been achieved.
  • the reaction solution was filtered through a pad of Celite and washed with copious amounts of ethanol. The filtrate was concentrated under reduced pressure and afforded pure 4-[2-(diethylamino)ethoxy]aniline as an oil.
  • Step 1 To N-(3-Hydroxypropyl)phthalamide (0.10 g, 0.490 mmol, l.Oeq.) and hexafluoro- 2-propanol (0.12 g, .730 mmol, 1.5eq.) in THF (4 mL) was added a mixture of triphenylphosphine (0.19 g, .730 mmol, 1.5 eq.) and diethylazodicarboxalate (0.13 g, 0.730 mmol, 1.5eq.) in THF (4 mL.) that was allowed to stir at 0 °C for lh. The reaction was allowed to stir at rt for 3 h.
  • Step 2 To 2- ⁇ 3-[2,2,2-trifluoro-l-(trifluoromethyl)ethoxy]propyl ⁇ -lH-isoindole-l,3(2H)- dione (1.0 g, 2.8 mmol, 1.0 eq.) in ethanol (10 mL) was added hydrazine hydrate (0.09 g, 2.8 mmol, leq.) and the reaction was allowed to stir at rt for 16 h. This was treated with IN hydrochloric acid (5 mL) and the reaction was filtered washing with water. The filtrate was concentrated under reduced pressure and filtered to give 0.20 g of 3-[2,2,2-trifluoro-l- (trifluoromethyl)ethoxy]propylamine (32%).
  • Step 1 To methylamine (2 M, 12.4 mL, 2.5eq.) and DMAP (0.24 g, 1.99 mmol, 0.2 eq.) in methylene chloride (15 mL.) was added 4-cyanobenzenesulfonyl chloride (2.0 g, 9.9 mmol., 1.0 eq.) portionwise at 0 °C. The reaction was allowed to warm rt and stir for 2h. The reaction was acidified with 2 N HCl to pH 1, and extracted with methylene chloride, dired with magnesium sulfate, filtered and concentated under reduced pressure to give 1.29 g of 4- cyano-N-methylbenzenesulfonamide (67%) as a colorless solid.
  • Step 2 To PtO 2 x H 2 O (0.13 g., 6.57 mmol., l.Oeq.) was added methanol (5 mL.) and HCl (0.13g, 7.88 mmol., 1.2 eq.) and 4-cyano-N-methylbenzenesulfonamide (1.29 g, 6.57 mmol., 1.0 eq.) and the reaction was placed under hydrogen gas (1 atm.) for 16 h. The reaction was filtered and concentrated under reduced pressure to give 230 mg of 4-(aminomethyl)-N- methylbenzenesulfonamide (18%).
  • Step 1 A solution of methyl 4-(aminomethyl)benzoate hydrochloride (5 g, 26.65, 1 eq) in THF (50 mL) was treated with a solution of di-tert-butyl dicarbonate (14 g, 63.96 mmol, 2.4 eq) in THF (50 mL) dropwise. Triethylamine (11.14 mL, 8.1 g, 80 mmol, 3 eq) was added and the reaction was magnetically stined over 16 hours.. Methylene chloride (100 mL) was added and the solution was washed with deionized water (100 mL), dried over magnesium sulfate and then filtered.
  • Triethylamine 11.14 mL, 8.1 g, 80 mmol, 3 eq
  • Step 2 4- ⁇ [(tert-Butoxycarbonyl)amino]methyl ⁇ benzoic acid (3g, 11.94 mmol, 1 eq) was dissolved in methylene chloride (50 mL) and treated with CDI (2.13 g, 13.13 mmol, 1.1 eq) and magnetically stined over 20 min at rt. Dimethylhydroxylamine HCl (5.82 g, 59.70 mmol, 5 eq.) was added to this solution and magnetically stined over 16 hours.
  • Aqueous citric acid (10 % by wt., lOOmL) were added and the organic sayer was separated and successivively washed with deionized water (100 mL) and brine (100 mL), dried over magnesium sulfate and then filtered.
  • the solution was concentrated in ⁇ acuo, and purified by column chromatography (50% Ethyl acetate:Hexanes) to yield tert-butyl 4- ⁇ [methoxy(methyl)amino]carbonyl ⁇ benzylcarbamate as a yellow oil.
  • Step 3 To a previously cooled solution (0 °C, via ice/water bath) of tert-butyl 4- ⁇ [methoxy(methyl)amino]carbonyl ⁇ benzylcarbamate (0.5 g , 1.70 mmol, 1 eq) in THF (34 mL) under argon in an oven-dried flask, «-butyllithium (1.6 M in hexanes, 3.2 mL, 5.1 mmol, 3 eq) was added dropwise and the mixture was magnetically stined for 1 hour.
  • «-butyllithium 1.6 M in hexanes, 3.2 mL, 5.1 mmol, 3 eq
  • Step 4 A solution of tert-butyl 4-pentanoylbenzylcarbamate (0.410 g) in methylene chloride (10 mL) was treated with TFA and magnetically stined for 45 min. A saturated aqueous solution of sodium bicarbonate was added slowly followed by ethyl acetate (40 mL). The organic layer was separated, dried over magnesium sulfate and then filtered. The solution was concenfrated under reduced pressure, resulting in l-[4-(aminomethyl)phenyl]-l- pentanone which was used without any further purification.
  • Step 1 Benzylamine 1 (General Flow Diagram I) (1.1 eq) and potassium carbonate (3.5 eq) were added to a solution of quinazoline 2 (1.0 eq) in isopropyl alcohol and water (as a 2 to 1 ratio, 0.1 M) and were magnetically stined at rt over a period of 16 h.
  • the isopropyl alcohol was removed in vacuo.
  • Ethyl acetate was added and this solution was washed with deionized water, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield intermediate 3 as a white solid.
  • Step 2 Amine 4 (1.1 eq) and concentrated hydrochloric acid (catalytic) were added to a solution of intermediate 3 (1.0 eq) in 7z-butanol (0.1M) were magnetically stined at 100 °C in a sealed tube over a period of 16 h. The excess n-butanol was removed under reduced pressure. Methylene chloride was added and the solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield compound 5.
  • Step 1 A suspension of 2,4,6-trichloroquinazoline (685 mg, 2.93 mmol), methyl 4- (aminomethyl)benzoate hydrochloride (651 mg, 3.28 mmol), and sodium acetate (722 mg, 8.80 mmol) in water (25 mL) was refluxed for 30 min vigorously. The white suspension is filtered through a coarse frit while still warm, and washed thoroughly with water (2 x 30 mL), then dried under P 2 O 5 in vacuo to give 884 mg of methyl 4- ⁇ [(2,6-dichloro-4- quinazolinyl)amino]methyl ⁇ benzoate as a white solid in (83%).
  • Step 2 A suspension of methyl 4- ⁇ [(2,6-dichloro-4-quinazolinyl)amino] methyl ⁇ benzoate (850 mg, 2.347 mmol) in piperidine (3.00 g, 35.21 mmol) was stined at 80 C under argon for 10 min. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo to give a yellow oil which crystallizes.
  • Step 1 To a suspension of 2,4,6-trichloroquinazoline (300 mg, 1.29 mmol) in dry DMF (10 mL) at 0 °C under argon was added piperidine (0.26 mL, 2.639 mmol) and the yellow suspension stined at 0 °C for 30 min, then at rt for 16 h. The reaction was diluted with water (75 mL) and sat. NaHCO 3 (25 mL) and extracted with EtOAc (2 X 150 mL). The organics were washed with water (2 X 50 mL), dried (MgSO 4 ), and concentrated in vacuo to give a yellow solid.
  • Step 2 A suspension of 2,6-dichloro-4-(l-piperidinyl)quinazoline (100 mg, 0.35 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (105 mg, 0.523 mmol), and potassium carbonate (144 mg, 1.044 mmol) in dry DMF (5 mL) under argon was heated to 120 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 150 mL).
  • Step 3 A solution of methyl 4-( ⁇ [6-chloro-4-(l-piperidinyl)-2-quinazolinyl]amino ⁇ methyl)benzoate (50 mg, 0.122 mmol) in methanol (5 mL) and 5 M NaOH (aq)(0.73 mL, 3.65 mmol) was stined at rt for 24 h. The reaction was quenched by addition of 1 M HCl (aq)(3.70 mL), then diluted with Na/K tartrate/NaHSO 4 buffer at pH 4.5 (50 mL).
  • Step 1 A solution of m-anisidine (0.017 g, 0.14 mmol) and tr ⁇ ns-methyl 4- ⁇ [(2,6-dichloro- 4-quinazolinyl)amino]methyl ⁇ cyclohexanecarboxylate (0.050 g, 0.14 mmol) in n-butanol (2 mL) was heated at reflux overnight. The reaction was cooled to rt and the zz-butanol was concentrated under reduced pressure.
  • Step 2 A solution of tr ⁇ w-methyl 4-[( ⁇ 6-chloro-2-[(3-methoxyphenyl)amino]-4- quinazolinyl ⁇ amino)methyl]cyclohexanecarboxylate (0.02 g, 0.04 mmol) and IN NaOH (0.04 mL) in MeOH/H 2 O/THF (1.5 mL/0.25 mL/0.25 mL) was stined at room temperature overnight then at 40 °C over 6 days. The reaction was cooled rt and the volatiles were removed under reduced pressure.
  • Step 1 A mixture of 2,4,7-trichloroquinazoline (0.20 g, 0.86 mmol), 4-(4- morpholinyl)phenylamine (0.229 g, 1.28 mmol), potassium carbonate (0.355 g, 2.57 mmol) in IP A/water (5.3 mL/2.7 mL) was heated at 60° C for 18 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The pH was adjusted to 6 with the addition of IN HCl and the mixture was concentrated in vacuo.
  • Step 2 A solution of methyl 4-(aminomethyl)benzoate (0.027 g, 0.13 mmol) and 2,7- dichloro-N-[4-(4-morpholinyl)phenyl]-4-quinazolinamine (0.050 g, 0.13 mmol) in n-butanol (1 mL) was heated to reflux for 18 h. The reaction was cooled rt and the 7?-butanol was removed under reduced pressure.
  • Step 1 A mixture of 2, 4, 7-trichloroquinazoline (0.125 g, 0.54 mmol), wo-butyl amine (0.059 g, 0.080 mmol), and potassium carbonate (0.222 g, 1.61 mmol) in IP A/water (2.7 mL/1.3 mL) was heated at 60 °C for 18 h. The reaction was cooled to rt and the volatiles were removed under reduced pressure. The pH was adjusted to pH 6 with the addition of IN HCl and the resulting solid was collected by filtration.
  • Step 2 A solution of methyl 4-(aminomethyl)benzoate hydrochloride (0.037 g, 0.19 mmol) and 2,7-dichloro-N-isobutyl-4-quinazolinamine (0.050 g, 0.19 mmol) in «-butanol (1 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the «-butanol was removed in vacuo.
  • HPLC conditions for parallel synthesis analysis A YMC Pro C-18 column (2 x 23mm, 120 A) was used, and the eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.5 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 90% B over 3.5 minutes, followed by a final hold at 90% B for 0.5 minutes. Total run time was 4.8 minutes.
  • Step 1 4-[( ⁇ 6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino)methyl]benzoic acid (1 eq) was dissolved in DMF (0.23 M) and cooled to -30 °C when hydroxybenzatriazolehydrate (1.7 eq) and l-[3-(dimethylaminopropyl)]-3-ethylcarbo diimide hydrochloride (1.7 eq) were added. This was allowed to stir for 15 min and 2- (aminooxy)ethanol (1.4 eq) in a solution of DMF (0.33 M was added via syringe.
  • the reaction was gradually allowed to reach rt and was magnetically stined over a period of 18 h.
  • the reaction was dissolved in EtOAc and water and poured into a seperatory funnel. The layers were separated and the aqueous was extracted with EtOAc (3x). The combined organics were washed with 10% citric acid (2x), 10% NaHCO 3 (2x), satd. NaCl, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 2 4-[( ⁇ 6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino)methyl]-N-(2- hydroxyethoxy)benzamide (1 eq) was dissolved in THF (0.02 M) were magnetically stined as a suspension and the Burgess reagent (1.1 eq) was added in one portion. The reaction was heated at 80 °C over a period of 3 h.
  • Step 2 To 4-[( ⁇ 6,7-dimethoxy-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino) methyl]benzoic acid (0.050 g) in iro-butanol (3 mL) was added a catalytic amount of cone, sulfuric acid and the reaction was heated to 100 °C for 2 h.
  • Step 1 To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (0.500 g, 1.93 mmol), tefrabutylammonium bromide (0.0311 g, 0.10 mmol), and 10% aqueous NaOH (4.0 mL) in toluene (4.8 mL) was added methyl 4-(hydroxymethyl)benzoate (0.330 g, 1.99 mmol) as a solution in toluene (3.3 mL), dropwise. The reaction was allowed to stir at rt for 18 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL).
  • Step 2 A solution of (2S)-2-(methoxymethyl) ⁇ ynolidine (0.033 g, 0.29 mmol) and 4- ⁇ [(2- chloro-6,7-dimethoxy-4-quinazolinyl)oxy]methyl ⁇ benzoic acid (0.108 g, 0.29 mmol) in n- butanol (1.5 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed under reduced pressure. The residue was triturated with MeOH and filtered. The filtrate was concentrated under reduced pressure.
  • Step 1 To a solution of 4-(chloromethyl)benzoic acid (1.00 g, 5.86 mmol) in EtOH (15 mL) was added thiourea (0.50 g, 5.86 mmol) as a solution in EtOH (5 mL), dropwise. The reaction was allowed to stir at room temperature overnight. Additional thiourea was added
  • Step 2 A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (0.50 g, 1.93 mmol), 4- (sulfanylmethyl)benzoic acid (0.487 g, 2.89 mmol), and potassium carbonate (0.800 g, 5.79 mmol) in IP A/water (10 mL/5 mL) was heated at 60 °C overnight. The reaction was cooled to rt and IN HCl was added to adjust the pH to 6.
  • Step 3 A solution of (2S)-2-(methoxymethyl)pynolidine (0.06 g, 0.51 mmol) and 4- ⁇ [(2- chloro-6,7-dimethoxy-4-quinazolinyl)sulfanyl]methyl ⁇ benzoic acid (0.20 g, 0.51 mmol) in 77-butanol (12 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed in vacuo. The residue was taken up in MeOH and adhered to silica gel.
  • Step 4 A solution of 4-[( ⁇ 6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l-pynolidinyl]-4- quinazolinyl ⁇ sulfanyl)methyl] benzoic acid (0.025 g, 0.05 mmol) and chlorotrimethylsilane (0.011 g, 0.10 mmol) in MeOH (1.0 mL) was stined rt for 18 h. Additional chlorotrimethylsilane (0.113 g, 0.10 mmol) was added and the mixture was allowed to stir 24 h. The mixture was concenfrated under reduced pressure. The residue was taken up in MeOH and, again, concenfrated under reduced pressure.
  • Step 1 To a heterogeneous magnetically stined solution of malonic acid (5.4 g, 52 mmol, 1.0 eq) in phosphorous oxychloride (60, 390 mmol, 7.5 eq) was added 3,4-dimethoxyaniline (10 g, 65 mmol, 1.25 eq). The reaction heated to reflux at 115 °C for 2 h when it was cooled to rt and carefully added to 500 mL ice. The resulting aqueous layer was extracted with dichloromethane (2 x 300 mL). The organic layers were combined, washed with brine (1 x 300 mL), dried over magnesium sulfate and concentrated in vacuo to yield 6 g of 2,4- dichloro-6,7-dimethoxyquinoline (45%).
  • Step 2 A solution of 2,4-dichloro-6,7-dimethoxyquinoline (3g, 11.7 mmol, 1 eq), methyl 4- (aminomethyl)cyclohexanecarboxylate (9.7 g, 46.8 mmol, 4 eq), DBU (7 mL, 46.8 mmol, 4 eq) in 60 mL of NMP was magnetically stined at 120 °C in a sealed tube over a period of 16 h. The reaction was concentrated in vacuo and the resulting residue diluted with 100 mL of dichloromethane.
  • Step 3 4-(4-Morpholinyl)phenylamine (0.89 g, 5 mmol, 20 eq) and methyl 4- ⁇ [(2-chloro- 6,7-dimethoxy-4-quinolinyl)amino]methyl ⁇ cyclohexanecarboxylate (100 mg, 0.25 mmol, 1 eq) were magnetically stined at 140 °C in a sealed tube over a period of 16 h.
  • Examples 24 - 345 listed in the tables below were synthesized by the preparative methods described above or by using other known synthetic techniques such as those described by D. J. Brown, Fused Pyrimidines (part 1. - Quinazolines), by W. L. F. Amarego, publ. by New York Interscience, (1967); D. J. Brown, Quinazolines (Supplement I), publ. by John Wiley & Sons, (1996); Vol.
  • Table 3 shows Examples 308 - 346 which are various other embodiments of the described invention.
  • Table 4 shows the accompanying analytical data for Examples 308 - 346 from Table 3.

Abstract

La présente invention concerne des dérivés de quinazoline ou de quinoline de formule (I) ou (II), dans lesquelles Z représente CH ou N, Y représente O ou S, X représente OR5 ou NR5R6 et R1, R2, R3, R4, R5 et R6 sont tels que définis dans cette invention. La présente invention concerne également un procédé pour inhiber la prolylpeptidase, induire une apoptose et traiter un cancer en administrant une quantité efficace d'un point de vue thérapeutique de composés de formule (I) ou (II).
PCT/US2002/041176 2001-12-21 2002-12-20 Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux WO2003055866A1 (fr)

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