WO2005082368A1 - Isoquinoline derivatives and methods of use thereof - Google Patents

Isoquinoline derivatives and methods of use thereof Download PDF

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Publication number
WO2005082368A1
WO2005082368A1 PCT/US2005/006243 US2005006243W WO2005082368A1 WO 2005082368 A1 WO2005082368 A1 WO 2005082368A1 US 2005006243 W US2005006243 W US 2005006243W WO 2005082368 A1 WO2005082368 A1 WO 2005082368A1
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Prior art keywords
alkyl
substituted
halo
membered monocyclic
monocyclic heterocycle
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PCT/US2005/006243
Other languages
French (fr)
Inventor
Prakash Jagtap
Erkan Baloglu
John H. Van Duzer
Csaba Szabo
Andrew L. Salzman
Aloka Roy
William Williams
Alexander Nivorozhkin
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Inotek Pharmaceuticals Corporation
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Application filed by Inotek Pharmaceuticals Corporation filed Critical Inotek Pharmaceuticals Corporation
Priority to CA002557547A priority Critical patent/CA2557547A1/en
Priority to MXPA06009701A priority patent/MXPA06009701A/en
Priority to AU2005216978A priority patent/AU2005216978A1/en
Priority to EA200601558A priority patent/EA200601558A1/en
Priority to JP2007501043A priority patent/JP2007527872A/en
Priority to EP05723909A priority patent/EP1722797A4/en
Priority to BRPI0508233-1A priority patent/BRPI0508233A/en
Publication of WO2005082368A1 publication Critical patent/WO2005082368A1/en
Priority to IL177650A priority patent/IL177650A0/en
Priority to NO20064328A priority patent/NO20064328L/en

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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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Definitions

  • the present invention relates to Isoquinoline Derivatives, compositions comprising an effective amount of a Isoquinoline Derivative and methods for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, cardiovascular disease, reoxygenation injury resulting from organ transplantation, Parkinson's disease, or cancer, comprising administering to an animal in need thereof an effective amount of an Isoquinoline Derivative.
  • Inflammatory diseases such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct from those associated with reperfusion injuries, e.g., stroke and heart attack, and can clinically manifest themselves as different entities.
  • reperfusion injuries e.g., stroke and heart attack
  • cytotoxic free radicals such as nitric oxide and superoxide.
  • NO and superoxide can react to form peroxynitrite (ONOO " ) (Szab ⁇ et al, Shock 6:79-88, 1996).
  • the ONOO " -induced cell necrosis observed in inflammatory disease and in reperfusion injury involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS).
  • PARS nuclear enzyme poly
  • a number of PARS inhibitors have been described in the art. See, e.g., Banasik et al, J. Biol. Chem., 267:1569-75, 1992, and Banasik et al, Mol. Cell.
  • the invention includes a compound of Formula I, Formula Formula II, Formula III, Formula IV or a pharmaceutically acceptable salt thereof (an "Isoquinoline Derivative") as set forth below.
  • Isoquinoline Derivatives are useful for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, cardiovascular disease, reoxygenation injury resulting from organ transplantation, Parkinson's disease, or cancer (each being a "Condition").
  • compositions comprising an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle.
  • methods for treating or preventing a Condition comprising administering to an animal in need of such treatment or prevention an effective amount of an Isoquinoline Derivative.
  • FIG. 1 is a graph showing the effect of compound 81 (mesylate salt) and temozolomide on tumor volume.
  • - ⁇ - control
  • - A- compound 81 (mesylate salt)
  • -x- temozolomide
  • -*- compound 81 (mesylate salt) and temozolomide. 5.
  • the present invention provides Isoquinoline Derivatives according to Formula I, Formula II, Formula III, and Formula IV below: (I) and pharmaceutically acceptable salts thereof, wherein: R 5 is O, NH or S; R 6 is -H or - -C 5 alkyl X is -C(O)-, -CH 2 ⁇ , -CH(halo)-, -CH(OH)-(CH 2 ) resort-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NR ⁇ R 12 )- or -N(SO 2 Y)-, wherein Y is -OH, -NH 2 or -(C C 5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R ⁇ and R 12 are independently -hydrogen or -C 1 -C1 0 alkyl, or N, R ⁇ and R 12 are taken
  • B is -C1-C1 0 alkyl, -C 2 -C ⁇ o alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C 3 -C 8 monocyclic cycloalkyl, -aryl, -NZ 1 Z 2 , -(C1-C 5 alkylene)-NZi,Z 2 , -amino-substituted Ci-C 5 alkyl, -( -C 5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H 2 NC(O)-substituted aryl, -C(O)OH,
  • X is -C(O)-, -CH 2 -, -CH(halo) ⁇ , -CH(OH)-(CH 2 ) n -, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S- or -CH(NR ⁇ R 12 )-, wherein n is an integer ranging from 0-5.
  • R 5 is O.
  • R 5 is S.
  • R 5 is NH.
  • X is -N(SO 2 Y)-.
  • A is -SO 2 - or -SO 2 NH-.
  • B is -C1-C1 0 alkyl, -C 2 -Cio alkenyl, -3- to 7-membered monocyclic heterocycle, -7- to 10-membered bicyclic heterocycle, -C 3 -C 8 monocyclic cycloalkyl, -aryl, -NZ 1 Z 2 , -amino-substituted -C 5 alkyl, -( -C 5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H 2 NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C C 5 alkyl) or -C(O)O-phenyl, each of which, other than -NZ ⁇ Z 2 , -C(O)OH, or -C(NH)NH 2 , is unsubstituted or substituted with one or more of -O-(C ⁇ -C 5 alkyl,
  • R ⁇ R t are hydrogen.
  • at least one of Ri , R 2 , R 3 , R 4 , R , R 8 , R and R ⁇ is other than hydrogen.
  • one of R 7 -R 10 is -NHC(O)-(CH 2 ) n -OAc or -NHC(O)-(CH 2 ) n -
  • R 5 and X in a compound of formula (I) are as set forth below:
  • the compounds of Formula (I) have the Formula (la):
  • the compounds of Formula (la) are those wherein R 8 is -H, R 9 is -A-B, A is -SO 2 - and B is -NZ . Z 2 or -( -C 5 alkylene)NZiZ 2 .
  • the compounds of Formula (I) have the Formula (lb):
  • the compounds of Formula (I) have the Formula (Ic):
  • the compounds of Formula (I) have the Formula (Id): (Id) where B is as defined above for the compounds of Formula (I).
  • B is or -(C1-C5 alkylene)-NZ 1 Z 2 , or -(C1-C5 alkylene) substituted with -NH 2 or -OH.
  • the invention also relates to compounds of Formula II:
  • R 6 is -H or -C5 alkyl
  • Ri is -hydrogen, -halo, -C1-C 10 alkyl, -halo-substituted -C5 alkyl, -C 2 -C 10 alkenyl, -C 3 -C 8 monocyclic cycloalkyl, -aryl, -NH 2 , -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(d-C 5 alkyl), -NO 2 or -A'-B';
  • A' is -SO 2 -, -SO 2 NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, alkyl)-, -NH-, -(CH 2 )-, -S- or -C(S)-;
  • B is -hydrogen, -hal
  • Zi and Z 2 are independently -H or -C1- 0 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z 3 )(Z ), where Z 3 and Z 4 are independently, -H or -C1-C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH 2 ; or N, Z 3 and Z 4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z 2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
  • B is a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
  • Ri is -hydrogen, -halo, -d-Cio alkyl, -halo- substituted Ci-C 5 alkyl, -C 2 -C 10 alkenyl, -C 3 -C 8 monocyclic cycloalkyl, -aryl, -NH 2 , - amino-substituted C1-C 5 alkyl, -C(O)OH, -C(O)O(Ci-C 5 alkyl), -NO 2 or -A'-B';
  • A' is -SO 2 -, -SO 2 NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
  • B' is -C 1 -C 10 alkyl, -C 2 -C 10 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C 3 -C 8 monocyclic cycloalkyl, -aryl, -amino- substituted Ci-C 5 alkyl, -C 1 -C 5 alkyl-(3- to 7-membered monocyclic heterocycle), - H 2 NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C ⁇ -C 5 alkyl), -C(O)O-phenyl or -NZ ⁇ Z 2 .
  • At least one of R l5 R 2 , R 3 , R ⁇ R 7 , R 8 , R and R 10 is not hydrogen. In another embodiment, at least one of R 2 , R and Rio is other than hydrogen. In one embodiment, A is other than -CONH-
  • the invention also relates to compounds of Formula III:
  • X is -CH 2 - or -O-;
  • R 2 and R 3 are independently -hydrogen, -halo, -halo-substituted Q-C 5 alkyl, -hydroxy, -O-(C ⁇ -C 5 alkyl), -C 1 -C 5 alkyl, -NO 2 , -NH 2 , -CONH 2 , -C(O)OH, -OC(O)-C!-C 5 alkyl or -C(O)O-C ⁇ -C 5 alkyl;
  • R 8 and R are independently -hydrogen or -A-B;
  • A is -SO 2 -, -SO 2 NH- or -NHCO-;
  • B is -Ci-Cs alkyl, -NZiZ ⁇ , -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted
  • -X- is -CH 2 -. In another embodiment, -X- is -O-.
  • R 8 is hydrogen and R 9 is -A-B. In another embodiment, R 8 is -A-B and R 9 is hydrogen. In one embodiment, either R 8 is hydrogen and R 9 is -A-B, or R 8 is -A-B and R 9 is hydrogen.
  • R 2 , R 3 and R 8 are hydrogen and R is -A-B, wherein A is -SO 2 - or -SO 2 NH-. In a further embodiment, at least one of R 2 , R 3 , R 8 and R is not hydrogen.
  • the invention further relates to compounds of Formula 13:
  • Ri, R 2 , R 3 , R- t , R 7 , R 8 , R 9 and Rio are independently -hydrogen, -halo, -hydroxy
  • A is -SO 2 -, -SO 2 NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-,
  • B is -Ci-Cio alkyl, -C 2 -Cio alkenyl, -3- to 7-membered monocyclic heterocycle, -
  • R 9 is -A-B, wherein -A- is -SO 2 - or -SO 2 NH-.
  • Ri- t are each hydrogen.
  • at least one of Ri, R 2 , R 3 , R., R , R 8 , R 9 and Rio is other than hydrogen.
  • A is other than -CONH-.
  • the invention further still relates to compounds of Formula 22:
  • Ri-E and R 7 -Rio are as defined above for Formula 13.
  • R is -A-B, wherein -A- is -SO 2 - or -SO 2 NH-
  • Ri-Ri are each hydrogen.
  • at least one of Ri, R 2 , R , P ⁇ , R7, Rs. R9 and Rio is other than hydrogen.
  • the invention further still relates to compounds of Formula 37:
  • Ri-R t and R 7 -R 10 are as defined above for Formula 13.
  • R 1 -R 4 are each hydrogen.
  • R 9 is -A-B, wherein -A- is -SO 2 - or -SO 2 NH-.
  • at least one of Ri, R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and Rio is other than hydrogen.
  • the invention also relates to compounds of Formula 40:
  • Ri-R t and R 7 -R 10 are as defined above for Formula 13.
  • Ri- ⁇ are each hydrogen.
  • R 9 is -A-B, wherein -A- is -SO 2 - or -SO 2 NH-.
  • at least one of Ri, R 2 , R 3 , R t , R , R 8 , R 9 and Rio is other than hydrogen.
  • the invention further relates to compounds of Formula (IV):
  • R ⁇ 3 and R ⁇ 6 are hydrogen; one of the R ⁇ and R 15 groups is -NHC(O)-(CH 2 ) n -NZ ⁇ Z 2 , and the other group is - hydrogen; Zi and Z 2 are independently -H or -Q-C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z 3 )(Z 4 ), where Z 3 and Z are independently, -H or -C 1 -C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH 2 ; or N, Z 3 and Z 4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and ⁇ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-
  • R u is -NHC(O)-(CH 2 ) n -NZ ⁇ Z 2 and R ⁇ 3 , R 15 , and R 16 are each hydrogen.
  • R 15 is -NHC(O)-(CH 2 ) n -NZ ⁇ Z 2 and R i3 , R 14 , and R ⁇ 6 are each hydrogen.
  • n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In one embodiment, n is 4. In another embodiment, n is 5.
  • Illustrative examples of the compounds of Formula (IV) include the compounds of Formula (IVa):
  • the compound of Formula (IVa) is:
  • Illustrative examples of the compounds of Formula (IV) also include the compounds of Formula (IVb):
  • Additional illustrative compounds of Formula (IV) include compounds 43, 45, and 97-109, above, and pharmaceutically acceptable salts thereof.
  • C 1 -C5 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms.
  • Examples of a C 1 -C 5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
  • C ⁇ -C 8 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-8 carbon atoms.
  • Examples of a C ⁇ -C 8 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl and isooctyl.
  • C1-C 1 0 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-10 carbon atoms.
  • Examples of a C 1 -Q0 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl.
  • C 2 -C ⁇ o alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms and at least one double bond.
  • Examples of a C 2 -C ⁇ o alkenyl group include, but are not limited to, ethylene, propylene, 1 -butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3- hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4- octene, 1-nonene, 2-nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene.
  • C 2 -C ⁇ o alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms and at least one triple bond.
  • Examples of a C 2 -Cio alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3-nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-de
  • C1-C 5 alkylene refers to a C 1 -C 5 alkyl group in which one of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with a bond.
  • Examples of a -C 5 alkylene include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • Halo-substituted C 1 -C 5 alkyl refers to a -C 5 alkyl group, as defined above, wherein one or more of the C1-C 5 alkyl group's hydrogen atoms has been replaced with - F, -CI, -Br or -I.
  • alkylhalo group include, but are not limited to, -CH 2 F, -CC1 3 , -CF 3 , -CH 2 C1, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F,
  • C1 -CH 2 CH 2 CH 2 C1 -CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(C1)CH 2 CH 3 , -CH(F)CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 C1).
  • “Amino-substituted C 1 -C 5 alkyl” refers to a C 1 -C 5 alkyl group, as defined above, wherein one or more of the -C5 alkyl group's hydrogen atoms has been replaced with -NH 2 .
  • an amino-substituted C1-C 5 alkyl group include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(NH 2 )CH 3 , -CH 2 CH(NH 2 )CH 2 CH 3 , -CH(NH 2 )CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 NH 2 ).
  • “Aryl” refers to a phenyl or pyridyl group.
  • an aryl group examples include, but are not limited to, phenyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • An aryl group can be unsubstituted or substituted with one or more of the following groups: -C 1 -C 5 alkyl, halo, -halo-substituted -C 5 alkyl, hydroxy, -O-C1-C5 alkyl, -N(R a ) 2 , -COOH, -C(O)O-(C ⁇ -C 5 alkyl), -OC(O)-(d-C 5 alkyl), -C(O)NH 2 , or -NO 2 , wherein each occurrence of R a is independently -H or C 1 - 0 alkyl, "NH C(O)-substituted aryl" refers to an aryl group, as defined above, wherein one of the ary
  • Representative examples of a -NH 2 C(O)-substituted aryl group include 2-C(O)NH 2 -phenyl, 3-C(O)NH 2 -phenyl, 4-C(O)NH 2 -phenyl, 2-C(O)NH 2 -pyridyl, 3-C(O)NH 2 -pyridyl and 4-C(O)NH 2 -pyridyl.
  • -(C 1 -C 5 alkyl)-(3- to 7-membered monocyclic heterocycle) refers to a C 1 -C 5 alkyl group, as defined above, wherein one of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with a -3- to 7-membered monocyclic heterocycle.
  • Representative examples of a -(C1-C5 alkyl)-(3- to 7-membered monocyclic heterocycle) group include, but are not limited to, -CH 2 CH 2 -morpholine, -CH CH 2 -piperidine, -CH 2 CH 2 CH 2 - morpholine and -CH 2 CH 2 CH 2 -imidazole.
  • Hydro-substituted C 1 -C 5 alkyl refers to a C1-C5 alkyl group, as defined above, wherein one of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with a hydroxyl group.
  • an alkanol group include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 , -CH 2 CH(OH)CH 2 CH 3 , -CH(OH)CH 2 CH 3 and -C(CH 3 ) 2 CH 2 OH.
  • An "Arylene” group is a phenyl group in which one of the phenyl group's hydrogen atoms has been replaced with a bond.
  • An arylene group can bein an ortho, meta, or para configuration and can be unsubstituted or independently substituted with one or more of the following groups: -C 1 -C 5 alkyl, halo, hydroxy, -O-C 1 -C5 alkyl, -N(R a ) 2 , -COOH, -halo-substituted C 1 -C 5 alkyl, -C(O)O-(d-C 5 alkyl), -OC(O)-(C ⁇ -C 5 alkyl), -C(O)NH 2 or -NO 2 , wherein each occurrence of R a is independently -H or Q-C10 alkyl.
  • a "C 3 -C 8 monocyclic cycloalkyl” is a non-aromatic, saturated hydrocarbon ring containing 3-8 carbon atoms.
  • Representative examples of a C 3 -C 8 monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a C 3 -C 8 monocyclic cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: -Q-C5 alkyl, halo, - halo-substituted C 1 -C 5 alkyl, hydroxy, -O-C 1 -C 5 alkyl, -N(R a ) 2 , -COOH, -C(O)O-(d-C 5 alkyl), -OC(O)-(d-C 5 alkyl), -C(O)NH 2 , or -NO 2 , wherein each occurrence of R a is independently -H or C 1 -C 10 alkyl.
  • a "3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7- membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the 3- to 7- membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • 3- to 7-membered monocyclic heterocycle group include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, and pyrimidinyl.
  • a "7- to 10-membered bicyclic heterocycle” refers to a bicyclic 7- to 10- membered aromatic or non-aromatic bicyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the 7- to 10-membered bicyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • a 7- to 10-membered bicyclic heterocycle group include, but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl.
  • a "nitrogen-containing 3- to 7-membered monocyclic heterocycle” refers to a 3- to 7-membered monocyclic heterocycle, defined above, which contains at least one ring nitrogen atom.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative examples of nitrogen- containing-3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, and morpholinyl.
  • “Halo” is -F, -CI, -Br or -I.
  • An "animal” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, an animal is a human.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 - disulfonate), benzenesulfonate, benzonate, besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactate, lactate, lactate
  • a hydrate is another example of a pharmaceutically acceptable salt.
  • An "effective amount" when used. in connection with an Isoquinoline Derivative is an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting PARS in an in vivo or an in vitro cell.
  • An "effective amount” when used in connection with another anticancer agent is an amount that is effective for treating or preventing cancer alone or in combination with an Isoquinoline Derivative.
  • “In combination with” includes administration within the same composition and within separate compositions. In the latter instance, the anticancer agent is administered during a time when the Isoquinoline Derivative exerts its prophylactic or therapeutic effect, or vr ' ce versa.
  • the invention also includes methods for inhibiting PARS in a cell.
  • PARS which is also known as poly(ADP-ribose)synthetase, PARP ((poly(ADP-ribose) polymerase, PARP-1 , EC 2.4.99) and ADP-ribosyltransferase (ADPRT, EC 2.4.2.30)
  • PARP poly(ADP-ribose) polymerase, PARP-1 , EC 2.4.99
  • ADP-ribosyltransferase ADPRT, EC 2.4.2.30
  • the method comprises contacting a cell with an Isoquinoline Derivative in an amount effective to inhibit PARS in the cell.
  • any cell having, or capable of having, PARS activity or capable of expressing PARS can be used.
  • the cell can be provided in any form.
  • the cell can be provided in vitro, ex vivo, or in vivo.
  • PARS activity can be measured using any method known in the art, e.g., methods as described in Banasik et al, J. Biol. Chem. 267:1569-75 (1991).
  • Illustrative examples of cells capable of expressing PARS include, but are not limited to, muscle, bone, gum, nerve, brain, liver, kidney, pancreas, lung, heart, bladder, stomach, colon, rectal, small intestine, skin, esophageal, eye, larynx, uterine, ovarian, prostate, tendon, bone marrow, blood, lymph, testicular, vaginal and neoplastic cells.
  • the Isoquinoline Derivatives are administered to an animal in need of treatment or prevention of a Condition.
  • Isoquinoline Derivatives can be used to treat an inflammatory disease.
  • Inflammatory diseases can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation.
  • inflammatory diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, organ transplant rejection; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy
  • Huntington's disease amyotrophic lateral sclerosis and viral or autoimmune encephalitis; diabetic complications, including, but not limited to, immune-complex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, and brain and spinal cord trauma.
  • SLE systemic lupus erythematosus
  • the inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the inflammatory disease is the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.
  • the Isoquinoline Derivatives can be used to treat a reperfusion injury.
  • Reperfusion refers to the process whereby blood flow in the blood vessels is resumed following ischemia, such as occurs following constriction or obstruction of the vessel.
  • Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction, stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked.
  • reperfusion injuries treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury, and reperfusion injury resulting from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery, or hemorrhagic shock.
  • the reperfusion injury results from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery or hemorrhagic shock. 5.2.3. Treatment or Prevention of a Reoxygenation Injury Resulting from Organ Transplantation
  • the reperfusion injury is a reoxygenation injury resulting from organ transplantation.
  • reoxygenation injuries treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, transplantation of the following organs: heart, lung, liver, kidney, pancreas, intestine, and cornea.
  • a reoxygenation injury resulting from organ transplantation occurs during the organ transplantation.
  • the Isoquinoline Derivatives can be used to treat an ischemic condition.
  • ischemic conditions treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
  • the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.
  • the Isoquinoline Derivatives can be used to treat or prevent renal failure.
  • the renal failure is chronic renal failure.
  • the renal failure is acute renal failure.
  • the Isoquinoline Derivatives can be used to treat or prevent a vascular disease other than a cardiovascular disease.
  • vascular diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, and lipedema.
  • the Isoquinoline Derivatives can be used to treat or prevent a cardiovascular disease.
  • cardiovascular diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, chronic heart failure, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, cardiac transplant, myocardial infarction, and a cardiac arrhythmia, such as atrial fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia.
  • the cardiovascular disease is chronic heart failure.
  • the cardiovascular disease is a cardiac arrhythmia.
  • the cardiac arrhythmia is atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia.
  • the Isoquinoline Derivatives can be used to treat or prevent diabetes mellitus or its complications.
  • diabetes treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by ⁇ -cell toxins.
  • the Isoquinoline Derivatives can be used to treat or prevent a diabetic complication.
  • diabetes mellitus or its complications that are treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy, (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathies
  • the Isoquinoline Derivatives can be used to treat or prevent Parkinson's disease.
  • the Isoquinoline Derivatives can be used to treat or prevent cancer.
  • Examples of cancers treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, the cancers disclosed below in Table 1 and metastases thereof.
  • Solid tumors including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer esophageal cancer stomach cancer oral cancer nasal cancer throat cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile duct carcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumor cervical cancer uter
  • CNS and brain cancers glioma pilocytic astrocytoma astrocytoma anaplastic astrocytoma glioblastoma multiforme medulloblastoma craniopharyngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma meningioma vestibular schwannoma adenoma metastatic brain tumor meningioma spinal tumor medulloblastoma
  • the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, a non-Hodgkin's lymphoma, a skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • the cancer is metastatic cancer.
  • the animal has previously undergone or is presently undergoing treatment for cancer. Such previous treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
  • the Isoquinoline Derivatives are also useful for the treatment or prevention of a cancer caused by a virus.
  • viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez- Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al, J Pafhol (2003) 199(2): 140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al, Leukemia (2003) 17(l):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see,
  • the Isoquinoline Derivatives can also be administered to prevent the progression of a cancer, including but not limited to the cancers listed in Table 1.
  • Such prophylactic use includes that in which non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred.
  • the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from an animal, can indicate the desirability of prophylactic/therapeutic administration of the Isoquinoline Derviatives.
  • Such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype).
  • leukoplakia a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ, are treatable or preventable according to the present methods.
  • fibrocystic disease cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia)
  • an animal that exhibits one or more of the following predisposing factors for malignancy can be administered an amount of a Isoquinoline Derivative which is effective to treat or prevent cancer: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14;18) for foUicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine
  • the present methods for treating cancer or preventing cancer further comprise administering another anticancer agent.
  • the present invention provides methods for treating or preventing cancer in a subject, the method comprising the administration of an effective amount of: (i) an Isoquinoline Derivative and (ii) another anticancer agent.
  • an Isoquinoline Derivative and (ii) another anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • an Isoquinoline Derivative and (ii) another anticancer agent act synergistically and are administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the dosage of the (i) an Isoquinoline Derivative, and (ii) another anticancer agent administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion.
  • An Isoquinoline Derivative can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent to a subject in need thereof.
  • an Isoquinoline Derivative and (ii) another anticancer agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart.
  • i) an Isoquinoline Derivative, and (ii) another anticancer agent are administered with 3 hours.
  • an Isoquinoline Derivative and (ii) another anticancer agent are administered 1 minute to 24 hours apart.
  • an effective amount of an Isoquinoline Derivative and an effective amount of another anticancer agent are present in the same composition.
  • this composition is useful for oral administration.
  • this composition is useful for intravenous administration.
  • Cancers that can be treated or prevented by administering an Isoquinoline Derivative and another anticancer agent include, but are not limited to, the list of cancers set forth in Table 1.
  • the cancer is brain cancer.
  • the brain cancer is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme or a metastatic brain cancer.
  • the cancer is melanoma.
  • the cancer is metastatic melanoma.
  • the Isoquinoline Derivative and the other anticancer agent can act additively or synergistically.
  • a synergistic combination of an Isoquinoline Derivative and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the Isoquinoline Derivatives and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer.
  • a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.
  • an Isoquinoline Derivative and another anticancer agent act synergistically when administered in doses typically employed when such agents are sued as monotherapy for the treatment of cancer.
  • an Isoquinoline Derivative and another anticancer agent act synergistically when administered in doses that are less than doses typically employed when such agents are used as monotherapy for the treatment of cancer.
  • the administration of an effective amount of an Isoquinoline Derivative and an effective amount of another anticancer agent inhibits the resistance of a cancer to the other anticancer agent.
  • the cancer is a tumor.
  • Suitable other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to temozolomide, a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docet
  • BCNU Carmustine
  • CCNU Lomustine
  • Alkylsulphonates Busulfan Treosulfan
  • Triazenes dacarbazine Procarbazine Temozolomide
  • Plant Alkaloids Vinca alkaloids Vincristine Vinblastine Nindesine Vinorelbine
  • Taxoids Paclitaxel Docetaxel
  • Mitomycins Mitomycin C Anti-metabolites
  • DHFR inhibitors Methotrexate Trimetrexate
  • IMP dehydrogenase Inhibitors Mycophenolic acid Tiazofurin Ribavirin EICAR
  • Cytosine analogs Cytarabine (ara C) Cytosine arabinoside Fludarabine Gemcitabine Capecitabine
  • DNA Antimetabolites 3-HP 2'-deoxy-5-fluorouridine 5-HP alpha-TGDR aphidicolin glycinate ara-C 5-aza-2'-deoxycytidine beta-TGDR cyclocytidine guanazole inosine glycodialdehyde macebecin II Pyrazoloimidazole
  • Hormonal therapies Receptor antagonists: Anti-estrogen: Tamoxifen Raloxifene Megestrol
  • Vitamin A derivative All-trans retinoic acid (ATRA-IV) Vitamin D3 analogs: EB 1089 CB 1093 KH 1060
  • Cytokines Interferon- ⁇ Interferon- ⁇ Interferon- ⁇ Tumor necrosis factor Interleukin-2
  • Angiogenesis Inhibitors Angiostatin (plasminogen fragment) antiangiogenic antithrombin HI Angiozyme ABT-627 Bay 12-9566 Benefin Bevacizumab BMS-275291 cartilage-derived inhibitor (CDI)
  • ribonuclease inhibitor Plasminogen activator inhibitor Platelet factor-4 (PF4) Prinomastat Prolactin 16kD fragment Proliferin-related protein (PRP) PTK 787/ZK 222594 Retinoids Solimastat Squalamine SS 3304 SU 5416 SU6668 SU11248 Tetrahydrocortisol-S Tetrathiomolybdate Thalidomide Thrombospondin-1 (TSP-1) TNP-470 Transforming growth factor-beta (TGF-b) Vasculostatin Vasostatin (calreticulin fragment) ZD6126 ZD 6474 famesyl transferase inhibitors (FTI) Bisphosphonates Antimitotic agents: Allocolchicine Halichondrin B Colchicine colchicine derivative dolstatin 10 Maytansine Rhizoxin Thiocolchicine trityl cysteine Others: Isoprenylation inhibitors: Dopaminergic neurotoxins: l-
  • anticancer agents that can be used in the compositions and methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin;
  • anticancer drugs that can be used in the methods and compositions of the invention include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-
  • the other anticancer agent is interferon- ⁇ . In another embodiment, the other anticancer agent is interleukin-2. In one embodiment, the other anticancer agent is an alkylating agent, such as a nitrogen mustard, a nitrosourea, an alkylsulfonate, a triazene, or a platinum-containing agent. In another embodiment, the other anticancer agent is a triazene alkylating agent. In a specific embodiment, the other anticancer agent is temozolomide.
  • Temozolomide can be administered to a subject at dosages ranging from about 60 mg/m 2 (of a subject's body surface area) to about 250 mg/m 2 and from about 100 mg/m 2 to about 200 mg/m 2 .
  • the dosages of temozolomide are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg
  • temozolomide is administered orally. In one embodiment, temozolomide is administered orally to a subject at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 . In another embodiment, temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 on days 1-5, then again orally once per day for five consecutive days on days 28- 32 at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 , then again orally once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • the other anticancer agent is procarbazine.
  • Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m 2 (of a subject's body surface area) to about 100 mg/m 2 and from about 60 mg/m 2 to about 100 mg/m 2 .
  • the dosages of procarbazine are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 0 0 0 0 mg/m , about 90 mg/m , about 100 mg/m , about 110 mg/m , about 120 mg/m , about 0 0 0 0 0 0 0 0
  • procarbazine is administered intravenously.
  • procarbazine is administered intravenously to a subject at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m to about 100 mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered intravenously to a subject once at a dose ranging from about 50 mg/m 0 to about 100 mg/m 0.
  • the other anticancer agent is dacarbazine.
  • dacarbazine can be administered to a subject at dosages ranging from about 60 0 0 0 mg/m (of a subject's body surface area) to about 250 mg/m and from about 150 mg/m to about 250 mg/m 2 .
  • the dosages of dacarbazine are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 o o o mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m/m
  • dacarbazine is administered intravenously. In one embodiment, dacarbazine is administered intravenously to a subject at a 0 0 dose ranging from about 150 mg/m to about 250 mg/m . In another embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 250 mg/m on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • dacarbazine is administered intravenously to a subject once at 0 0 a dose ranging from about 150 mg/m to about 250 mg/m .
  • the other anticancer agent is a Topoisomerase I inhibitor, such as etoposide, teniposide, topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or crisnatol.
  • the other anticancer agent is irinotecan. Irinotecan can be administered to a subject at dosages ranging from about 50 mg/m 2 (of a subject's body surface area) to about 150 mg/m 2 and from about 75 mg/m 2 to about 150 mg/m 2 .
  • the dosages of irinotecan are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 0 0 0 0 mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 0 0 0 0 mg/m , about 90 mg/m , about 100 mg/m , about 110 mg/m , about 120 mg/m , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg/m 2 , about 210 mg/m 2 , about 220 mg/m , about 230 mg/m , about 240 mg/m , about 250 mg/m , about 260
  • irinotecan is administered intravenously.
  • irinotecan is administered intravenously to a subject at a dose 0 0 ranging from about 50 mg/m to about 150 mg/m .
  • irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 .
  • irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days 0 0 on days 28-32 at a dose ranging from about 50 mg/m to about 150 mg/m , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 .
  • the invention provides administration of an effective amount of: (i) an Isoquinoline Derivative (ii) one or more other anticancer agents.
  • an Isoquinoline Derivative and (ii) one or more other anticancer agents are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • an Isoquinoline Derivative and (ii) one or more other anticancer agents act synergistically and are administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the dosage of the (i) an Isoquinoline Derivative and (ii) one or more other anticancer agents administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion.
  • the other anticancer agent is O-6-benzylguanine. In another embodiment, the other anticancer agent is O-6-benzylguanine and temozolomide. In another embodiment, the other anticancer agent is O-6-benzylguanine and procarbazine. In still another embodiment, the other anticancer agent is O-6-benzylguanine and dacarbazine. 5.2.10.2. Multi-Therapy For Cancer The Isoquinoline Derivatives can be administered to an animal that has undergone or is currently undergoing one or more additional anticancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines.
  • the invention provides methods for treating or preventing cancer comprising administering to an animal in need thereof (a) an amount of a Isoquinoline Derivative effective to treat or prevent cancer; and (b) another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
  • the other anticancer therapy is radiation therapy.
  • the other anticancer therapy is surgery.
  • the other anticancer therapy is immunotherapy.
  • the present methods for treating or preventing cancer comprise administering an Isoquinoline Derivative and radiation therapy.
  • the radiation therapy can be administered concurrently with, prior to, or subsequent to the Isoquinoline Derivative, in one embodiment, at least an hour, five hours, 12 hours, a day, a week, a month, in another embodiment, several months (e.g., up to three months), prior or subsequent to administration of the Isoquinoline Derivatives.
  • the other anticancer therapy is radiation therapy
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • X-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeN energy) can be used for deep tumors, and electron beam and orthovoltage X-ray radiation can be used for skin cancers.
  • Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
  • the invention provides methods of treatment of cancer using an Isoquinoline Derivative as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy results in negative side effects, in the subject being treated.
  • the subject being treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy.
  • the Isoquinoline Derivative can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants.
  • the invention also includes pharmaceutical compositions useful for treating or preventing a Condition.
  • the compositions are suitable for internal use and comprise an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle.
  • the Isoquinoline Derivatives can be administered in amounts that are effective to treat or prevent a Condition in an animal.
  • Administration of the Isoquinoline Derivatives can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. In some instances, administration will result in the release of an Isoquinoline Derivative into the bloodstream.
  • the Isoquinoline Derivatives are administered orally.
  • the compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle.
  • Illustrative carriers or vehicles include a) a diluent, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the Isoquinoline Derivative is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • the Isoquinoline Derivatives can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the Isoquinoline Derivatives can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564.
  • Isoquinoline Derivatives can also be delivered by the use of monoclonal antibodies as individual carriers to which the Isoquinoline Derivative molecules are coupled.
  • the Isoquinoline Derivatives can also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • Isoquinoline Derivatives can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drag, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Parental injectable administration can be used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • compositions for parenteral administration employs the implantation of a slow-release or sustained-released system, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.
  • the compositions can be sterilized or contain non-toxic amounts of adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate. In addition, they can also contain other therapeutically valuable substances.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, preferably from about 1% to about 70% of the Isoquinoline Derivative by weight or volume.
  • the dosage regimen utilizing the Isoquinoline Derivative can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the animal; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the animal; and the particular Isoquinoline Derivative employed.
  • a person skilled in the art can readily determine and prescribe the effective amount of the drag useful for treating or preventing a Condition.
  • Effective dosage amounts of the Isoquinoline Derivatives when administered to an animal, range from about 0.05 to about 1000 mg of Isoquinoline Derivative per day.
  • Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of Isoquinoline Derivative.
  • the compositions are in the form of a tablet that can be scored.
  • Effective plasma levels of the Isoquinoline Derivatives can range from about 0.002 mg to about 50 mg per kg of body weight per day.
  • the amount of an Isoquinoline Derivative that is effective in the treatment or prevention of a Condition can be determined by clinical techniques that are known to those of skill in the art.
  • in vitro and in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each patient's circumstances in view of, e.g., published clinical studies.
  • Suitable effective dosage amounts can range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours.
  • the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours.
  • Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one Isoquinoline Derivative is administered, the effective dosage amounts correspond to the total amount administered.
  • the dosage regimen utilizing the Isoquinoline Derivative can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular Isoquinoline Derivative employed.
  • a person skilled in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the Condition.
  • Isoquinoline Derivatives can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.
  • Isoquinoline Derivatives can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of Isoquinoline Derivative ranges from about 0.1% to about 15%, w/w or w/v.
  • the compositions comprise an amount of each of an intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of I
  • Isoquinoline Derivative and another anticancer agent which together are effective to treat or prevent cancer.
  • the amount of Isoquinoline Derivative and another anticancer agent is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition.
  • Some oral compositions can comprise from about 4% to about 50% of an Isoquinoline Derivative and another anticancer agent.
  • Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition.
  • the Isoquinoline Derivatives can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered an Isoquinoline Derivative.
  • the other prophylactic or therapeutic agent is administered in an effective amount.
  • the other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovasculare disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-renal failure agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-diabetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-cardiovascular disease agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. In one embodiment of the invention, where, another therapeutic agent is administered to a subject, the effective amount of the Isoquinoline Derivative is less than its effective amount would be where the other therapeutic agent is not administered.
  • Anti-inflammatory agents useful in the methods of the present invention include but are not limited to adrenocorticosteroids, such as cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methyl ⁇ rednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam,
  • NSAIDs non-steroidal anti-inflammatory agents
  • Anti-renal failure agents useful in the methods of the present invention include include but are not limited to ACE (angiotensin-converting enzyme) inhibitors, such as captopril, enalaprilat, lisinopril, benazepril, fosinopril, trandolapril, quinapril, and ramipril; diuretics, such as mannitol, glycerin, furosemide, toresemide, tripamide, chlorothiazide, methyclothiazide, indapamide, amiloride, and spironolactone; and fibric acid agents, such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.
  • ACE angiotensin-converting enzyme
  • Anti-diabetic agents useful in the methods of the present invention include include but are not limited to glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and -glucosidase inhibitors, such as acarbose and miglitol.
  • Anti-cardiovascular disease agents useful in the methods of the present invention include include but are not limited to carnitine; thiamine; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine.
  • Antiemetic agents useful in the methods of the present invention include include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.
  • Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.
  • Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
  • kits that can simplify the administration of an
  • kits of the invention comprises a unit dosage form of an Isoquinoline Derivative.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle.
  • the kit can further comprise a label or printed instructions instracting the use of the Isoquinoline Derivative to treat or prevent a Condition.
  • the kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent.
  • kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
  • R 4-CH 2 C0 2 Me-piperazine-1 -yl r.
  • R -N(CH 2 CH 2 OH) a c.
  • R 4-(CH 2 CH 2 OH)-piperazine-1-yl s.
  • R -NHCH 2 CH 2 CN d.
  • R imidazole-1-yl t.
  • R -NHC(NH)NH 2 e.
  • R L-prolinol u.
  • R -NH[4-(1 ,2,4-triazole)] f.
  • R morpholine-4-yl V.
  • R -NH[4-(morp ⁇ o//n-4-y/)phenyl] g-
  • R NHCH 2 CH 2 NMe 2 w.
  • R ⁇ NHCH 2 CH 2 (4-N-benzylpiperidine) h.
  • R NHCH 2 CH 2 -piperidine-1 -yl
  • R -NHCH 2 CH 2 (2-thienyl) i.
  • R NHCH 2 CH 2 N-(pyridine-2-yl) y-
  • R -NH[1 -(4-azabenzimidazole)] i-
  • R NHCH 2 CH 2 -morpholine-4-yl z.
  • R -NH[1-(4-(2'-pyridyl)piperazine)] k.
  • R -NH[1-(4-benzlpiperazine)] 1.
  • R NHCH 2 CH 2 CH 2 -morpholine-4-yl ac.
  • R -NH 2 m.
  • R NHCH 2 CH 2 CH 2 -(tetrahydropyrrolidine-1-yl) ad. .
  • R -NHCH 2 CH 2 Ph n.
  • R NHCH 2 CH 2 CH 2 -imidazole-1 -yl ae. .
  • R -NHCH 2 CH 2 [4-OMe(phenyl)] 0.
  • R NHCH 2 CH 2 CH 2 -(4-methylpiperazine-1-yl) af.
  • R -NHC(0)(morp/)o/ ⁇ -4-y/)
  • P- R N(CH 2 CH 2 NEt 2 ) 2 5,6-dihydro-5,ll-diketo-llH-isoquinoline (2) was prepared by reacting compound 1 (Aldrich Chemical, Milwaukee, WI) with ammonia in methanol.
  • ( ⁇ ) ll-hydroxy-5,6-dihydro-5-oxo-HH-indeno[l,2-c]isoquinoline (3a) was prepared by reacting 2 with NaB ⁇ 4 in ethanol.
  • ( ⁇ ) ll-hydroxy-ll-methyl-5,6-dihydro-5-oxo-HH-isoquinoline (3b) was prepared by reacting 2 with MeMgl.
  • ( ⁇ ) 11-hydroxy-l l-(m-methoxyphenyl)-5,6-dihydro-5-oxo-l l ⁇ -indeno[l,2- c]isoquinoline (3c) was prepared from 2 using m-MeO-C 6 H 4 MgI.
  • (+) ll-N-(morpholino-4-yl)-5,6-dihydro-5-oxo- HH-indeno[l,2-c]isoquinoline (5e) was also prepared from ( ⁇ ) ll-bromo-5,6-dihydro-5- oxo-1 lH-indeno[l,2-c]isoquinoline (4b).
  • 5,6-Dihydro-5-oxo-llH-indeno-[l,2-c]isoquinoline (6) is prepared by reduction of 5,6-dihydro-5,l 1-diketo-l l ⁇ -isoquinoline (2) or ( ⁇ ) 1 l-hydroxy-5,6-dihydro5-oxo-l 1 ⁇ -isoquinoline (3a) using CF 3 COO ⁇ /triethylsilane.
  • Scheme 2 illustrates a method useful for making terminal carboxylic acid compounds of formulas 8ag-8ao. This method comprises reacting sulfonyl chloride 7 with the alkyl ester of an amino acid in the presence of a base, such as triethyamine, to provide an intermediate terminal carboxylic acid alkyl ester, which is then hydrolyzed using a base such as sodium hydroxide to provide the corresponding terminal carboxylic acid.
  • a base such as triethyamine
  • R -NHCH 2 COOH ah.
  • R -NH(CH 2 ) 2 COOH ai.
  • R -NH(CH 2 ) 3 COOH aj.
  • R -NH(CH 2 ) 4 COOH ak.
  • R -NH(CH 2 ) 5 COOH al.
  • R -NHCH(CH 2 COOH)COOH am.
  • R -NHCH((CH 2 ) 2 COOH)COOH an.
  • R -NHCH((CH 2 ) 4 NH 2 )COOH ao.
  • R -NHCH(CH 2 OH)COOH wherein: R' is -amino-substituted C1-C 5 alkyl or -hydroxy-substituted C ⁇ -C 5 alkyl R" is -C ⁇ -C 6 alkyl; and n is an integer ranging from 1 to 6.
  • Isoquinoline Derivatives of general formula 13 can be made by a method comprising contacting a compound of formula 11 and a compound of formula 12 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 13.
  • R R4 and R -R 1 o are as defined above for formula (I); and R b is -CI, -Br, -I, -OMs, -OTs or -OTf.
  • R D is -Br. In another embodiment, Rb and R_ are both -Br. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula
  • Suitable bases for use in the method of Scheme 3 are organic bases such as triethylamine, lithium N-diisopropylamide, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates, including sodium carbonate, potassium carbonate and cesium carbonate.
  • the base is triethylamine.
  • the base is potassium carbonate.
  • the method of Scheme 3 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.
  • the solvent is acetonitrile. In another embodiment, the solvent is DMF. In still another embodiment, where the solvent is not water, the solvent is substantially anhydrous, i.e., comprises less than about 1 % water. In one embodiment, the method of Scheme 3 is carried out for a time of about 0.5 hours to about 48 hours. In another embodiment, the method of Scheme 3 is carried out for a time of about 3 hours to about 36 hours. In still another embodiment, the method of Scheme 3 is carried out for a time of about 8 hours to about 24 hours. In yet another embodiment, the method of Scheme 3 is carried out for a time of about 15 hours to about 20 hours. In a further embodiment, the method of Scheme 3 is carried out at a temperature of about 0°C to about 200°C. In another embodiment, the method of Scheme 3 is carried out at a temperature of about 25°C to about 150°C. In yet another embodiment, the method of Scheme 3 is carried out at a temperature of about 50°C to about 100°C.
  • the amide derivative 2-dimethylamino-N-(5-oxo-5,ll-dihydro- 6H-indeno[l,2c]isoquinoiin-2-yl)-acetamide (17) was prepared from 5-chloro- H ⁇ -indeno [l,2c]isoquinoline (14).
  • Compound 14 was subjected to nitration to provide nitro compound 15, which was reduced using ammonium formate to provide amine 16, which was derivatized to acetamide 17, and followed by animation of the chloroacetamide intermediate.
  • 2-bromo5,6-dihydro-5-oxo-l l ⁇ -indeno[l,2- c]isoquinoline (18) was prepared by bromination of Compound 14.
  • Scheme 5 illustrates methods useful for making oxygen-substituted Isoquinoline Derivatives of formula (I), where R 5 and X are oxygen.
  • R 1 -R 5 are as defined above for formula (I); each occurrence of R a is independently Ci-Cs alkyl; R b is -CI, -Br, -I, -OMs, -OTs or -OTf; R is -C1-C 1 0 alkyl, alkanol or alkylcarboxy; and R " is -C1-C1 0 alkyl, aryl, heterocycle, alkanol or alkylcarboxy.
  • R a is methyl.
  • R b is -Br
  • Isoquinoline Compounds of formula 22 can be made by a method comprising contacting a compound of formula 20 and a compound of formula 21 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 22.
  • about 0.1 to about 10 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21.
  • about 0.5 to about 5 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21.
  • about 1 to about 2 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21.
  • about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 21.
  • about 3 to about 7 equivalents of base are used per about
  • Suitable bases for use in the method are organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate.
  • the base is potassium carbonate.
  • the base is triethylamine.
  • the method can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.
  • a solvent such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.
  • the solvent is DMF.
  • the solvent is acetonitrile.
  • the solvent is substantially anhydrous, i.e., comprises less than about 1 % water.
  • the method is carried out for a time of about 1 hour to about 96 hours. In another embodiment, the method is carried out for a time of about 18 hours to about 72 hours.
  • the method is carried out for a time of about 24 hours to about 48 hours. In one embodiment, the method is carried out at a temperature of about 25 °C to about 200°C. In another embodiment, the method is carried out at a temperature of about 50°C to about 150°C. In still another embodiment, the method is carried out at a temperature of about
  • Scheme 6 illustrates methods useful for making nitrogen-substituted Isoquinoline Derivatives of the invention.
  • nitrogen-substituted Isoquinoline Derivatives of general formula 37 can be made by a method comprising contacting a compound of formula 36 and a compound of formula 11 or formula 20 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 37.
  • R 1 -R 4 and R -Rio are as defined above for formula (I); each occurrence of R a is independently C1-C 5 alkyl; R b is -CI, -Br, -I, -OMs, -OTs or -OTf, and R c , is C1-C5 alkyl.
  • R a is methyl.
  • R b is -Br.
  • R a is methyl and Rb is -Br.
  • R c is methyl.
  • about 0.1 to about 10 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36.
  • about 0.5 to about 5 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36.
  • about I to about 2 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36.
  • about 0.1 to about 10 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 36.
  • about 0.5 to about 5 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 36.
  • Formula 20 are used per about 1 equivalent of a compound of Formula 36.
  • about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 36.
  • about 3 to about 7 equivalents of base are used per about 1 equivalent of a compound of Formula 11.
  • about 5 to about 6 equivalents of base are used per about 1 equivalent of a compound of Formula 11.
  • Suitable bases for use in the method of Scheme 7 are organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate.
  • the base is potassium carbonate. In another embodiment, the base is triethylamine.
  • the method of Scheme 7 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.
  • the solvent is DMF.
  • the solvent is acetonitrile.
  • the solvent is substantially anhydrous, i.e., comprises less than about 1 % water.
  • the method of Scheme 7 is carried out for a time of about 1 hour to about 96 hours.
  • the method of Scheme 7 is carried out for a time of about 18 hours to about 72 hours. In yet another embodiment, the method of Scheme 7 is carried out for a time of about 24 hours to about 48 hours. In one embodiment, the method of Scheme 7 is carried out at a temperature of about 25°C to about 200°C. In another embodiment, the method of Scheme 7 is carried out at a temperature of about 50°C to about 150°C. In still another embodiment, the method of Scheme 7 is carried out at a temperature of about 75°C to about 125°C.
  • a homophthalate To a solution of a homophthalate of Formula 20 (about 1 eq) and an N- acylanthranilonitrile of Formula 36 (about 1 to about 2 eq) in a solvent such as DMF, under inert atmosphere, is added a base (about 5 eq), such as potassium carbonate and the reaction is allowed to stir for about 48 hours at about 100°C, then cooled to room temperature. The reaction mixture is then poured into about 1 ⁇ sodium hydroxide and the resulting solution is extracted with EtOAc. The EtOAc layer is washed sequentially with about 1 ⁇ HC1, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo.
  • a base about 5 eq
  • R 7 -R are as defined above for formula (I); and R c is C1-C 5 alkyl.
  • Suitable acids for use in the method of Scheme 8 include, but are not limited to, sulfuric acid and phosphoric acid. In one embodiment, the acid is sulfuric acid. In another embodiment, R c is methyl.
  • the method of Scheme 8 can be carried out in the presence of a solvent, including, but not limited to, acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether or mixtures thereof.
  • sulfur substituted Isoquinoline Derivatives of formula 40 can be made by a method comprising contacting a compound of formula 39 and a compound of formula 11a or formula 20 in the presence a base for a time and at a temperature sufficient to make a compound of formula 40.
  • Ri-R t and R 7 -R 10 are as defined above for formula (I); each occurrence of R a is independently C1-C 5 alkyl; R b is -CI, -Br, -I, -OMs, -OTs or -OTf; and R is -H or -Br.
  • R a is methyl. In another embodiment, R b is -Br. In still another embodiment, R a is methyl and Rb is -Br. In yet another embodiment, R is -H. In a further embodiment, R d is -Br. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula a are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In still another embodiment, about 1 to about 2 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39.
  • about 0.1 to about 10 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In yet another embodiment, about 1 to about 2 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula
  • Suitable bases for use in the method of Scheme 9 are organic bases such as triethylamine, lithium N-diisopropylamide, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates, including sodium carbonate, potassium carbonate and cesium carbonate.
  • the base is potassium carbonate.
  • the base is triethylamine.
  • the method of Scheme 9 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof.
  • the solvent is DMF. In another embodiment, the solvent is acetonitrile. In one embodiment, the method of Scheme 9 is carried out for a time of about 1 hour to about 120 hours. In another embodiment, the method of Scheme 9 is carried out for a time of about 24 hours to about 96 hours. In yet another embodiment, the method of Scheme 9 is carried out for a time of about 60 hours to about 80 hours. In one embodiment, the method of Scheme 9 is carried out at a temperature of about 0°C to about 200°C. In another embodiment, the method of Scheme 9 is carried out at a temperature of about 25 °C to about 150°C. In still another embodiment, the method of Scheme 9 is carried out at a temperature of about 50°C to about 100°C.
  • a solution of a mercaptobenzonitrile of Formula 39 (about 1.0 eq) and a homophthalic anhydride of Formula 11a (about 2.0 eq) in a suitable solvent such as acetonitrile under inert atmosphere is warmed with stirring until all reactants are in solution.
  • a suitable base such as triethylamine (about 1 to about 5 eq) is added and the reaction is allowed to stir at about 90°C for about 72 hours, then cooled to room temperature.
  • the reaction mixture is filtered, and the collected solid is washed using methanol, then dried in a vacuum oven at about 50°C to provide a compound of Formula 40.
  • X is a leaving group such as bromide or chloride;
  • R b is -CI, -Br, -I, -OMs, -OTs, or -OTf;
  • one R e is -H and the other R_ is -NO 2 ;
  • one R f is -H and the other R f is -NH 2 ;
  • one R g is -H and the other R g is -NHC(O)-(CH 2 ) n -X;
  • one R h is -H and the other R h is -NHC(O)-(CH 2 ) n -NZ ⁇ Z 2 .
  • Rb is -Br.
  • a suitable solvent such as acetonitrile
  • a suitable base such as triethylamine (about 1 to about 5 equivalents).
  • the resultant reaction mixture is allowed to stir for about 1 hour, at which time a precipitate appears.
  • the reaction mixture is then heated to reflux for about 20 hours, cooled to room temperature and filtered.
  • the collected solid is washed with acetonitrile and dried under vacuum to provide a compound of Formula 53.
  • Compound 52 can be prepared from homophthalic anhydride (lib) and benzoic anhydride in two steps. Homophthalic anhydride and benzoic anhydride are reacted in a suitable solvent such as pyridine in the presence of an acid such as HC1; subsequently reacted with acetic anhydride in pyridine and heated to reflux; and then refluxed in the presence of an amine such as NH 3 in MeOH; to provide the compound of Formula 52. To a solution of the compound of Formula 52 or 53 in a suitable solvent, such as
  • R 4-Methyl-piperazine-1-yl q.
  • R -N(CH 2 CH 2 NMe 2 ) 2 b.
  • R 4-CH 2 C0 2 Me-piperazine-1-yl r.
  • R -N(CH 2 CH 2 OH) 2 c.
  • R 4-CH 2 CH 2 OH-piperazine-1-yl s.
  • R -NHCH 2 CH 2 CN d.
  • R imidazole-1-yl t.
  • R -NHC(NH)NH 2 Method I: To a stirred suspension of 3-(4-morpholino)-l-propylamine (17.28 g, 0.12 mol) in EtOAc was added sat. aq.
  • the free bases of 8d, 8g, 8h, 8j, 8m-8r were also prepared by Method I, but substituting 3-(4-morpholino)-l-propylamine with imidazole, 2-dimethylamino- ethylamine, 2-(N-piperidinyl)-ethylamine, 2-(N-mo holinyl)-e ylamine, 3-(N-tetrahydropyrrolidinyl)-propylamine, 3-(N-imidazolyl)-propylamine, 3(N-(4- methylpiperazinyl)-propylamine, di-(2-(diethylamino)-ethyl)amine, di-(2(dimethylamino)-ethyl)amine and di-(2-hydroxyethyl)amine, respectively.
  • N-bromosuccinimide (121 g, 1.7 eq) was added.
  • the resulting suspension was irradiated for 18 h with a 500 Watt quartz-halogen lamp, which brought the reaction mixture to reflux.
  • the reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate (4 L), saturated aqueous sodium bisulfite (2 L), and saturated aqueous sodium chloride (2 L).
  • the organic phase was dried using sodium sulfate with a small amount of silica added to remove polar impurities.
  • the resulting suspension was allowed to stir for 1 h, filtered, and the solids were washed with water (2 x 200 mL). The solids were then diluted with 5 N sodium hydroxide (600 mL) using heating. The resulting solution was cooled to 0°C using an ice bath and the solution was acidified to pH 1 using cone. HCl. The resulting precipitate was vacuum filtered, and the solids washed sequentially with water (3 x 300 mL) and diethyl ether (300 mL) then dried overnight using a vacuum oven at 50°C to provide Compound 23a as a gray solid. Yield 4.74 g (100 %).
  • the bromo compound was dissolved in MeCN (200 ml), and to the reaction mixture was added homophthalic anhydride (30.780 g, 0.19 mol) at room temperature and under inert atmosphere. The reaction mixture was then treated with a solution of triethylamine (84 ml, 0.6 mol) in acetonitrile (100 ml). The reaction mixture was refluxed for 8 hours. The precipitate that formed was removed by filtration and washed with MeCN (100 ml). The washed precipitate was suspended in DMF (300 ml), which was heated at 130 °C, then cooled and filtered.
  • Compound 55b As set forth above for Compound 55a, Compound 55b (N-[5,6-dihydro-5-oxo- indeno[l,2-c]isoquinolin-9-yl]-4-chloro-butylamide) was prepared from the amino compound 54a using chlorobutyryl chloride in the presence of aqueous NaHCO 3 and ethyl acetate.
  • camphor sulfonic acid (0.915 g, 0.0039 mol). The reaction mixture was allowed to at room temperature for 1 hour, and concentrated in vacuo. The resultant residue was dissolved in distilled, deionized water (300 ml); filtered; treated with decolorising charcoal (1 g); and allowed to stir at 100 to 105 °C for 30 minutes. The resultant solution was filtered through a pad of celite, and the celite was washed with water. The filtrate was lyophilized to provide the camphor sulfonic acid salt of Compound 43 (1.660 g, 75%).
  • Example 2 Effect of Illustrative Isoquinoline Derivatives on PARS activity in cultured macrophages, using a whole-cell based assay and a purified enzyme assay. Demonstration of illustrative Isoquinoline Derivatives' ability to inhibit PARS and prevent peroxynitrite induced cytotoxicity was shown using methods described in Virag et al., Br. J. Pharmacol. 1999, 126(3):769-77; and Immunology 1998, 94(3):345- 55.
  • Raw mouse macrophages were cultured in DMEM medium with high glucose and supplemented with 10 % fetal bovine serum. Cells were used at 80 % confluence in 12- well plates.
  • Peroxynitrite a prototypical oxidant which induces DNA single strand breakage, was used to induce PARS activation.
  • Peroxynitrite was diluted in phosphate buffered saline (PBS) (pH 11.0) and added to the cells in a bolus of 50 ⁇ l. Cells were then incubated for 20 min. Peroxynitrite was decomposed by incubation for 30 min at pH 7.0, used as a control, and failed to influence the parameter studied.
  • PBS phosphate buffered saline
  • the PARS inhibitor 81 (mesylate salt) exerted 50 % inhibition of PARS activity in this assay at 3 nM, and thus was approximately 50,000 times more potent than the reference compound 3-aminobenzamide.
  • Example 3 Effect of Illustrative Isoquinoline Derivatives on PARS activity using cell protection assay The ability of illustrative Isoquinoline Derivatives to inhibit PARS and prevent peroxynitrite induced cytotoxicity was measured in a cell protection assay using the methods described in Jagtap et al., Bioorg. &Med. Chem. Letters 14 (2004) 81-85.
  • raw mouse macrophages were cultured then treated with an illustrative Isoquinoline Derivative at various concentrations ranging from 10 nM to 10 ⁇ M for about 15 minutes.
  • Peroxynitrite 750 ⁇ M was then added to the treated macrophages for a 15 minute incubation period to induce PARS activation.
  • the media was removed and replaced with 0.5 mL HEPES (pH 7.5) containing 0.01% digitonin and 3 H-NAD (0.5 ⁇ Ci/mL, final concentration of NAD+ in buffer is 20 nM/L) and the resultant mixture was allowed to stand for 20 minutes.
  • the cells were then scraped from the wells and placed in Eppendorf tubes containing 50% (w/v) of ice-cold TCA (200 ⁇ L). The tubes were maintained at 4 °C for four hours, centrifuged at 1800g for 10 minutes, and the supernatant removed. The resultant pellets were washed with 5% (w/v) TCA (200 ⁇ L, 2x), then solubilized overnight in 2 % (w/v) SDS/0.1 N NaOH (250 ⁇ l) at 37 °C. The contents of the tubes were then added to ScintiSafe Plus scintillation liquid (6.5 ml, Fisher Scientific) and radioactivity was measured using a liquid scintillation counter (Wallac, Gaithersburg, MD). The results shown in Table 4 demonstrate that the illustrative Isoquinoline Derivatives dose-dependently inhibit the activation of PARS. Table 4. Inhibitory effect of illustrative Isoquinoline Derivatives on cell protection
  • Example 4 Effects of illustrative Isoquinoline Derivatives in various disease models a: Effects of illustrative Isoquinoline Derivatives on in vitro cell disease models In additional in vitro studies in isolated thymocytes, cells were exposed to peroxynitrite or hydrogen peroxide (toxic oxidant species) to induce cytotoxicity. In this system the toxicity is, at least in part, related to activation of the nuclear enzyme PARS.
  • mice were pretreated with intraperitoneal injection of 0.1 and 1 mg/kg of compounds 81 (mesylate salt), 8p and 8j, and LPS at 10 mg/kg was injected i.p., and T ⁇ F-alpha was measured in the plasma at 90 minutes. As shown in Table 5, all compounds substantially reduced T ⁇ F production, indicative of the compounds' anti- inflammatory activity.
  • LPS LPS induced TNF production when compared to control.
  • LPS causes multiple organ dysfunction resembling of septic shock, and ultimately death (in part because of the early release of TNF-alpha).
  • CLP cecal ligation and puncture
  • the live bacteria that derive from the intestinal flora induce systemic inflammation and shock.
  • Agents that inhibit inflammatory mediator production, PARS activation, and cell death in this model prevent mortality induced by LPS or CLP.
  • the data demonstrating the reduction of TNF production by illustrative Isoquinoline Derivatives in animals subjected to an inflammation model, coupled with the fact that TNF production is an important trigger of inflammation in various inflammatory diseases (such as, for example, colitis, arthritis and neuroinflammation and shock) indicate that the Isoquinoline Derivatives have therapeutic effects in various systemic and local inflammatory diseases, including the rejection of transplanted organs, which entails both an inflammatory disease component and a reperfusion injury component and, accordingly, are useful for treating or preventing an inflammatory disease or a reperfusion injury.
  • Ischemia-reperfusion increased the permeability of the gut from ll ⁇ 4 to 216 ⁇ 27 ml min/cm 2 , indicative of severe damage of the reperfused gut.
  • Treatment with Compound 81 (mesylate salt) (3 mg/kg i.v., injected 10 min prior to initiation of reperfusion) reduced the increase in the permeability of the gut by approximately 73 %, indicating a marked maintenance of the gut function.
  • the ischemia-reperfusion studies in the gut were associated with a 80 % mortality over 12 hours, whereas only 15 % mortality was noted in the animals treated with 81 (mesylate salt).
  • Isoquinoline Derivatives have therapeutic effects in various systemic and local conditions of reperfusion injuries, including the rejection of transplanted organs, which entails both an inflammatory disease component and a reperfusion injury component and, accordingly, are useful for treating or preventing an inflammatory disease or a reperfusion injury or reoxygenation injury resulting from organ transplantation.
  • the data shown in Table 6 demonstrate that the illustrative Isoquinoline Derivatives attenuate the streptozotocin- induced onset of diabetes as they reduce the hyperglycemia.
  • the Isoquinoline Derivatives are useful for treating or preventing diabetes or a diabetic complication.
  • TMZ Temozolomide
  • DNA is methylated by TMZ primarily at the O6 and N7 positions of guanine and N3 of adenine.
  • MMR mismatch repair system
  • the N-methylpurine adducts are efficiently removed by base excision repair (BER).
  • BER base excision repair
  • Cells that are deficient in BER have heightened sensitivity to methylating agents.
  • One of the components of BER is the enzyme PARP.
  • Inhibition of PARP was examined to determine whether it increases the cytotoxicity of TMZ, particularly in MMR-deficient cells.
  • Groups of ten mice bearing procarbazine resistant xenograft tumors, which are cross-resistant to TMZ, were randomly assigned to one of four separate treatment arms. The four treatment arms were: 1) control arm (5% dextrose in sterile water); 2) compound 81 (mesylate salt) alone; 3) TMZ alone; and 4) combination of compound 81 (mesylate salt) and TMZ.
  • Treatments were administered when the tumor volumes reached the size of 100-500 mm on Day 1 only, by mtraperitoneal injections as set forth below. The tumors were subsequently measured twice weekly with hand-held vernier calipers and tumor volumes were calculated as follows: (width 2 x length)/2. Animals tested out of the study when the tumor volume exceeded 1000 mm 3 and when tumor volume was greater than five times the tumor volume at the time of initial treatment. Athymic mice, transplanted with MMR proficient (D-245 MG) or deficient (D- 245 MG (PR) xenografts were treated with a combination of TMZ and Compound 81 (mesylate salt).
  • the most effective dose of compound 81 was found to be 150 mg/kg, administered i.p. three times at 4 hr intervals with the first injection in combination with 262.5 mg/kg TMZ (0.75 LD10).
  • This dose of TMZ induced no partial regressions and approximately a 4-day tumor- control growth delay in two experiments.
  • the addition of compound 81 (mesylate salt) also increased the tumor growth delay in MMR proficient xenografts.
  • mice were treated with 200 mg/kg of compound 81 (mesylate salt) in combination with 88 mg/kg TMZ.
  • the tumor growth delay for TMZ alone in these mice was 43.1 and 39.2 days, in two sets of experiments.
  • Isoquinoline Derivative increases the efficacy of TMZ in treatment of malignant gliomas, particularly in tumors deficient in MMR.
  • compound 81 (mesylate salt) markedly enhances the anti- tumor effects of TMZ in vivo.
  • Compound 81 (mesylate salt), an illustrative Isoquinoline Derivative is useful for treating or preventing cancer, such as CNS and brain cancers, including gliomas.
  • the present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention.

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Abstract

The present invention relates to Isoquinoline Derivatives, compositions comprising an effective amount of a Isoquinoline Derivative and methods for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, cardiovascular disease, reoxygenation injury resulting from organ transplantation, Parkinson's disease, or cancer, comprising administering to an animal in need thereof an effective amount of a Isoquinoline Derivative.

Description

ISOQUINOLINE DERIVATIVES AND METHODS OF USE THEREOF
This application claims the benefit of U.S. Provisional Application No. 60/547,899, filed February 26, 2004, which is incorporated by reference herein in its entirety.
1. FIELD OF THE INVENTION The present invention relates to Isoquinoline Derivatives, compositions comprising an effective amount of a Isoquinoline Derivative and methods for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, cardiovascular disease, reoxygenation injury resulting from organ transplantation, Parkinson's disease, or cancer, comprising administering to an animal in need thereof an effective amount of an Isoquinoline Derivative.
2. BACKGROUND OF THE INVENTION Inflammatory diseases, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct from those associated with reperfusion injuries, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammatory disease and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO") (Szabό et al, Shock 6:79-88, 1996). The ONOO"-induced cell necrosis observed in inflammatory disease and in reperfusion injury involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabό et al, Trends Pharmacol. Sci. 19:287-98, 1998). A number of PARS inhibitors have been described in the art. See, e.g., Banasik et al, J. Biol. Chem., 267:1569-75, 1992, and Banasik et al, Mol. Cell. Biochem., 138:185-97, 1994; WO 00/39104; WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO 99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang et al, Biochem. Biophys. Res. Commun., 278:590-98,2000; White et al, J. Med. Chem., 43:4084-4097, 2000; Griffin et al, J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al, Bioorg. Med. Chem., 7:297-308, 1999; and Soriano etat., Nature Medicine, 7: 108-113, 2001. Adverse effects associated with administration of PARS inhibitors have been discussed in Milan et al, Science, 223:589-591, 1984. Isoquinoline compounds have been previously discussed in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al, J. Med. Chem., 43:3688-3698, 2300 and Cushman et al, J. Med. Chem. 42:446-57, 1999; indeno[l,2-c]isoquinolines are reported as antineoplastic agents in Cushman et al, WO 00/21537; and as neoplasm inhibitors in Hrbata et al, WO 93/05023. Syntheses of isoquinoline compounds have been reported. For example, see Wawzonek et al, Org. Prep. Proc. Int., 14:163-8, 1982; Wawzonek et al, Can. J. Chem., 59:2833, 1981; Andoi et al, Bull. Chem. Soc. Japan, 47:1014-17, 1974; Dusemund et al, Arch. Pharm (Weinheim, Ger.), 3 17:381-2, 1984; and Lai et al, Indian J. Chem., Sect. B, 38B:33-39, 1999. There remains, however, a need in the art for compounds useful for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, or cancer. Citation of any reference in Section 2 of this application is not an admission that the reference is prior art.
3. SUMMARY OF THE INVENTION Accordingly, in one aspect the invention includes a compound of Formula I, Formula Formula II, Formula III, Formula IV or a pharmaceutically acceptable salt thereof (an "Isoquinoline Derivative") as set forth below. Isoquinoline Derivatives are useful for treating or preventing an inflammatory disease, a reperfusion injury, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease other than a cardiovascular disease, cardiovascular disease, reoxygenation injury resulting from organ transplantation, Parkinson's disease, or cancer (each being a "Condition"). Also provided are compositions comprising an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle. Also provided by the invention are methods for treating or preventing a Condition, comprising administering to an animal in need of such treatment or prevention an effective amount of an Isoquinoline Derivative.
Figure imgf000004_0001
(I)
Figure imgf000004_0002
(II)
Figure imgf000004_0003
(HI)
Figure imgf000005_0001
The details of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. All references cited in this specification are incorporated by reference. 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the effect of compound 81 (mesylate salt) and temozolomide on tumor volume. In Figure 1, -■- = control; - A- = compound 81 (mesylate salt); -x- = temozolomide; and -*- = compound 81 (mesylate salt) and temozolomide. 5. DETAILED DESCRIPTION OF THE INVENTION The present invention provides Isoquinoline Derivatives according to Formula I, Formula II, Formula III, and Formula IV below:
Figure imgf000006_0001
(I) and pharmaceutically acceptable salts thereof, wherein: R5 is O, NH or S; R6 is -H or - -C5 alkyl X is -C(O)-, -CH2~, -CH(halo)-, -CH(OH)-(CH2)„-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRπR12)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(C C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); Rπ and R12 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and R12 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; R1 is -hydrogen, -halo, - -C10 alkyl, -halo-substituted C1--C5 alkyl, -C2-C1o alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted Ci-Cs alkyl, -C(O)OH, -C(O)O(Ci-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Ci-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ1Z2, -(C1-C5 alkylene)-NZi,Z2, -amino-substituted Ci-C5 alkyl, -( -C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -KZ_Z_, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZ1Z , -nitrogen-containing-3- to 7-membered monocyclic heterocycle, ~Cι-C10 alkyl, -C2-C10 alkenyl, -C2-Cio alkynyl, -aryl, -benzyl, -C(O)OH, -d-Cs alkylene-C(O)O-(C1-C5 alkyl) or - -C5 alkylene-OC(O)-(CrC5 alkyl); R2, R3, R4, R , R8, R9 and R^ are independently -hydrogen, -halo, -hydroxy, -©-(Ci-Cs alkyl), - -C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and TJI are independently -H or - -Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z^ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
In one embodiment, X is -C(O)-, -CH2-, -CH(halo)~, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S- or -CH(NRπR12)-, wherein n is an integer ranging from 0-5. In one embodiment, R5 is O. In another embodiment, R5 is S. In a further embodiment, R5 is NH. In another embodiment, X is -N(SO2Y)-. In one embodiment, A is -SO2- or -SO2NH-. In another embodiment, B is -C1-C10 alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, -7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ1Z2, -amino-substituted -C5 alkyl, -( -C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C C5 alkyl) or -C(O)O-phenyl, each of which, other than -NZιZ2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -NZiZ^ -nitrogen-containing-3- to 7-membered monocyclic heterocycle, - - o alkyl, -C -Cio alkenyl, -C2-Cιo alkynyl, -aryl, -benzyl, -C1-C5 alkylene-C(O)O-C1-C5 alkyl or - -C5 alkylene-OC(O)-Cι-C5 alkyl. In another embodiment, R^Rt are hydrogen. In a further embodiment, at least one of Ri , R2, R3, R4, R , R8, R and R^ is other than hydrogen. In one embodiment, one of R7-R10 is -NHC(O)-(CH2)n-OAc or -NHC(O)-(CH2)n-
OH. In other illustrative embodiments R5 and X in a compound of formula (I) are as set forth below:
Figure imgf000008_0001
Figure imgf000009_0002
In another embodiment, the compounds of Formula (I) have the Formula (la):
Figure imgf000009_0001
(la) where R8 and R9 are as defined above for Formula (I).
In one embodiment, the compounds of Formula (la) are those wherein R8 is -H, R9 is -A-B, A is -SO2- and B is -NZ.Z 2 or -( -C5 alkylene)NZiZ2.
Illustrative examples of compounds of Formula (la) are set forth below:
Figure imgf000010_0002
and pharmaceutically acceptable salts thereof.
In another embodiment, the compounds of Formula (I) have the Formula (lb):
Figure imgf000010_0001
(lb) where R , R8, R9 and R10 are as defined above for Formula (I).
Illustrative examples of compounds of Formula (lb) are set forth below:
Figure imgf000011_0001
and pharmaceutically acceptable salts thereof.
In another embodiment, the compounds of Formula (I) have the Formula (Ic):
Figure imgf000012_0001
(Ic) where X and R9 are as defined above for Formula (I).
Illustrative examples of compounds of Formula (Ic) are set forth below:
Figure imgf000012_0002
and pharmaceutically acceptable salts thereof.
In another embodiment, the compounds of Formula (I) have the Formula (Id):
Figure imgf000013_0001
(Id) where B is as defined above for the compounds of Formula (I). In one embodiment, B is
Figure imgf000013_0002
or -(C1-C5 alkylene)-NZ1Z2, or -(C1-C5 alkylene) substituted with -NH2 or -OH.
The invention also relates to compounds of Formula II:
Figure imgf000013_0003
(II) and pharmaceutically acceptable salts thereof, wherein: R6 is -H or -C5 alkyl; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted -C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(d-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
Figure imgf000013_0004
alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -Ci-C10 alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -arnino- substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C1-C5 alkyl), -C(O)O-phenyl or - Z1Z2; R2, R3, Ri, R7, R8, R9 and R10 are independently -hydrogen, -halo, -hydroxy, -O-(C C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(CrC5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C2-C10 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C!-C5 alkyl), -C(O)O-phenyl or -NZ1Z2; and Zi and Z2 are independently -H or -C1- 0 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z ), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle. In one embodiment, B is a nitrogen-containing-3- to 7-membered monocyclic heterocycle. In still another embodiment, Ri is -hydrogen, -halo, -d-Cio alkyl, -halo- substituted Ci-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, - amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Ci-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Ci-C5 alkyl)-, -NH-, -CH , -S- or -C(S)-; and B' is -C1-C10 alkyl, -C2-C10 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted Ci-C5 alkyl, -C1-C5 alkyl-(3- to 7-membered monocyclic heterocycle), - H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZιZ2. In a further embodiment, at least one of Rl5 R2, R3, R^ R7, R8, R and R10 is not hydrogen. In another embodiment, at least one of R2, R and Rio is other than hydrogen. In one embodiment, A is other than -CONH-
The invention also relates to compounds of Formula III:
Figure imgf000015_0001
(III) and pharmaceutically acceptable salts thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted Q-C5 alkyl, -hydroxy, -O-(Cι-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-C!-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -Ci-Cs alkyl, -NZiZ^, -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted C1-C5 alkyl, -amino-substituted Q-C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -C1-C10 alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and Z2 are independently -hydrogen or -Ci-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -Ci-Cs alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3 - to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
In one embodiment, -X- is -CH2-. In another embodiment, -X- is -O-. In one embodiment, R8 is hydrogen and R9 is -A-B. In another embodiment, R8 is -A-B and R9 is hydrogen. In one embodiment, either R8 is hydrogen and R9 is -A-B, or R8 is -A-B and R9 is hydrogen. In still another embodiment, R2, R3 and R8 are hydrogen and R is -A-B, wherein A is -SO2- or -SO2NH-. In a further embodiment, at least one of R2, R3, R8 and R is not hydrogen.
The invention further relates to compounds of Formula 13:
Figure imgf000016_0001
13 and pharmaceutically acceptable salts thereof, wherein: Ri, R2, R3, R-t, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy,
-O-(Ci-C5 alkyl), -Ci-C10 alkyl, -halo-substituted Ci-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH,
-C(O)O(Ci-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-,
-CONH-, -CON(d-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZιZ2,
-(C1-C5 alkylene)-NZιZ2, -amino-substituted Q-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Ci-Cs alkyl), -halo, -hydroxy, -NO2, -CN, -ΗZ _, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -Ci-Cio alkyl, -C2-Cιo alkenyl, -C2-Cι0 alkynyl, -aryl, -benzyl, -C(O)OH, -Ci-Cs alkylene-C(O)O-(Ci-C5 alkyl) or -C C5 alkylene-OC(O)-(C1-C5 alkyl); and Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
In one embodiment, R9 is -A-B, wherein -A- is -SO2- or -SO2NH-. In another embodiment, Rι-R-= are each hydrogen. In another embodiment, Ri- t are each hydrogen. In a further embodiment, at least one of Ri, R2, R3, R., R , R8, R9 and Rio is other than hydrogen. In one embodiment, A is other than -CONH-.
The invention further still relates to compounds of Formula 22:
Figure imgf000017_0001
22 and pharmaceutically acceptable salts thereof, wherein: Ri-E and R7-Rio are as defined above for Formula 13. In one embodiment, R is -A-B, wherein -A- is -SO2- or -SO2NH- In another embodiment, Ri-Ri are each hydrogen. In a further embodiment, at least one of Ri, R2, R , P^, R7, Rs. R9 and Rio is other than hydrogen. The invention further still relates to compounds of Formula 37:
Figure imgf000018_0001
37 and pharmaceutically acceptable salts thereof, wherein: Ri-Rt and R7-R10 are as defined above for Formula 13.
In one embodiment, R1-R4 are each hydrogen. In another embodiment, R9 is -A-B, wherein -A- is -SO2- or -SO2NH-. In a further embodiment, at least one of Ri, R2, R3, R4, R7, R8, R9 and Rio is other than hydrogen.
The invention also relates to compounds of Formula 40:
Figure imgf000018_0002
40 and pharmaceutically acceptable salts thereof, wherein: Ri-Rt and R7-R10 are as defined above for Formula 13.
In one embodiment, Ri- φ are each hydrogen. In one embodiment, R9 is -A-B, wherein -A- is -SO2- or -SO2NH-. In a further embodiment, at least one of Ri, R2, R3, Rt, R , R8, R9 and Rio is other than hydrogen. The invention further relates to compounds of Formula (IV):
Figure imgf000019_0001
(IV) and pharmaceutically acceptable salts thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Rι and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -Q-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and ^ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5. In one embodiment, Ru is -NHC(O)-(CH2)n-NZιZ2 and Rι3, R15, and R16 are each hydrogen. In one embodiment, R15 is -NHC(O)-(CH2)n-NZιZ2 and Ri3, R14, and Rι6 are each hydrogen. In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In one embodiment, n is 4. In another embodiment, n is 5.
Illustrative examples of the compounds of Formula (IV) include the compounds of Formula (IVa):
Figure imgf000020_0001
(IVa) and pharmaceutically acceptable salts thereof. In one embodiment, the compound of Formula (IVa) is:
Figure imgf000020_0002
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof.
Illustrative examples of the compounds of Formula (IV) also include the compounds of Formula (IVb):
Figure imgf000021_0001
(IVb) and pharmaceutically acceptable salts thereof. In one embodiment, the compound of Formula (IVb) is:
Figure imgf000021_0003
or a pharmaceutically acceptable salt thereof.
Additional illustrative compounds of Formula (IV) include compounds 43, 45, and 97-109, above, and pharmaceutically acceptable salts thereof.
5.1 DEFINITIONS The following definitions are used in connection with the Isoquinoline
Derivatives: "C1-C5 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C1-C5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl. "Cι-C8 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-8 carbon atoms. Examples of a Cι-C8 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl and isooctyl. "C1-C10 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-10 carbon atoms. Examples of a C1-Q0 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl. "C2-Cιo alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms and at least one double bond. Examples of a C2-Cιo alkenyl group include, but are not limited to, ethylene, propylene, 1 -butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3- hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4- octene, 1-nonene, 2-nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene. "C2-Cιo alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms and at least one triple bond. Examples of a C2-Cio alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3-nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne. "C1-C5 alkylene" refers to a C1-C5 alkyl group in which one of the C1-C5 alkyl group's hydrogen atoms has been replaced with a bond. Examples of a -C5 alkylene include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2-. "Halo-substituted C1-C5 alkyl" refers to a -C5 alkyl group, as defined above, wherein one or more of the C1-C5 alkyl group's hydrogen atoms has been replaced with - F, -CI, -Br or -I. Representative examples of an alkylhalo group include, but are not limited to, -CH2F, -CC13, -CF3, -CH2C1, -CH2CH2Br, -CH2CH2I, -CH2CH2CH2F,
-CH2CH2CH2C1, -CH2CH2CH2CH2Br, -CH2CH2CH2CH2I, -CH2CH2CH2CH2CH2Br, -CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(C1)CH2CH3, -CH(F)CH2CH3 and -C(CH3)2(CH2C1). "Amino-substituted C1-C5 alkyl" refers to a C1-C5 alkyl group, as defined above, wherein one or more of the -C5 alkyl group's hydrogen atoms has been replaced with -NH2. Representative examples of an amino-substituted C1-C5 alkyl group include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2CH2CH2NH2, -CH2CH(NH2)CH3, -CH2CH(NH2)CH2CH3, -CH(NH2)CH2CH3 and -C(CH3)2(CH2NH2). "Aryl" refers to a phenyl or pyridyl group. Examples of an aryl group include, but are not limited to, phenyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: -C1-C5 alkyl, halo, -halo-substituted -C5 alkyl, hydroxy, -O-C1-C5 alkyl, -N(Ra)2, -COOH, -C(O)O-(Cι-C5 alkyl), -OC(O)-(d-C5 alkyl), -C(O)NH2, or -NO2, wherein each occurrence of Ra is independently -H or C1- 0 alkyl, "NH C(O)-substituted aryl" refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more -C(O)NH2 groups. Representative examples of a -NH2C(O)-substituted aryl group include 2-C(O)NH2-phenyl, 3-C(O)NH2-phenyl, 4-C(O)NH2-phenyl, 2-C(O)NH2-pyridyl, 3-C(O)NH2-pyridyl and 4-C(O)NH2-pyridyl. "-(C1-C5 alkyl)-(3- to 7-membered monocyclic heterocycle)" refers to a C1-C5 alkyl group, as defined above, wherein one of the C1-C5 alkyl group's hydrogen atoms has been replaced with a -3- to 7-membered monocyclic heterocycle. Representative examples of a -(C1-C5 alkyl)-(3- to 7-membered monocyclic heterocycle) group include, but are not limited to, -CH2CH2-morpholine, -CH CH2-piperidine, -CH2CH2CH2- morpholine and -CH2CH2CH2-imidazole. "Hydroxy-substituted C1-C5 alkyl" refers to a C1-C5 alkyl group, as defined above, wherein one of the C1-C5 alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2CH(OH)CH2CH3, -CH(OH)CH2CH3 and -C(CH3)2CH2OH. An "Arylene" group is a phenyl group in which one of the phenyl group's hydrogen atoms has been replaced with a bond. An arylene group can bein an ortho, meta, or para configuration and can be unsubstituted or independently substituted with one or more of the following groups: -C1-C5 alkyl, halo, hydroxy, -O-C1-C5 alkyl, -N(Ra)2, -COOH, -halo-substituted C1-C5 alkyl, -C(O)O-(d-C5 alkyl), -OC(O)-(Cι-C5 alkyl), -C(O)NH2 or -NO2, wherein each occurrence of Ra is independently -H or Q-C10 alkyl. A "C3-C8 monocyclic cycloalkyl" is a non-aromatic, saturated hydrocarbon ring containing 3-8 carbon atoms. Representative examples of a C3-C8 monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A C3-C8 monocyclic cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: -Q-C5 alkyl, halo, - halo-substituted C1-C5 alkyl, hydroxy, -O-C1-C5 alkyl, -N(Ra)2, -COOH, -C(O)O-(d-C5 alkyl), -OC(O)-(d-C5 alkyl), -C(O)NH2, or -NO2, wherein each occurrence of Ra is independently -H or C1-C10 alkyl. A "3- to 7-membered monocyclic heterocycle" refers to a monocyclic 3- to 7- membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 3- to 7- membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, and pyrimidinyl. A "7- to 10-membered bicyclic heterocycle" refers to a bicyclic 7- to 10- membered aromatic or non-aromatic bicyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 7- to 10-membered bicyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of a 7- to 10-membered bicyclic heterocycle group include, but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl. A "nitrogen-containing 3- to 7-membered monocyclic heterocycle" refers to a 3- to 7-membered monocyclic heterocycle, defined above, which contains at least one ring nitrogen atom. The nitrogen-containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of nitrogen- containing-3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, and morpholinyl. "Halo" is -F, -CI, -Br or -I. An "animal" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, an animal is a human. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 - disulfonate), benzenesulfonate, benzonate, besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A hydrate is another example of a pharmaceutically acceptable salt. An "effective amount" when used. in connection with an Isoquinoline Derivative is an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting PARS in an in vivo or an in vitro cell. An "effective amount" when used in connection with another anticancer agent is an amount that is effective for treating or preventing cancer alone or in combination with an Isoquinoline Derivative. "In combination with" includes administration within the same composition and within separate compositions. In the latter instance, the anticancer agent is administered during a time when the Isoquinoline Derivative exerts its prophylactic or therapeutic effect, or vr'ce versa.
The following abbreviations are used herein and have the indicated definitions: AcOH is acetic acid, AIBN is azibisisobutyronitrile, CCL is carbon tetrachloride, CEP is Cecal Ligation and Puncture, DMEM is Dulbecco' s Modified Eagle Medium, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, EtOAc is ethyl acetate, EtOH is ethanol, HEPES is 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid, HPLC is high pressure liquid chromatography, LPS is lipopolysaccharide, Me is methyl, MeCΝ is acetonitrile, MeOH is methanol, MS is mass spectrometry, Ms is mesyl (methanesulfonyl), ΝBS is Ν-bromosuccinimide, ΝEt3 is triethylamine, NMR is nuclear magnetic resonance, PBS is phosphate-buffered saline (pH 7.4), PARS is poly(ADP- ribose)synthetase, Py is pyridine, SDS is dodecyl sulfate (sodium salt), STZ is streptozotocin, TCA is tricholoroacetic acid, Tf is triflyl (trifluoromethanesulfonyl), TFA is trifluoroacetic acid, THF is tetrahydrofuran; TLC is thin layer chromatography, TMZ is temozolomide, TNF is tumor necrosis factor, TRIS is Tris(hydroxymethyl)aminomethane and Ts is tosyl (p-toluenesulfonyl).
5.2 Methods For Using The Isoquinoline Derivatives The invention also includes methods for inhibiting PARS in a cell. PARS, which is also known as poly(ADP-ribose)synthetase, PARP ((poly(ADP-ribose) polymerase, PARP-1 , EC 2.4.99) and ADP-ribosyltransferase (ADPRT, EC 2.4.2.30), is a nuclear enzyme that catalyzes a transfer of the ADP ribose moiety of NAD+ to an acceptor protein. In one embodiment, the method comprises contacting a cell with an Isoquinoline Derivative in an amount effective to inhibit PARS in the cell. In general, any cell having, or capable of having, PARS activity or capable of expressing PARS can be used. The cell can be provided in any form. For example, the cell can be provided in vitro, ex vivo, or in vivo. PARS activity can be measured using any method known in the art, e.g., methods as described in Banasik et al, J. Biol. Chem. 267:1569-75 (1991). Illustrative examples of cells capable of expressing PARS include, but are not limited to, muscle, bone, gum, nerve, brain, liver, kidney, pancreas, lung, heart, bladder, stomach, colon, rectal, small intestine, skin, esophageal, eye, larynx, uterine, ovarian, prostate, tendon, bone marrow, blood, lymph, testicular, vaginal and neoplastic cells. In accordance with the invention, the Isoquinoline Derivatives are administered to an animal in need of treatment or prevention of a Condition.
5.2.1. Treatment or Prevention of an Inflammatory Disease The Isoquinoline Derivatives can be used to treat an inflammatory disease. Inflammatory diseases can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation. Examples of inflammatory diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, organ transplant rejection; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimers disease, infectious meningitis, encephalomyelitis, Parkinson's disease,
Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; diabetic complications, including, but not limited to, immune-complex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, and brain and spinal cord trauma. The inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer. In one embodiment, the inflammatory disease is the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.
5.2.2. Treatment or Prevention of a Reperfusion Injury The Isoquinoline Derivatives can be used to treat a reperfusion injury. Reperfusion refers to the process whereby blood flow in the blood vessels is resumed following ischemia, such as occurs following constriction or obstruction of the vessel. Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction, stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked. Examples of reperfusion injuries treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury, and reperfusion injury resulting from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery, or hemorrhagic shock. In one embodiment, the reperfusion injury results from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery or hemorrhagic shock. 5.2.3. Treatment or Prevention of a Reoxygenation Injury Resulting from Organ Transplantation In another embodiment, the reperfusion injury is a reoxygenation injury resulting from organ transplantation. Examples of reoxygenation injuries treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, transplantation of the following organs: heart, lung, liver, kidney, pancreas, intestine, and cornea. In one embodiment, a reoxygenation injury resulting from organ transplantation occurs during the organ transplantation.
5.2.4. Treatment or Prevention of an Ischemic Condition The Isoquinoline Derivatives can be used to treat an ischemic condition.
Examples of ischemic conditions treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia. In one embodiment, the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.
5.2.5. Treatment or Prevention of Renal Failure The Isoquinoline Derivatives can be used to treat or prevent renal failure. In one embodiment, the renal failure is chronic renal failure. In another embodiment, the renal failure is acute renal failure.
5.2.6. Treatment or Prevention of a Vascular Disease The Isoquinoline Derivatives can be used to treat or prevent a vascular disease other than a cardiovascular disease. Examples of such vascular diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, and lipedema. 5.2.7. Treatment or Prevention of a Cardiovascular Disease The Isoquinoline Derivatives can be used to treat or prevent a cardiovascular disease. Examples of cardiovascular diseases treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, chronic heart failure, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, cardiac transplant, myocardial infarction, and a cardiac arrhythmia, such as atrial fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia. In one embodiment, the cardiovascular disease is chronic heart failure. In another embodiment, the cardiovascular disease is a cardiac arrhythmia. In still another embodiment, the cardiac arrhythmia is atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia.
5.2.8. Treatment or Prevention of Diabetes or a Diabetic Complication The Isoquinoline Derivatives can be used to treat or prevent diabetes mellitus or its complications. Examples of diabetes treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by β-cell toxins. The Isoquinoline Derivatives can be used to treat or prevent a diabetic complication. Examples of diabetes mellitus or its complications that are treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy, (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathies, autonomic neuropathy, a foot ulcer, a joint problem, a fungal infection, a bacterial infection, and cardiomyopathy.
5.2.9. Treatment or Prevention of Parkinson's Disease The Isoquinoline Derivatives can be used to treat or prevent Parkinson's disease.
5.2.10. Treatment or Prevention of Cancer The Isoquinoline Derivatives can be used to treat or prevent cancer. Examples of cancers treatable or preventable using the Isoquinoline Derivatives include, but are not limited to, the cancers disclosed below in Table 1 and metastases thereof.
TABLE 1 Solid tumors, including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer esophageal cancer stomach cancer oral cancer nasal cancer throat cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile duct carcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumor cervical cancer uterine cancer testicular cancer small cell lung carcinoma bladder carcinoma lung cancer epithelial carcinoma skin cancer melanoma neuroblastoma retinoblastoma blood-borne cancers, including but not limited to: acute lymphoblastic leukemia ("ALL") acute lymphoblastic B-cell leukemia acute lymphoblastic T-cell leukemia acute myeloblastic leukemia ("AML") acute promyelocytic leukemia ("APL") acute monoblastic leukemia acute erythroleukemic leukemia acute megakaryoblastic leukemia acute myelomonocytic leukemia acute nonlymphocyctic leukemia acute undifferentiated leukemia chronic myelocytic leukemia ("CML") chronic lymphocytic leukemia ("CLL") hairy cell leukemia multiple myeloma acute and chronic leukemias: lymphoblastic myelogenous lymphocytic myelocytic leukemias Lymphomas: Hodgkin's disease non-Hodgkin's Lymphoma Multiple myeloma Waldenstrδm's macroglobulinemia Heavy chain disease Polycythemia vera
CNS and brain cancers: glioma pilocytic astrocytoma astrocytoma anaplastic astrocytoma glioblastoma multiforme medulloblastoma craniopharyngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma meningioma vestibular schwannoma adenoma metastatic brain tumor meningioma spinal tumor medulloblastoma
In one embodiment the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, a non-Hodgkin's lymphoma, a skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer. In another embodiment the cancer is metastatic cancer. In still another embodiment, the animal has previously undergone or is presently undergoing treatment for cancer. Such previous treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines. The Isoquinoline Derivatives are also useful for the treatment or prevention of a cancer caused by a virus. Such viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez- Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al, J Pafhol (2003) 199(2): 140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al, Leukemia (2003) 17(l):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see, e.g., Kadow et al, Curr Opin Investig Drugs (2002) 3(11): 1574-9); and Human Immune deficiency Virus (HIV) infection, which can lead to cancer as a consequence of immunodeficiency (see, e.g., Dal Maso et al., Lancet Oncol (2003) 4(2): 110-9). The Isoquinoline Derivatives can also be administered to prevent the progression of a cancer, including but not limited to the cancers listed in Table 1. Such prophylactic use includes that in which non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred. Alternatively or in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia, the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from an animal, can indicate the desirability of prophylactic/therapeutic administration of the Isoquinoline Derviatives. Such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype). In a specific embodiment, leukoplakia, a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ, are treatable or preventable according to the present methods. In another embodiment, fibrocystic disease (cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia)) are treatable or preventable according to the present methods. In other embodiments, an animal that exhibits one or more of the following predisposing factors for malignancy can be administered an amount of a Isoquinoline Derivative which is effective to treat or prevent cancer: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14;18) for foUicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of Von Recklinghausen, retinoblastoma, carotid body tumor, cutaneous melanocarcinoma, intraocular melanocarcinoma, xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi's aplastic anemia, and Bloom's syndrome; and exposure to carcinogens (e.g., smoking, second-hand smoke exposure, and inhalation of or contacting with certain chemicals).
5.2.10.1 Combination Chemotherapy For the Treatment of Cancer In one embodiment, the present methods for treating cancer or preventing cancer further comprise administering another anticancer agent. , In one embodiment, the present invention provides methods for treating or preventing cancer in a subject, the method comprising the administration of an effective amount of: (i) an Isoquinoline Derivative and (ii) another anticancer agent. In one embodiment, (i) an Isoquinoline Derivative and (ii) another anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer. In another embodiment, (i) an Isoquinoline Derivative and (ii) another anticancer agent act synergistically and are administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer. The dosage of the (i) an Isoquinoline Derivative, and (ii) another anticancer agent administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion. An Isoquinoline Derivative can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent to a subject in need thereof. In various embodiments, i) an Isoquinoline Derivative, and (ii) another anticancer agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, i) an Isoquinoline Derivative, and (ii) another anticancer agent are administered with 3 hours. In another embodiment, i) an Isoquinoline Derivative, and (ii) another anticancer agent are administered 1 minute to 24 hours apart. In one embodiment, an effective amount of an Isoquinoline Derivative and an effective amount of another anticancer agent are present in the same composition. In one embodiment, this composition is useful for oral administration. In another embodiment, this composition is useful for intravenous administration. Cancers that can be treated or prevented by administering an Isoquinoline Derivative and another anticancer agent include, but are not limited to, the list of cancers set forth in Table 1. In one embodiment, the cancer is brain cancer. In specific embodiments, the brain cancer is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme or a metastatic brain cancer. In a specific embodiment, the cancer is melanoma. In one embodiment, the cancer is metastatic melanoma. The Isoquinoline Derivative and the other anticancer agent can act additively or synergistically. A synergistic combination of an Isoquinoline Derivative and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the Isoquinoline Derivatives and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer. In addition, a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone. In one embodiment, an Isoquinoline Derivative and another anticancer agent act synergistically when administered in doses typically employed when such agents are sued as monotherapy for the treatment of cancer. In another embodiment, an Isoquinoline Derivative and another anticancer agent act synergistically when administered in doses that are less than doses typically employed when such agents are used as monotherapy for the treatment of cancer. In one embodiment, the administration of an effective amount of an Isoquinoline Derivative and an effective amount of another anticancer agent inhibits the resistance of a cancer to the other anticancer agent. In one embodiment, the cancer is a tumor. Suitable other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to temozolomide, a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, nitrosoureas such as carmustine and lomustine, vinca alkaloids such as vinblastine, vincristine and vinorelbine, platinum complexes such as cisplatin, carboplatin and oxaliplatin, imatinib mesylate, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins herbimycin A, genistein, erbstatin, and lavendustin A. In one embodiment, the other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to, a drug listed in Table 2 or a pharmaceutically acceptable salt thereof.
TABLE 2 Alkylating agents Nitrogen mustards: Cyclophosphamide Ifosfamide Trofosfamide Chlorambucil
Nitrosoureas: Carmustine (BCNU) Lomustine (CCNU)
Alkylsulphonates : Busulfan Treosulfan
Triazenes: Dacarbazine Procarbazine Temozolomide
Platinum containing complexes: Cisplatin Carboplatin Aroplatin Oxaliplatin
Plant Alkaloids Vinca alkaloids: Vincristine Vinblastine Nindesine Vinorelbine
Taxoids: Paclitaxel Docetaxel
DNA Topoisomerase Inhibitors Epipodophyllins: Etoposide Teniposide Topotecan Irinotecan 9-aminocamptothecin Camptothecin Crisnatol
Mitomycins: Mitomycin C Anti-metabolites
Anti-f olates: DHFR inhibitors: Methotrexate Trimetrexate
IMP dehydrogenase Inhibitors: Mycophenolic acid Tiazofurin Ribavirin EICAR
Ribonuclotide reductase Hydroxyurea Inhibitors: Deferoxamine
Pyrimidine analogs: Uracil analogs: 5-Fluorouracil Fluoxuridine Doxifluridine Ralitrexed
Cytosine analogs: Cytarabine (ara C) Cytosine arabinoside Fludarabine Gemcitabine Capecitabine
Purine analogs: Mercaptopurine Thioguanine O-6-benzylguanine
DNA Antimetabolites: 3-HP 2'-deoxy-5-fluorouridine 5-HP alpha-TGDR aphidicolin glycinate ara-C 5-aza-2'-deoxycytidine beta-TGDR cyclocytidine guanazole inosine glycodialdehyde macebecin II Pyrazoloimidazole
Hormonal therapies: Receptor antagonists: Anti-estrogen: Tamoxifen Raloxifene Megestrol
LHRH agonists: Goscrclin Leuprolide acetate
Anti-androgens: Flutamide Bicalutamide
Retinoids/Deltoids Cis-retinoic acid
Vitamin A derivative: All-trans retinoic acid (ATRA-IV) Vitamin D3 analogs: EB 1089 CB 1093 KH 1060
Photodynamic therapies: Vertoporfin (BPD-MA) Phthalocyanine Photosensitizer Pc4 Demethoxy-hypocrellin A (2BA-2-DMHA)
Cytokines: Interferon-α Interferon- β Interferon-γ Tumor necrosis factor Interleukin-2
Angiogenesis Inhibitors: Angiostatin (plasminogen fragment) antiangiogenic antithrombin HI Angiozyme ABT-627 Bay 12-9566 Benefin Bevacizumab BMS-275291 cartilage-derived inhibitor (CDI)
CAI
CD59 complement fragment
CEP-7055
Col 3
Combretastatin A-4
Endostatin (collagen XVJTi fragment)
Fibronectin fragment
Gro-beta
Halofuginone
Heparinases
Heparin hexasaccharide fragment
HMN833
Human chorionic gonadotropin
(hCG)
EVI-862
Interferon alpha/beta/gamma
Interferon inducible protein (IP-
10)
Interleukin-12
Kringle 5 (plasminogen fragment)
Marimastat
Metalloproteinase inhibitors
(T Ps)
2-Methoxyestradiol
MMI 270 (CGS 27023A)
MoAb C-lCll
Νeovastat
ΝM-3
Panzem
PI-88
Placenta! ribonuclease inhibitor Plasminogen activator inhibitor Platelet factor-4 (PF4) Prinomastat Prolactin 16kD fragment Proliferin-related protein (PRP) PTK 787/ZK 222594 Retinoids Solimastat Squalamine SS 3304 SU 5416 SU6668 SU11248 Tetrahydrocortisol-S Tetrathiomolybdate Thalidomide Thrombospondin-1 (TSP-1) TNP-470 Transforming growth factor-beta (TGF-b) Vasculostatin Vasostatin (calreticulin fragment) ZD6126 ZD 6474 famesyl transferase inhibitors (FTI) Bisphosphonates Antimitotic agents: Allocolchicine Halichondrin B Colchicine colchicine derivative dolstatin 10 Maytansine Rhizoxin Thiocolchicine trityl cysteine Others: Isoprenylation inhibitors: Dopaminergic neurotoxins: l-methyl-4-phenylpyridinium ion Cell cycle inhibitors: Staurosporine Actinomycins: Actinomycin D Dactinomycin Bleomycins: Bleomycin A2 Bleomycin B2 Peplomycin Anthracyclines: Daunorubicin Doxorubicin Idarubicin Epirubicin Pirarubicin Zorubicin Mitoxantrone MDR inhibitors: Nerapamil Ca2+ATPase inhibitors: Thapsigargin
Other anticancer agents that can be used in the compositions and methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin 2 (including recombinant interleukin 2, or rIL2), interferon alfa-2α; interferon alfa-2β; interferon alfa-nl ; interferon alfa-n3; interferon beta-I ; interferon gamma-Iβ; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Further anticancer drugs that can be used in the methods and compositions of the invention include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-
1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin in derivatives; balanol; batimastat; BCR ABL antagonists; benzochlorins; benzoylstaurosporine; beta Lactam Derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox E -2; carboxamide- amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosf amide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-acytidine; dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum complexes; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MTF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agents; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum complexes; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RE retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. In another embodiment, the other anticancer agent is interferon-α. In another embodiment, the other anticancer agent is interleukin-2. In one embodiment, the other anticancer agent is an alkylating agent, such as a nitrogen mustard, a nitrosourea, an alkylsulfonate, a triazene, or a platinum-containing agent. In another embodiment, the other anticancer agent is a triazene alkylating agent. In a specific embodiment, the other anticancer agent is temozolomide. Temozolomide can be administered to a subject at dosages ranging from about 60 mg/m2 (of a subject's body surface area) to about 250 mg/m2 and from about 100 mg/m2 to about 200 mg/m2. In specific embodiments, the dosages of temozolomide are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, or about 250 mg/m2. In a particular embodiment, temozolomide is administered orally. In one embodiment, temozolomide is administered orally to a subject at a dose ranging from about 150 mg/m2 to about 200 mg/m2. In another embodiment, temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 200 mg/m2. In a specific embodiment, temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 200 mg/m2 on days 1-5, then again orally once per day for five consecutive days on days 28- 32 at a dose ranging from about 150 mg/m2 to about 200 mg/m2, then again orally once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m2 to about 200 mg/m2. In a specific embodiment, the other anticancer agent is procarbazine. Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 100 mg/m2 and from about 60 mg/m2 to about 100 mg/m2. In specific embodiments, the dosages of procarbazine are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 0 0 0 0 0 mg/m , about 90 mg/m , about 100 mg/m , about 110 mg/m , about 120 mg/m , about 0 0 0 0 0
130 mg/m , about 140 mg/m , about 150 mg/m , about 160 mg/m , about 170 mg/m , about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 0 0 0 0 0 mg/m , about 230 mg/m , about 240 mg/m , about 250 mg/m , about 260 mg/m , about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 0 0 0 0 0 mg/m , about 370 mg/m , about 380 mg/m , about 390 mg/m , about 400 mg/m , about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m , about 470 mg/m2, about 480 mg/m , about 490 mg/m2, or about 500 mg/m2. In a particular embodiment, procarbazine is administered intravenously. In one embodiment, procarbazine is administered intravenously to a subject at a dose ranging from about 50 mg/m2 to about 100 mg/m2. In another embodiment, procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2. In a specific embodiment, procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m to about 100 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m2 to about 100 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m2 to about 100 mg/m2. In another embodiment, procarbazine is administered intravenously to a subject once at a dose ranging from about 50 mg/m 0 to about 100 mg/m 0. In a specific embodiment, the other anticancer agent is dacarbazine. Dacarbazine can be administered to a subject at dosages ranging from about 60 0 0 0 mg/m (of a subject's body surface area) to about 250 mg/m and from about 150 mg/m to about 250 mg/m2. In specific embodiments, the dosages of dacarbazine are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 o o o mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, about 250 mg/m2, about 260 mg/m2, about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2. In a particular embodiment, dacarbazine is administered intravenously. In one embodiment, dacarbazine is administered intravenously to a subject at a 0 0 dose ranging from about 150 mg/m to about 250 mg/m . In another embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 250 mg/m2. In a specific embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 250 mg/m on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m2 to about 250 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m2 to about 250 mg/m2. In one embodiment, dacarbazine is administered intravenously to a subject once at 0 0 a dose ranging from about 150 mg/m to about 250 mg/m . In one embodiment, the other anticancer agent is a Topoisomerase I inhibitor, such as etoposide, teniposide, topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or crisnatol. In a specific embodiment, the other anticancer agent is irinotecan. Irinotecan can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 150 mg/m2 and from about 75 mg/m2 to about 150 mg/m2. In specific embodiments, the dosages of irinotecan are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 0 0 0 0 0 mg/m , about 40 mg/m , about 50 mg/m , about 60 mg/m , about 70 mg/m , about 80 0 0 0 0 0 mg/m , about 90 mg/m , about 100 mg/m , about 110 mg/m , about 120 mg/m , about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m , about 230 mg/m , about 240 mg/m , about 250 mg/m , about 260 mg/m , about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2. In a particular embodiment, irinotecan is administered intravenously. In one embodiment, irinotecan is administered intravenously to a subject at a dose 0 0 ranging from about 50 mg/m to about 150 mg/m . In another embodiment, irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 150 mg/m2. In a specific embodiment, irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 150 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days 0 0 on days 28-32 at a dose ranging from about 50 mg/m to about 150 mg/m , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m2 to about 150 mg/m2. In one embodiment, the invention provides administration of an effective amount of: (i) an Isoquinoline Derivative (ii) one or more other anticancer agents. In one embodiment, (i) an Isoquinoline Derivative and (ii) one or more other anticancer agents are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer. In another embodiment, (i) an Isoquinoline Derivative and (ii) one or more other anticancer agents act synergistically and are administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer. The dosage of the (i) an Isoquinoline Derivative and (ii) one or more other anticancer agents administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion. In one embodiment, the other anticancer agent is O-6-benzylguanine. In another embodiment, the other anticancer agent is O-6-benzylguanine and temozolomide. In another embodiment, the other anticancer agent is O-6-benzylguanine and procarbazine. In still another embodiment, the other anticancer agent is O-6-benzylguanine and dacarbazine. 5.2.10.2. Multi-Therapy For Cancer The Isoquinoline Derivatives can be administered to an animal that has undergone or is currently undergoing one or more additional anticancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines. In one embodiment, the invention provides methods for treating or preventing cancer comprising administering to an animal in need thereof (a) an amount of a Isoquinoline Derivative effective to treat or prevent cancer; and (b) another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine. In one embodiment, the other anticancer therapy is radiation therapy. In another embodiment, the other anticancer therapy is surgery. In still another embodiment, the other anticancer therapy is immunotherapy. In a specific embodiment, the present methods for treating or preventing cancer comprise administering an Isoquinoline Derivative and radiation therapy. The radiation therapy can be administered concurrently with, prior to, or subsequent to the Isoquinoline Derivative, in one embodiment, at least an hour, five hours, 12 hours, a day, a week, a month, in another embodiment, several months (e.g., up to three months), prior or subsequent to administration of the Isoquinoline Derivatives. Where the other anticancer therapy is radiation therapy, any radiation therapy protocol can be used depending upon the type of cancer to be treated. For example, but not by way of limitation, X-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeN energy) can be used for deep tumors, and electron beam and orthovoltage X-ray radiation can be used for skin cancers. Gamma-ray emitting radioisotopes, such as radioactive isotopes of radium, cobalt and other elements, can also be administered. Additionally, in one embodiment the invention provides methods of treatment of cancer using an Isoquinoline Derivative as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy results in negative side effects, in the subject being treated. The subject being treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy. The Isoquinoline Derivative can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants. This can involve a process in which the subject's autologous hematopoietic stem cells are harvested and purged of all cancer cells, the subject's remaining bone-marrow cell population is then eradicated via the administration of an Isoquinoline Derivative and/or radiation, and the resultant stem cells are infused back into the subject. Supportive care can be subsequently provided while bone marrow function is restored and the subject recovers.
5.3 Therapeutic/Prophylactic Administration The invention also includes pharmaceutical compositions useful for treating or preventing a Condition. The compositions are suitable for internal use and comprise an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle. The Isoquinoline Derivatives can be administered in amounts that are effective to treat or prevent a Condition in an animal. Administration of the Isoquinoline Derivatives can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. In some instances, administration will result in the release of an Isoquinoline Derivative into the bloodstream. In one embodiment, the Isoquinoline Derivatives are administered orally. Depending on the intended mode of administration, the compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts. Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle. Illustrative carriers or vehicles include a) a diluent, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt, or effervescent mixtures; and/or e) absorbent, colorant, flavorant and sweetener. Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the Isoquinoline Derivative is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. The Isoquinoline Derivatives can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. The Isoquinoline Derivatives can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564. Isoquinoline Derivatives can also be delivered by the use of monoclonal antibodies as individual carriers to which the Isoquinoline Derivative molecules are coupled. The Isoquinoline Derivatives can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Isoquinoline Derivatives can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drag, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Parental injectable administration can be used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. One embodiment, for parenteral administration employs the implantation of a slow-release or sustained-released system, according to U.S. Pat. No. 3,710,795, incorporated herein by reference. The compositions can be sterilized or contain non-toxic amounts of adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate. In addition, they can also contain other therapeutically valuable substances. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, preferably from about 1% to about 70% of the Isoquinoline Derivative by weight or volume. The dosage regimen utilizing the Isoquinoline Derivative can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the animal; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the animal; and the particular Isoquinoline Derivative employed. A person skilled in the art can readily determine and prescribe the effective amount of the drag useful for treating or preventing a Condition. Effective dosage amounts of the Isoquinoline Derivatives, when administered to an animal, range from about 0.05 to about 1000 mg of Isoquinoline Derivative per day. Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of Isoquinoline Derivative. In one embodiment, the compositions are in the form of a tablet that can be scored. Effective plasma levels of the Isoquinoline Derivatives can range from about 0.002 mg to about 50 mg per kg of body weight per day. The amount of an Isoquinoline Derivative that is effective in the treatment or prevention of a Condition can be determined by clinical techniques that are known to those of skill in the art. In addition, in vitro and in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each patient's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, can range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours. In one embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Isoquinoline Derivative is administered, the effective dosage amounts correspond to the total amount administered. The dosage regimen utilizing the Isoquinoline Derivative can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular Isoquinoline Derivative employed. A person skilled in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the Condition. Isoquinoline Derivatives can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, Isoquinoline Derivatives can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of Isoquinoline Derivative ranges from about 0.1% to about 15%, w/w or w/v. In one embodiment, the compositions comprise an amount of each of an
Isoquinoline Derivative and another anticancer agent which together are effective to treat or prevent cancer. In another embodiment, the amount of Isoquinoline Derivative and another anticancer agent is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition. Some oral compositions can comprise from about 4% to about 50% of an Isoquinoline Derivative and another anticancer agent. Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition. The Isoquinoline Derivatives can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. The present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered an Isoquinoline Derivative. In one embodiment the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovasculare disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent. In one embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In another embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-renal failure agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In still another embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-diabetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In yet another embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anti-cardiovascular disease agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In a further embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In another embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other. In still embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. In yet another embodiment, the Isoquinoline Derivative can be administered prior to, concurrently with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other. Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. In one embodiment of the invention, where, another therapeutic agent is administered to a subject, the effective amount of the Isoquinoline Derivative is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that The Isoquinoline Derivative and the other therapeutic agent act synergistically to treat or prevent a Condition. Anti-inflammatory agents useful in the methods of the present invention include but are not limited to adrenocorticosteroids, such as cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylρrednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nimesulide. Anti-renal failure agents useful in the methods of the present invention include include but are not limited to ACE (angiotensin-converting enzyme) inhibitors, such as captopril, enalaprilat, lisinopril, benazepril, fosinopril, trandolapril, quinapril, and ramipril; diuretics, such as mannitol, glycerin, furosemide, toresemide, tripamide, chlorothiazide, methyclothiazide, indapamide, amiloride, and spironolactone; and fibric acid agents, such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate. Anti-diabetic agents useful in the methods of the present invention include include but are not limited to glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and -glucosidase inhibitors, such as acarbose and miglitol. Anti-cardiovascular disease agents useful in the methods of the present invention include include but are not limited to carnitine; thiamine; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine. Antiemetic agents useful in the methods of the present invention include include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa. Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene. Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac. Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
5.4 Kits The invention encompasses kits that can simplify the administration of an
Isoquinoline Derivative to a subject. A typical kit of the invention comprises a unit dosage form of an Isoquinoline Derivative. In one embodiment the unit dosage form is a container, which can be sterile, containing an effective amount of an Isoquinoline Derivative and a physiologically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instracting the use of the Isoquinoline Derivative to treat or prevent a Condition. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment the kit comprises a container containing an effective amount of an Isoquinoline Derivative and an effective amount of another prophylactic or therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above. Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
5.5 Methods For Making The Isoquinoline Derivatives Examples of synthetic pathways useful for making Isoquinoline Derivatives are set forth in the Examples below and generalized in Schemes 1-10. Methods useful for making Isoquinoline Derivatives of formula (I) wherein X is -CH2- and R5 is O are illustrated below in Scheme 1. Scheme 1
-yl
Figure imgf000061_0001
wherein compounds 8a-8af are as follows:
Figure imgf000062_0001
8a-af a. R=4- ethyl-piperazine-1 -yl q- R=-N(CH2CH2N e2)2 b. R=4-CH2C02Me-piperazine-1 -yl r. R=-N(CH2CH2OH)a c. R=4-(CH2CH2OH)-piperazine-1-yl s. R=-NHCH2CH2CN d. R=imidazole-1-yl t. R=-NHC(NH)NH2 e. R=L-prolinol u. R=-NH[4-(1 ,2,4-triazole)] f. R=morpholine-4-yl V. R=-NH[4-(morp ιo//n-4-y/)phenyl] g- R=NHCH2CH2NMe2 w. R=~NHCH2CH2(4-N-benzylpiperidine) h. R=NHCH2CH2-piperidine-1 -yl X. R=-NHCH2CH2(2-thienyl) i. R=NHCH2CH2N-(pyridine-2-yl) y- R=-NH[1 -(4-azabenzimidazole)] i- R=NHCH2CH2-morpholine-4-yl z. R=-NH[1-(4-(2'-pyridyl)piperazine)] k. R=NHCH2CH2-(2-N- e-tetrahydropyrrolidine-1- aa. , R=-NHCH2CH2N[CH2CH2OH]2 yi) ab. . R=-NH[1-(4-benzlpiperazine)] 1. R=NHCH2CH2CH2-morpholine-4-yl ac. R=-NH2 m. R=NHCH2CH2CH2-(tetrahydropyrrolidine-1-yl) ad. . R=-NHCH2CH2Ph n. R=NHCH2CH2CH2-imidazole-1 -yl ae. . R=-NHCH2CH2[4-OMe(phenyl)] 0. R=NHCH2CH2CH2-(4-methylpiperazine-1-yl) af. R=-NHC(0)(morp/)o/π-4-y/) P- R=N(CH2CH2NEt2)2 5,6-dihydro-5,ll-diketo-llH-isoquinoline (2) was prepared by reacting compound 1 (Aldrich Chemical, Milwaukee, WI) with ammonia in methanol. (±) ll-hydroxy-5,6-dihydro-5-oxo-HH-indeno[l,2-c]isoquinoline (3a) was prepared by reacting 2 with NaBΗ4 in ethanol. (±) ll-hydroxy-ll-methyl-5,6-dihydro-5-oxo-HH-isoquinoline (3b) was prepared by reacting 2 with MeMgl. (±) 11-hydroxy-l l-(m-methoxyphenyl)-5,6-dihydro-5-oxo-l lΗ-indeno[l,2- c]isoquinoline (3c) was prepared from 2 using m-MeO-C6H4MgI. (±) ll-N,N-dimethylamino-5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (5a) was prepared from 3a using chloroacetylchloride followed by reacting with dimethylamine. Similarly prepared are: (±) ll-Ν,Ν-diethylamino-5,6-dihydro-5-oxo- HH-indeno[l,2-c]isoquinoline (5b), (±) ll-N-(piperidino-l-yl)-5,6-dihydro-5-oxo- HH-indeno[l,2-c]isoquinoline (5d), (±) ll-N-(4-methylpiperazino-l-yl)-5,6-dihydro-5- oxol IH-indeno[l,2-c]isoquinoline (5c), (±) ll-N-(morpholino-4-yl)-5,6-dihydro-5- oxollH-isoquinoline (5e). (+) ll-N-(morpholino-4-yl)-5,6-dihydro-5-oxo- HH-indeno[l,2-c]isoquinoline (5e) was also prepared from (±) ll-bromo-5,6-dihydro-5- oxo-1 lH-indeno[l,2-c]isoquinoline (4b). 5,6-Dihydro-5-oxo-llH-indeno-[l,2-c]isoquinoline (6) is prepared by reduction of 5,6-dihydro-5,l 1-diketo-l lΗ-isoquinoline (2) or (±) 1 l-hydroxy-5,6-dihydro5-oxo-l 1 Η-isoquinoline (3a) using CF3COOΗ/triethylsilane. 9-Chlorosulphonyl-5,6-dihydro-5- oxo-1 lH-indeno-[l,2-c]isoquinoline (7) was prepared by chlorosulfonation of 5,6- dihydro-5-oxo-l lH-indeno-[l,2-c]isoquinoline (6). 9-[Ν-(4-methylpiperazine- lyl)sulphonyl]-5,6-dihydro-5-oxo-HH-indeno-[l,2-c]isoquinoline (8a) was prepared from 9-chlorosulphonyl-5,6-dihydro-5-oxo-l lH-indeno-[l,2-c] isoquinoline (7), and N-methylpiperazine. Similarly prepared are: 9-[N-(4- carbomethoxymethylenepiperazino-lyl)sulphonyl] -5 ,6-dihydro-5-oxo- 11 H-indeno- [1,2- c]isoquinoline (8b), 9-[N-4-(2-hydroxyethylpiperazino-l-yl)-sulphonyl]-5,6-dihydro-5- oxo-11 H-indeno- [1,2-c] isoquinoline (8c), 9-[N-(imidazolo-l-yl)sulphonyl]-5,6-dihydro- 5-oxo-l IH-isoquinoline (8d), 9-[N-(2-hydroxyρrolinyl)sulphonyl]-5,6-dihydro-5-oxo- 1 lH-indeno[l,2-c]isoquinoline (8e), 9-[N-morpholinesulphonyl]-5,6-dihydro-5-oxo- 1 lH-indeno[l,2-c]isoquinoline (8f), 9-[N-(2-[N)N-dimethylamino]ethyl)aminosulphonyl]- 5,6-dihydro-5-oxo-l lH-indeno[l ,2-c] isoquinoline (8g), 9-[N-(2-[piperidino-l- yl] ethyl)-aminosulphonyl] -5 ,6-dihydro-5-oxo-l 1 H-indeno [ 1 ,2-c] isoquinoline (8h) , 9- [N (2-(pyridino-2-yl)-ethyl)-aminosulphonyl]-5,6-dihydro-5-oxo-
HH-indeno[l,2c]isoquinoline (8i), 9-[N-(2 -[morpholino-4-yl]ethyl) -aminosulphonyl]- 5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (8j), 9-[N-(2- [N-methyltetrahydropyrroiidino-l-yl]ethyl) aminosulphonyl]-5,6-dihydro-5-oxo- HH-indeno-[l,2-c]isoquinoline (8k), 9-[N-(3-[morpholino-4-yl] propyl)-aminosulphonyl]-5,6-dihydro-5-oxo-l lH-indeno-[l ,2c] isoquinoline (81), 9-[N-(3- [tetrahydroρyrrolodino-l-yl]propyl)aminosulphonyl]-5,6-dihydro-5-oxo-llH-indeno- [l,2-c]isoquinoline (8m), 9-[N-(3-[imidazolo-l-yl]propyl)aminosulphonyl]-5,6-dihydro- 5-oxo-l lH-indeno-[l,2-c]isoquinoline (8n), 9-[N-[3-(4-methylpiperazino- l-yl]propyl)-aminosulphonyl]-5,6-dihydro-5-oxo-l lH-indeno-[ l,2c]isoquinoline (8o), 9-[N,N-di-(2-[N,N-diethylamino]ethyl)-aminosulphonyl]-5,6-dihydro-5-oxo-llH-indeno- [l,2-c]isoquinoline (8p), 9-[N,N di-(2-[N,N dimethylamino]ethyl)aminosulphonyl]-5,6- dihydro-5-oxo-HH-indeno-[l,2-c]isoquinoline (8q), and 9-[N,N-di(2- [N,N-dihydroxyethylamino] ethyl)-aminosulphonyl]-5,6-dihydro-5-oxo- 1 lH-indeno- [1,2c] isoquinoline (8r). Compounds 8s-8af can be prepared using the methods described above for making compounds of 8a-8r, using appropriate amine intermediates. Scheme 2 illustrates a method useful for making terminal carboxylic acid compounds of formulas 8ag-8ao. This method comprises reacting sulfonyl chloride 7 with the alkyl ester of an amino acid in the presence of a base, such as triethyamine, to provide an intermediate terminal carboxylic acid alkyl ester, which is then hydrolyzed using a base such as sodium hydroxide to provide the corresponding terminal carboxylic acid.
Scheme 2
Figure imgf000064_0001
8ag-ao ag. R=-NHCH2COOH ah. R=-NH(CH2)2COOH ai. R=-NH(CH2)3COOH aj. R=-NH(CH2)4COOH ak. R=-NH(CH2)5COOH al. R=-NHCH(CH2COOH)COOH am. R=-NHCH((CH2)2COOH)COOH an. R=-NHCH((CH2)4NH2)COOH ao. R=-NHCH(CH2OH)COOH wherein: R' is -amino-substituted C1-C5 alkyl or -hydroxy-substituted Cι-C5 alkyl R" is -Cι-C6 alkyl; and n is an integer ranging from 1 to 6. General Procedure for making 9-sulfonamide carboxylic acid derivatives
Preparation of 9-sulfonamido carboxylic acid ester To a 0.5 M solution of an ester of formula 41 or 42 in CH2C12 is added compound 7 (1.0 eq) and the resulting mixture is stirred for 5 minutes. Triethylamine (about 5 eq) is then added and the resulting reaction is stirred at room temperature and monitored using TLC or HPLC until complete. The reaction mixture is filtered, the solid is washed using MeOH to provide the intermediate 9-sulfonamido carboxylic acid ester which can be used without further purification.
Ester Hydrolysis To an approximately 0.5 M solution of a 9-sulfonamide carboxylic acid ester in ethanol is added about 3.0 N aqueous sodium hydroxide (about 5.0 eq) and the resulting reaction is refluxed if necessary and monitored using TLC or HPLC until completion. The reaction mixture is neutralized to about pH 7.0 using about 1.0 N HC1 and the neutralized reaction mixture is extracted twice using EtOAc. The combined EtOAc layers are washed sequentially with water and saturated aqueous sodium chloride, then dried over sodium sulfate and concentrated in vacuo to afford a crude residue which is purified using flash column chromatography to provide the desired 9-sulfonamide carboxylic acid compound. Acid hydrolysis with neat TFA can be useful where the sulfonamide has a t-butyl ester group.
In another embodiment, illustrated below in Scheme 3, Isoquinoline Derivatives of general formula 13 can be made by a method comprising contacting a compound of formula 11 and a compound of formula 12 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 13. Scheme 3
Figure imgf000066_0001
wherein: R R4 and R -R1o are as defined above for formula (I); and Rb is -CI, -Br, -I, -OMs, -OTs or -OTf.
In one embodiment, RD is -Br. In another embodiment, Rb and R_ are both -Br. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula
12 are used per about 1 equivalent of a compound of Formula 11. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 12 are used per about 1 equivalent of a compound of Formula 11. In still another embodiment, about 1 to about 2 equivalents of a compound of Formula 12 are used per about 1 equivalent of a compound of Formula 11. In one embodiment, about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 11. In another embodiment, about 3 to about 7 equivalents of base are used per about 1 equivalent of a compound of Formula 11. In a yet another embodiment, about 5 to about 6 equivalents of base are used per about 1 equivalent of a compound of Formula 11. Suitable bases for use in the method of Scheme 3 are organic bases such as triethylamine, lithium N-diisopropylamide, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates, including sodium carbonate, potassium carbonate and cesium carbonate. In one embodiment, the base is triethylamine. In another embodiment, the base is potassium carbonate. The method of Scheme 3 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof. In one embodiment, the solvent is acetonitrile. In another embodiment, the solvent is DMF. In still another embodiment, where the solvent is not water, the solvent is substantially anhydrous, i.e., comprises less than about 1 % water. In one embodiment, the method of Scheme 3 is carried out for a time of about 0.5 hours to about 48 hours. In another embodiment, the method of Scheme 3 is carried out for a time of about 3 hours to about 36 hours. In still another embodiment, the method of Scheme 3 is carried out for a time of about 8 hours to about 24 hours. In yet another embodiment, the method of Scheme 3 is carried out for a time of about 15 hours to about 20 hours. In a further embodiment, the method of Scheme 3 is carried out at a temperature of about 0°C to about 200°C. In another embodiment, the method of Scheme 3 is carried out at a temperature of about 25°C to about 150°C. In yet another embodiment, the method of Scheme 3 is carried out at a temperature of about 50°C to about 100°C.
General Procedure For The Preparation of Compounds of Formula 13 To a solution of a homophthalic anhydride of formula 11 (about 1 to about 2 equivalents) in a suitable solvent, such as acetonitrile, is added a compound of Formula 12 (about 1 to about 2 eq) followed by a suitable base, such as triethylamine (about 1 to about 5 eq). The resulting reaction is reaction is allowed to stir for about 1 hour, at which time a colored precipitate appears. The reaction is then heated at reflux for about 20 hours, cooled to room temperature and filtered. The collected solid is washed using acetonitrile and dried under vacuum to provide a compound of Formula 13. Scheme 4
Figure imgf000068_0001
The amide derivative 2-dimethylamino-N-(5-oxo-5,ll-dihydro- 6H-indeno[l,2c]isoquinoiin-2-yl)-acetamide (17) was prepared from 5-chloro- HΗ-indeno [l,2c]isoquinoline (14). Compound 14 was subjected to nitration to provide nitro compound 15, which was reduced using ammonium formate to provide amine 16, which was derivatized to acetamide 17, and followed by animation of the chloroacetamide intermediate. 2-bromo5,6-dihydro-5-oxo-l lΗ-indeno[l,2- c]isoquinoline (18) was prepared by bromination of Compound 14.
Scheme 5 illustrates methods useful for making oxygen-substituted Isoquinoline Derivatives of formula (I), where R5 and X are oxygen. Scheme 5
Figure imgf000069_0001
wherein: R1-R5 are as defined above for formula (I); each occurrence of Ra is independently Ci-Cs alkyl; Rb is -CI, -Br, -I, -OMs, -OTs or -OTf; R is -C1-C10 alkyl, alkanol or alkylcarboxy; and R" is -C1-C10 alkyl, aryl, heterocycle, alkanol or alkylcarboxy.
In one embodiment, Ra is methyl. In another embodiment, Rb is -Br In another embodiment, illustrated above in Scheme 5, Isoquinoline Compounds of formula 22 can be made by a method comprising contacting a compound of formula 20 and a compound of formula 21 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 22. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21. In still another embodiment, about 1 to about 2 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 21. In one embodiment, about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 21. In another embodiment, about 3 to about 7 equivalents of base are used per about
1 equivalent of a compound of Formula 21. In a yet another embodiment, about 5 to about 6 equivalents of base are used per about 1 equivalent of a compound of Formula 21. Suitable bases for use in the method are organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. In one embodiment, the base is potassium carbonate. In another embodiment, the base is triethylamine. The method can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof. In one embodiment, the solvent is DMF. In another embodiment, the solvent is acetonitrile. In still another embodiment, the solvent is substantially anhydrous, i.e., comprises less than about 1 % water. In one embodiment, the method is carried out for a time of about 1 hour to about 96 hours. In another embodiment, the method is carried out for a time of about 18 hours to about 72 hours. In yet another embodiment, the method is carried out for a time of about 24 hours to about 48 hours. In one embodiment, the method is carried out at a temperature of about 25 °C to about 200°C. In another embodiment, the method is carried out at a temperature of about 50°C to about 150°C. In still another embodiment, the method is carried out at a temperature of about
75°C to about 125°C.
Scheme 6 illustrates methods useful for making nitrogen-substituted Isoquinoline Derivatives of the invention.
Scheme 6
Figure imgf000072_0001
27 28
Figure imgf000072_0002
30
Figure imgf000072_0003
32 C1S03H
Figure imgf000072_0004
In an alternate embodiment, illustrated below in Scheme 7, nitrogen-substituted Isoquinoline Derivatives of general formula 37 can be made by a method comprising contacting a compound of formula 36 and a compound of formula 11 or formula 20 in the presence of a base for a time and at a temperature sufficient to make a compound of formula 37.
Scheme 7
Figure imgf000073_0001
Figure imgf000073_0002
11 wherein: R1-R4 and R -Rio are as defined above for formula (I); each occurrence of Ra is independently C1-C5 alkyl; Rb is -CI, -Br, -I, -OMs, -OTs or -OTf, and Rc, is C1-C5 alkyl. In one embodiment, Ra is methyl. In another embodiment, Rb is -Br. In a further embodiment, Ra is methyl and Rb is -Br. In still another embodiment, Rc is methyl. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36. In still another embodiment, about I to about 2 equivalents of a compound of Formula 11 are used per about 1 equivalent of a compound of Formula 36. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 36. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 36. In still another embodiment, about 1 to about 2 equivalents of a compound of
Formula 20 are used per about 1 equivalent of a compound of Formula 36. In one embodiment, about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 36. In another embodiment, about 3 to about 7 equivalents of base are used per about 1 equivalent of a compound of Formula 11. In a yet another embodiment, about 5 to about 6 equivalents of base are used per about 1 equivalent of a compound of Formula 11. Suitable bases for use in the method of Scheme 7 are organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. In one embodiment, the base is potassium carbonate. In another embodiment, the base is triethylamine. The method of Scheme 7 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof. In one embodiment, the solvent is DMF. In another embodiment, the solvent is acetonitrile. In still another embodiment, the solvent is substantially anhydrous, i.e., comprises less than about 1 % water. In one embodiment, the method of Scheme 7 is carried out for a time of about 1 hour to about 96 hours. In another embodiment, the method of Scheme 7 is carried out for a time of about 18 hours to about 72 hours. In yet another embodiment, the method of Scheme 7 is carried out for a time of about 24 hours to about 48 hours. In one embodiment, the method of Scheme 7 is carried out at a temperature of about 25°C to about 200°C. In another embodiment, the method of Scheme 7 is carried out at a temperature of about 50°C to about 150°C. In still another embodiment, the method of Scheme 7 is carried out at a temperature of about 75°C to about 125°C.
General Procedure For The Preparation of Compounds of Formula 37
From a homophthalate: To a solution of a homophthalate of Formula 20 (about 1 eq) and an N- acylanthranilonitrile of Formula 36 (about 1 to about 2 eq) in a solvent such as DMF, under inert atmosphere, is added a base (about 5 eq), such as potassium carbonate and the reaction is allowed to stir for about 48 hours at about 100°C, then cooled to room temperature. The reaction mixture is then poured into about 1 Ν sodium hydroxide and the resulting solution is extracted with EtOAc. The EtOAc layer is washed sequentially with about 1 Ν HC1, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue is dissolved using warming in toluene and the resulting solution is cooled to room temperature and precipitated using hexanes. The solid precipitate is filtered, washed using hexanes and dried in a vacuum oven at 50°C for 72 h to provide a Compound of Formula 36. The synthesis of phenyl amide 36, which is a useful intermediate in Scheme 7, is described below in Scheme 8. In this procedure, the amine group of a cyanoaniline compound of formula 38 is acylated using an acyl chloride or an anhydride in the presence of an acid. Scheme 8
Figure imgf000076_0001
38 36 36a: R7-Rιo=-H Rc = CH3
wherein: R7-R are as defined above for formula (I); and Rc is C1-C5 alkyl. Suitable acids for use in the method of Scheme 8 include, but are not limited to, sulfuric acid and phosphoric acid. In one embodiment, the acid is sulfuric acid. In another embodiment, Rc is methyl. The method of Scheme 8 can be carried out in the presence of a solvent, including, but not limited to, acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether or mixtures thereof.
General Procedure For Making a Compound of Formula 36 To a solution of a compound of Formula 38 (about 1 eq) in acetic anhydride (about 6 eq) at 90°C is added 1 drop of sulfuric acid (catalytic) and the resulting reaction is stirred at about 90°C for about 2 h, and is then allowed to sit at room temperature for about 12 h. The reaction mixture is poured onto ice and the resulting solution is stirred for about 2 h, after which time the solution is neutralized to about pH 7.0 using 1 N sodium hydroxide. The resulting precipitate is filtered, washed using water (about 4x) and dried under vacuum for about 72 h to provide a compound of Formula 36. In another embodiment, illustrated below in Scheme 9, sulfur substituted Isoquinoline Derivatives of formula 40 can be made by a method comprising contacting a compound of formula 39 and a compound of formula 11a or formula 20 in the presence a base for a time and at a temperature sufficient to make a compound of formula 40.
Scheme 9
Figure imgf000077_0001
Ri-Rt and R7-R10 are as defined above for formula (I); each occurrence of Ra is independently C1-C5 alkyl; Rb is -CI, -Br, -I, -OMs, -OTs or -OTf; and R is -H or -Br.
In one embodiment, Ra is methyl. In another embodiment, Rb is -Br. In still another embodiment, Ra is methyl and Rb is -Br. In yet another embodiment, R is -H. In a further embodiment, Rd is -Br. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula a are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In still another embodiment, about 1 to about 2 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In yet another embodiment, about 1 to about 2 equivalents of a compound of Formula 11a are used per about 1 equivalent of a compound of Formula 39. In one embodiment, about 0.1 to about 10 equivalents of a compound of Formula
20 are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 0.5 to about 5 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 39. In yet another embodiment, about 1 to about 2 equivalents of a compound of Formula 20 are used per about 1 equivalent of a compound of Formula 39. In one embodiment, about 1 to about 10 equivalents of base are used per about 1 equivalent of a compound of Formula 39. In another embodiment, about 3 to about 7 equivalents of base are used per about 1 equivalent of a compound of Formula 39. In a yet another embodiment, about 5 to about 6 equivalents of base are used per about 1 equivalent of a compound of Formula 39. Suitable bases for use in the method of Scheme 9 are organic bases such as triethylamine, lithium N-diisopropylamide, diisopropylethylamine, pyridine, lutidine and imidazole; and inorganic bases such as alkali metal carbonates, including sodium carbonate, potassium carbonate and cesium carbonate. In one embodiment, the base is potassium carbonate. In another embodiment, the base is triethylamine. The method of Scheme 9 can be carried out in the presence of a solvent, such as acetonitrile, methylene chloride, chloroform, THF, DMF, DMSO, ethyl acetate, acetone, benzene, diethyl ether, water or mixtures thereof. In one embodiment, the solvent is DMF. In another embodiment, the solvent is acetonitrile. In one embodiment, the method of Scheme 9 is carried out for a time of about 1 hour to about 120 hours. In another embodiment, the method of Scheme 9 is carried out for a time of about 24 hours to about 96 hours. In yet another embodiment, the method of Scheme 9 is carried out for a time of about 60 hours to about 80 hours. In one embodiment, the method of Scheme 9 is carried out at a temperature of about 0°C to about 200°C. In another embodiment, the method of Scheme 9 is carried out at a temperature of about 25 °C to about 150°C. In still another embodiment, the method of Scheme 9 is carried out at a temperature of about 50°C to about 100°C.
General Procedure for the Preparation Compounds of Formula 40
From a homophthalic anhydride: A solution of a mercaptobenzonitrile of Formula 39 (about 1.0 eq) and a homophthalic anhydride of Formula 11a (about 2.0 eq) in a suitable solvent such as acetonitrile under inert atmosphere is warmed with stirring until all reactants are in solution. A suitable base such as triethylamine (about 1 to about 5 eq) is added and the reaction is allowed to stir at about 90°C for about 72 hours, then cooled to room temperature. The reaction mixture is filtered, and the collected solid is washed using methanol, then dried in a vacuum oven at about 50°C to provide a compound of Formula 40.
From a homophthalate: A solution of a mercaptobenzonitrile of Formula 39 (about 1.0 eq) and a homophthalate of Formula 20 (about 2.0 eq) in a suitable solvent such as acetonitrile under inert atmosphere is warmed with stirring until all reactants are in solution. A suitable base such as triethylamine (about 1 to about 5 eq) is added and the reaction is allowed to stir at about 90°C for about 72 hours, then cooled to room temperature. The reaction mixture is filtered, and the collected solid is washed using methanol, then dried in a vacuum oven at about 50°C to provide a compound of Formula 40. Methods for making Isoquinoline Derivatives of Formula (IN) are illustrated below in Scheme 10. Scheme 10
Figure imgf000080_0001
wherein: n, Zi, and Z2 as defined above for Formula (IV); X is a leaving group such as bromide or chloride; Rb is -CI, -Br, -I, -OMs, -OTs, or -OTf; one Re is -H and the other R_ is -NO2; one Rf is -H and the other Rf is -NH2; one Rg is -H and the other Rg is -NHC(O)-(CH2)n-X; and one Rh is -H and the other Rh is -NHC(O)-(CH2)n-NZιZ2. In one embodiment, Rb is -Br. General Procedure For The Preparation of Compounds of Formula 56 To a solution of homophthalic anhydride (lib) (about 1 equivalent) in a suitable solvent, such as acetonitrile, is added a compound of Formula 51 (about 1 to about 2 equivalents), follwed by a suitable base, such as triethylamine (about 1 to about 5 equivalents). The resultant reaction mixture is allowed to stir for about 1 hour, at which time a precipitate appears. The reaction mixture is then heated to reflux for about 20 hours, cooled to room temperature and filtered. The collected solid is washed with acetonitrile and dried under vacuum to provide a compound of Formula 53. Compound 52 can be prepared from homophthalic anhydride (lib) and benzoic anhydride in two steps. Homophthalic anhydride and benzoic anhydride are reacted in a suitable solvent such as pyridine in the presence of an acid such as HC1; subsequently reacted with acetic anhydride in pyridine and heated to reflux; and then refluxed in the presence of an amine such as NH3 in MeOH; to provide the compound of Formula 52. To a solution of the compound of Formula 52 or 53 in a suitable solvent, such as
DMF, is added a reducing agent, such as ammonium formate in the presence of palladium on carbon. The reaction mixture is heated to a temperature of about 90 to 100°C, cooled to room temperature and filtered to provide a compound of the Formula 54. The compound of the Formula 54 can be reacted with X-(CH2)n-COCl, under conditions effective to form an amide of the Formula 55. The compound of Formula 55 can be reacted with an amine of formula HNZιZ2, in the presence of a solvent such as ethanol or DMF and heating to reflux, to form the compound of Formula 56. The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. The following examples illustrate the synthesis of illustrative Isoquinoline Derivatives and demonstrate their usefulness for treating or preventing a Condition. 6. EXAMPLES
Example 1: Preparation of Illustrative Isoquinoline Derivatives
a) General Methods Proton NMR spectra were obtained using a Varian 300 MHz spectrophotometer and chemical shift values (δ) are reported in parts per million (ppm). TLC was performed using TLC plates precoated with silica gel 60 F-254, and preparative TLC was performed using precoated Whatman 60 A TLC plates. All intermediates and products were characterized on the basis of 1H NMR and/or MS data.
b) Preparation of 5,6-dihydro-5,ll-diketo-llH-indeno[l,2-c]isoquinoline (2):
Figure imgf000082_0001
A stirred suspension of 1 (55 g, 0.22 mol) (Scheme 1) in NH3/MeOH (7.0 N, 700 mL) was refluxed for 24 h. The reaction mixture was then allowed to cool to room temperature and was filtered and washed with MeOH to provide 46 g of the orange colored above-titled product in 84 % yield. 1H NMR (DMSO-d6): δ 7.48-7.61 (m, 4H), 7.80-7.88 (m, 1H), 7.86 (d, J= 8.7 Hz, 1H), 8.22 (d, J= 8.4 Hz, 1H), 8.44 (d, J= 7.5 Hz, 1H), 13.05 (s, 1H); 13C NMR (DMSO-D6): δ 106.33, 121.63, 122.94, 123.27, 124.80, 128.45, 132.17, 133.60, 134.03, 134.68, 134.68, 134.81, 137.09, 156.41, 163.76,190.57; MS (ES"): m z 246.2 (M-l); Anal. Calcd for C16H9NO2: C, 77.72; H, 3.67; N, 5.67; Found: C, 77.54; H, 3.69, N, 5.69. C) Preparation of (±) ll-hydroxy-5,6-dihydro-5-oxo-llH-indeno[l,2- cjisoquinoline (3a):
Figure imgf000083_0001
To a stirred suspension of 2 (2.5 g, 0.01 mol) in EtOH (25 mL) was added NaBIL
(3.75 g, 0.1 mol) at room temperature in small portions over 30 min. The reaction mixture was stirred for an additional 2 h and then cooled to 0°C. It was then triturated with 10 % HC1 (10 % soln.). The resulting solid precipitated was filtered and washed with water and MeOH to provide 3a (2.326 g, 92 %). 1H NMR (DMSO-d6): δ 5.58 (d, J = 8.1 Hz, IH), 5.78 (d, J =8.7 Hz, IH), 7.33 -7.89 (m, 6H), 7.95 (d, J = 7.8 Hz, IH, 8.22 (d, J= 7.8 Hz, IH), 12.29 (s, IH); 13C NMR (DMSO-d6): S 77.44, 118.81, 120.15, 124.28, 125.04, 125.67, 126.34, 128.46, 128.64, 128.95, 133.27, 135.62, 136.12, 139.93, 148.55, 163.69.; MS (ES+): m/z 250.1 (M+1); Anal. Calcd for C6HπNO2: C, 77.10; H, 4.45; N, 5.62. Found: C, 77.01; H, 4.57, N, 5.59. Similarly, by reacting 2 with MeMgl and m-MeO-CelLMgBr, respectively, compounds (±) ll-hydroxy-ll-methyl-5,6-dihydro-5-oxo-HH-indeno[l,2-c]isoquinoline (3b) and (±) ll-hydroxy-ll-(3-methoxyphenyl)-5,6-dihydro-5-oxo-HH-indeno[l,2c] isoquinoline (3c) were prepared.
d) Preparation of 11-substituted S.ό-dihydro-S-oxo-llJEf-indenotl^- c]isoquinolines (5a-e):
Figure imgf000084_0001
4a 5a-e 5a: R = NMe2 5b: R = NEt2 5c: R = -N-methyl-piperazin-4-yl 5d: R = -piperidine- 1-yl 5e: R = -morpholin-1-yl To a stirred suspension of 3a (0.5 g, 2 mmol) in pyridine (10 mL) was added chloroacetyl chloride (0.81 g, 0.006 mol) at 0°C. The reaction mixture was allowed to warm to room temperature and allowed to stir for 24 h. The reaction mixture was then poured on ice and extracted with EtOAc. The organic layer was separated, dried and concentrated to provide crude compound 4a, which was treated further with dimethylamine and stirred at room temperature for 24 h. The reaction mixture was poured on ice, and treated with 10 % HCl. The resultant mixture was then basified using saturated aqueous NaHCO3 and the resulting solid was filtered to provide the desired product 5a. 1H NMR (DMSO-D6): δ 2.31 (s, 6H), 5.00 (s, IH), 7.28-7.45 (m, 3H), 7.68-7.73 (m, 2H), 7.95 (d,J= 6.9 Hz, IH), 8.10 (d, J = 7.8 Hz, IH), 8.21 (d, J= 8.1 Hz, IH), 12.26 (s, IH); 13C NMR (DMSO-D6): δ 68.09, 116.28, 120.52, 124.58, 125.74, 126.27, 126.34, 127.68, 128.64, 133.02, 136.27, 144.45, 163.80; MS (ES+): m/z 277.2 (M+1). The following compounds were also prepared by reacting 4a as above with diethylamine, piperidine, N-methylpiperazine and morpholine, respectively: (±) 11 - diethylamino-5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (5b), (±) 11-(N- methylpiperazin)-5,6-dihydro-5-oxo-l lH-indeno[l,2-c]isoquinoline (5c), (±) ll-(piperidin)-5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (5d), and (±) 11- morpholino-5,6-dihydro-5-oxo-l lH-indeno[l,2-c]isoquinoline (5e).
e) Preparation of (±) ll-morpholino-5,6-dihydro-5-oxo-llΗ-indeno[l,2- c]isoquinoline (5e):
Figure imgf000085_0001
4b 5e To a stirred suspension of 3a (0.6 g, 2.4 mmol) in trifluoroacetic acid (5 mL) was added phosphorus tribromide (1.0 M soln. in CH2C12, 3 mL) at room temperature, and the reaction mixture was stirred for 8 h. The reaction mixture was poured on ice and the resulting solid was filtered to provide bromo compound 4b (0.61 g, 76 %). 1H NMR (DMSO-d6): δ 7.35-7.50 (m, 3H), 7.61 (d, J= 6.6 Hz, IH), 7.73 -7.82 (m, 2H), 7.94 (d, J = 6.6 Hz, IH), 8.23 (d, J = 7.8 Hz, IH, 12.41 (s, IH); 13NMR (DMSO-d6): δ 52.06, 79.35, 114.43, 120.56, 123.58, 125.27, 125.50, 126.68, 128.55, 128.86, 129.66, 133.73, 135.91, 136.61, 141.39, 143.95, 163.74. Compound 4b (0.5 g) was suspended in MeOH (10 mL) and treated with excess morpholine (about 5.0 eq) at room temperature and stirred at 60 °C for 3 h. The reaction mixture was poured on ice, and diluted with ethyl acetate (40 mL). The organic layer was separated and extracted in dil. HCl (10 % soln.), the aqueous layer was then basified with saturated aqueous NaHCO3 and the resulting solid precipitated was filtered and dried to provide compound 5e (0.46 g, 90 %). 1H NMR (DMSO-d6): δ 2.56 (m, 4H), 3.49 (m, 4H), 5.04 (s, IH), 7.31-7.45 (m, 3H), 7.65 -7.76 (m, 2H), 7.96 (d, J= 7.2 Hz, IH), 8.20- 8.24 (m, 2H), 12.29 (s, IH); 13C NMR (DMSO-D6): δ 49.36, 67.62, 68.11, 115.20, 120.60, 124.47, 125.84, 126.34, 126.41, 127.76, 128.30, 128.72, 133.09, 136.30, 13δ.96,140.35, 144.44, 163.67. f) Preparation of 5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (6):
Figure imgf000086_0001
Method I: To a stirred solution of the alcohol 3a (0.35 g, 1.4 mmol) in trifluoroacetic acid (10 mL) was added at room temperature triethylsilane (0.812 g, 7 mmol) and the reaction mixture was stirred for 24 h. Trifluoroacetic acid was evaporated in vacuo and EtOAc was added to the resulting crude product. The resulting solid was filtered and washed with H2O and EtOAc to provide the above-titled compound 6 (0.285 g, 87 %). 1H NMR (DMSO-D6): δ 3.89 (s, 2H), 7.30 -7.47 (m, 3H), 7.59 (d, J = 6.9 Hz, IH), 7.72 -7.74 (m, 2H), 7.98 (d, J= 7.8 Hz, IH), 8.23 (d, J= 8.4 Hz, IH), 12.31 (s, IH); 13C NMR(DMSO-d6): δ 33.51, 116.50, 120.19, 124.01, 125.51, 125.55, 126.42, 127.50, 127.68, 128.56, 133.45, 136.39, 137.53, 140.18, 143.80, 163.46; MS (ES): m/z 232.1 (M-l); Anal. Calcd forCι6HnNO: C, 82.38; H, 4.75; N, 6.00. Found: C, 81.79; H, 4.45, N, 5.99. Method H: To a stirred suspension of 2 (40 g, 0.16 mol) in trifluoroacetic acid
(2.5 L) was added triethylsilane (94 g, 0.8 mol) in small portions at room temperature and the reaction mixture was stirred for 96 h, during which time the reaction progress was monitored using TLC (eluent - 5 % MeOH/CH2Cl2). The reaction mixture was slowly poured on ice, filtered, washed with copious amounts of H2O and MeOH and dried in vacuo to provide the above-titled compound 6 (33.1 g, 88 %), whose spectral data were identical to those of a sample of compound 6 that was obtained using Method I. g) Preparation of 9-chlorosulfonyl-5,6-dihydro-5-oxo-llH-indeno[l,2« c]isoquinoline (7):
Figure imgf000087_0001
Compound 6 (40 g, 0.17 mol) was added in small portions to chlorosulfonic acid (112 mL, 1.71 mol) at 0°C and the reaction mixture was allowed to warm to room temperature and allowed to stir for 2 h. The reaction mixture was slowly poured on ice and the resulting yellow solid was filtered, washed thoroughly with water and EtOAc and dried in vacuo to provide the above-titled product 7 (52 g, 92 %). 1H NMR (DMSO-d6): δ 3.91 (s, 2H), 7.43 -7.48 (m, IH), 7.60 (d, J = 7.2 Hz, IH), 7.74 -7.76 (m, 2H), 7.79 (s, IH), 7.90 (d, J = 7.5 Hz, IH), 8.23 (d, J = 7.8 Hz, IH), Anal. Calcd. for Cι6H12ClNO4S: C, 54.94; H, 3.46; N, 4.00. Found: C, 55.28; H, 3.43, N, 3.68, Karl-Fisher, 2.95.
h) Preparation of 9-sulphonamido derivatives of 5,6-dihydro-5-oxo-llH- indeno[l,2-c]isoquinolines (8a-af) :
Figure imgf000087_0002
8a-af a. R=4-Methyl-piperazine-1-yl q. R=-N(CH2CH2NMe2)2 b. R=4-CH2C02Me-piperazine-1-yl r. R=-N(CH2CH2OH)2 c. R=4-CH2CH2OH-piperazine-1-yl s. R=-NHCH2CH2CN d. R=imidazole-1-yl t. R=-NHC(NH)NH2
Figure imgf000088_0001
Method I: To a stirred suspension of 3-(4-morpholino)-l-propylamine (17.28 g, 0.12 mol) in EtOAc was added sat. aq. NaHCO3 (300 mL), and the mixture was allowed to stir for 15 min. Compound 7 (4.0 g, 0.012 mol) was then introduced in small portions at room temperature. The reaction mixture was stirred for 24 h; filtered and washed with H2O, EtOAc and MeOH; refluxed in MeOH for 30 min; filtered while still warm; and washed with MeOH to provide compound 81 as a free base (2.33 g, 44 %). 1H NMR(DMSO-d6): δ 1.47-1.52 (m, 2H), 2.16-2.21 (m, 4H), 2.47-2.48 (m, 2H), 3.44-3.48 (m, 2H), 3.23 (m, 4H), 4.02 (s, 2H), 7.49 -7.58 (m,lH), 7.78-7.82 (m, 3H), 7.97 (s, IH), 8.14 (d, J = 7.8 Hz, IH), 8.26 (d, J= 7.8 Hz, IH), 9.59 (s, IH), 12.42 (s, IH). The free bases of 8d, 8g, 8h, 8j, 8m-8r were also prepared by Method I, but substituting 3-(4-morpholino)-l-propylamine with imidazole, 2-dimethylamino- ethylamine, 2-(N-piperidinyl)-ethylamine, 2-(N-mo holinyl)-e ylamine, 3-(N-tetrahydropyrrolidinyl)-propylamine, 3-(N-imidazolyl)-propylamine, 3(N-(4- methylpiperazinyl)-propylamine, di-(2-(diethylamino)-ethyl)amine, di-(2(dimethylamino)-ethyl)amine and di-(2-hydroxyethyl)amine, respectively. Method II: To a stirred suspension of 3-(4-morpholino)-l-propylamine (4.250 g) in CH2C12 (100 mL) was added 7 (1.950 g, 5.89 mmol) and the resulting mixture was stirred for 5 minutes. Subsequently, triethylamine (3 mL) was added and the reaction mixture was stirred for 24 h at room temperature. After this time the precipitate was collected and washed with MeOH (2 xlOO mL) and the crude solid product transferred to a round bottom flask. This material was diluted with MeOH (200 mL), heated to reflux for 30 min. and filtered while still warm. The resulting filtercake was washed with MeOH (200 mL) to provide the desired product as the free base of 81 (1.460 g, 56 %). The free bases of compounds 8d, 8g, 8h, 8j, 8m, 8n, 8o, 8p, 8q, and 8r were prepared using Method II, but substituting 3-(4-morpholino)-l-propylamine with about an equivalent amount of imidazole, 2-dimethylamino-ethylamine, 2-(N-piperidinyl)-ethylamine, 2-(N-moφholinyl)-ethylarnine, 3-(N-tetrahydropyrtolidinyl)-propylamine, 3-(N-imidazolyl)propylamine, 3-(N-(4- methylpiperazinyl) propyla ine, di-(2-(diethylamino)-ethyl)amine, di(2-(dimemylamino)-efhyl)amine and di-(2-hydroxyethyl)amine, respectively.
k) Preparation of the mesylate salt of 81: Free base 81 (l.Og) was added to methanesulfonic acid (10 mL) at 0°C and the resulting mixture was allowed to warm to room temperature and to stir for 2 h. The reaction mixture was then poured into cold MeOH (100 mL, between -10°C and 0°C) and the precipitated solid was filtered, washed with MeOH (100 mL) and dried in vacuo. The dried solid was then dissolved in water (100 mL), filtered and lyophilized to provide the methanesulfonate monohydrate salt 81. (1.020 g, 84 %). 1H ΝMR (DMSO-d6): δ l.75- 1.85 (m, 2H), 2.35 (s, 3H), 2.78-2.84 (m, 2H), 2.96-3.12 (m, 4H), 3.36 (d, J= 12.3 Hz, 2H), 3.61 (t, J= 11.4 Hz, 2H), 3.94 (d, J= 12.9 Hz, 2H), 4.03 (s, 2H), 7.49 -7.55 (m, IH), 7.76-7.84 (m, 3H), 7.99 (d, J= 0.9 Hz, IH), 8.15 (d, J= 8.4 Hz, IH), 8.25 (d, J= 8.4 Hz, IH), 9.59 (s, IH), 12.42 (s, IH); 13C ΝMR (DMSO-d6): δ 24.27, 33.86, 51.89, 54.51, 64.02, 119.70, 120.39, 123.53, 126.09, 126.45, 128.63, 133.66, 135.80, 138.71, 141.21, 144.57, 163.29; Anal. Calcd for C24H31Ν3O4S2: C 52.06; H, 5.46; N, 7.59, Karl-Fisher, 3.36. Found: C, 51.85; H, 5.35, N, 7.30, Karl-Fisher, 4.32. Similarly, HCl, H2SO , CH3COOH, and succinic acid salts of 81 were prepared by substituting methanesulfonic acid with about an equivalent amount of HCl, H2SO and CH3COOH, respectively.
I) Preparation of 5,6-dihydro-5-oxo-llH-indeno[l,2-c]isoquinoline (6)
Figure imgf000089_0001
To a solution of homophthalic anhydride (324 mg, 2.0 mmol) in acetonitrile (15 mL) was added 2-cyanobenzyl bromide (431 mg, 2.0 mmol, 1.0 eq) and triethylamine (5 mL). The reaction was allowed to stir under inert atmosphere at room temperature for 30 minutes, after which time a yellow precipitate appeared. The reaction mixture was then heated at reflux for 18 h and the resulting white precipitate was filtered, washed using acetonitrile (3 x 8 mL) and dried under vacuum to provide Compound 6 as a white crystalline solid. Yield = 150 mg (32 %).
m) Preparation of -Bromodimethylhomophthalate (20a) Dimethylhomophthalate (83.1 g) was dissolved in dichloromethane (2 L) and
N-bromosuccinimide (121 g, 1.7 eq) was added. The resulting suspension was irradiated for 18 h with a 500 Watt quartz-halogen lamp, which brought the reaction mixture to reflux. The reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate (4 L), saturated aqueous sodium bisulfite (2 L), and saturated aqueous sodium chloride (2 L). The organic phase was dried using sodium sulfate with a small amount of silica added to remove polar impurities. The organic phase was filtered and concentrated in vacuo to provide Compound 20a as a dark orange oil. Yield = 120.3 g (100 %).
n) Preparation of 8-Methoxy-o'H-ll-oxa-6-aza-benzo[α]fluoren-5-one (22a) α-Bromodimethylhomophthalate (20a) (1.16 g) and 2-hydroxy-5 - methoxybenzonitrile (0.6 g, 4 mmol, 1 eq) were dissolved by warming in acetonitrile (6 mL). Triethylamine (5.6 mL, 10 eq) was then added and the reaction was heated at reflux for 48 h under inert atmosphere, then cooled to room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (40 mL) and the resulting suspension was allowed to stir for 2 h, and was then filtered. The filtercake was washed sequentially with 1 N HCl (2 x 50 mL), acetonitrile (2 x 50 mL) and dichloromethane (50 mL), then dried in a vacuum oven at 50°C for three days to provide Compound 22a as an white solid. Yield = 0.81 g (76 %).
o) Preparation of 8-Hydroxy-6 /-ll-oxa-6-aza-benzo[α]fluoren-5-one (23a) 8-Methoxy-6"H-ll-oxa-6-aza-benzo[ ]fluoren-5-one (22a) (5.0 g) was cooled using an ice bath, and boron tribromide (1 M in methylene chloride, 95 mL, 95 mmol, 5 eq) added in a steady stream under nitrogen. The reaction was heated at reflux under inert atmosphere for two hours, then cooled to room temperature and poured into water (150 mL). The resulting suspension was allowed to stir for 1 h, filtered, and the solids were washed with water (2 x 200 mL). The solids were then diluted with 5 N sodium hydroxide (600 mL) using heating. The resulting solution was cooled to 0°C using an ice bath and the solution was acidified to pH 1 using cone. HCl. The resulting precipitate was vacuum filtered, and the solids washed sequentially with water (3 x 300 mL) and diethyl ether (300 mL) then dried overnight using a vacuum oven at 50°C to provide Compound 23a as a gray solid. Yield 4.74 g (100 %).
p) Preparation of 3-Nitroso-2-Phenyindole (28) A solution of 2-phenylindole (27) (25 gm, 0.129 mol) in acetic acid (250 mL) was cooled to 18°C and a solution of sodium nitrite (8 g, 0.115 mol) in water (10 mL) was added dropwise while keeping the temperature of the reaction at ca. 20°C. The resulting reaction was stirred for 30 min at room temperature then diluted with ice water (250 mL). The reaction mixture was was filtered and the solid was washed with water then recrystallized using methanol to provide Compound 28. Yield = 27.5 gm (96.4.%). ES- MS: 223.22 (M++l); NMR (DMSO-d6): δ 7.0 (m,lH), 7.1 (m, IH), 7.22 (m, IH), 7.32 (m, 2H), 7.40 (m, IH), 7.48 (m, 2H), 7.60 (m,lH).
q) Preparation of 3-Amino-2-Phenylindole (29) To a solution of 3-nitroso-2-phenyl indole (28) (25 gm, 0.129 mol) in ethanol (450 ml) was added 2N sodium hydroxide (300 mL, 5.0 eq) followed by sodium dithionite (38 g). The reaction was heated at reflux for 5 h, then filtered. The solid was washed with water and dried under vacuum to provide Compound 29 as a yellow solid. Yield = 15 g (72.1 %). ES-MS: 209.25 (M++ 1); NMR (DMSO-d6): δ 7.0 (m, IH), 7.1 (m, IH), 7.22 (m, IH), 7.32 (m, 2H), 7.40 (m, IH), 7.48 (m, 2H), 7.60 (m, IH).
r) Preparation of 2-Phenylindole-3-ethylcarbamate (30) To a 0 °C solution of 3-amino-2-ρhenylindole (29) (1.7 g, 8.17 mmol) in dichloromethane (150 ml) was added triethylamine (5 mL, 4.5 eq) followed by ethyl chloroformate (1 mL). The reaction was allowed to stir for 15 h, after which time the reaction mixture was diluted with water and transferred to a separatory funnel. The dichloromethane (50 mL), washed with water (2 x 50 rnL), brine (50 mL) and dried over sodium sulfate. The solvent was removed and dried under vacuum to provide Compound 30 as a black solid (1.6 gm, 72.7 %). ES-MS: 281.25 (M++l); NMR (DMSO-d6): δ 1.30 (t,3H), 4.12 (t, 2H), 7.0 (m, IH), 7.1 (m, IH), 7.22 (m,2H), 7.32 (m, 2H), 7.40(m,lH), 7.48 (m, 2H), 7.60 (m, IH).
s) Preparation of 6H,llH-Indolo[3,2-c]Isoquinoline-5-one (31). A solution of 2-Phenylindole-3-aminoethylcarbamate (30) (1.4 g, 5 mmol) in diphenyl ether (10 ml) was heated at reflux for 4 h, then cooled to room temperature. The reaction mixture was filtered and the solid was washed sequentially using warm hexane and warm dichloromethane and dried under vacuum to provide Compound 31 as a gray solid. Yield = 1.6 g (72.7 %). ES-MS: 235.25 (M++l).
t) Preparation of 6H,llH-Indolo[3,2-c]Isoquinoline-5-one-9,ll-diacetate (32). To a 0°C solution of 6H,llH-Indolo[3,2-c]Isoquinoline-5-one (31) (117 mg, 0.5 mmol) in dichloromethane (10 mL) was added triethylamine (2 mL, 30 eq) followed by acetic anhydride (1.8 mL, 35 eq). The reaction was stirred at room temperature for 48 h, then poured over ice and extracted with dichloromethane (100 mL). The dichloromethane layer was washed sequentially using water (2 x 20 mL) and brine (25 mL), then dried using sodium sulfate and concentrated in vacuo. The resulting solid residue was dried under vacuum to provide Compound 32 as a brown solid. Yield = 180 mg, 83.7 %. ES-MS: 430.57 (M++l).
u) Preparation of 6H,llH-Indolo[3,2-c]Isoquinoline-5-one-9,ll- disulfonylchloride (33). Compound 31 (117 mg, 0.5 mmol) was added to chlorosulfonic acid (2 mL, 60 eq) and the resulting reaction mixture was allowed to stir at room temperature for 4 hours, after which time the reaction mixture was poured over ice. The resulting precipitate was filtered, washed sequentially with water and ethyl acetate and dried under vacuum to provide Compound 33 as a light-yellow solid. Yield = 180 mg (83.7 %). ES-MS: 430.57 (M++l). v) Preparation of 6H,llH-Indolo[3,2-c]Isoquinoline-5-one-9,ll-disulfonamide (35a). To a solution of 33 (215 mg, 0.5 mmol) in methanol (10 mL) at 0°C was added a 20 % solution of ammonia in methanol (10 mL). The reaction mixture was allowed to stir at room temperature for 15 hours and was then filtered. The resulting solid was washed with methanol and the dried under vacuum to provide Compound 35a as a yellow solid. Yield = 140 mg , 71.4 %). ES-MS: 392.81 (M++l).
w) Preparation of N-acetylanthranilonitrile (36a)
Figure imgf000093_0001
36a To a solution of anthranilonitrile (4.0 g, 32 mmol) in acetic anhydride (18 mL, 5.5 eq) at 90°C was added 1 drop of sulfuric acid and the resulting reaction was stirred at 90°C for 2 h, then allowed to sit at room temperature for 12 h. The reaction mixture was poured onto ice (ca. 200 mL) and the resulting solution was stirred for 2 h, after which time the solution was neutralized to pH 7.0 using 5 N sodium hydroxide. The resulting precipitate was filtered, washed using water (4 x 50 mL) and dried under vacuum for 72 h to provide Compound 36a as a white crystalline solid. Yield = 1.07 g (16 %).
x) Preparation of 6H,llH-indolo[3,2-c]isoquinolin-5-one (31)
Figure imgf000093_0002
31 From a-Bwmodimethylhomophthalate α-Bromodimethylhomophthalate (20a) (603 mg, 2.1 mmol) and N- acetylanthranilonitrile (36a) (370 mg, 1.1 eq) were dissolved in DMF (5 mL) under inert atmosphere. Potassium carbonate (1.45 g, 5.0 eq) was added and the reaction was stirred for 48 h at 100°C, then cooled to room temperature. The reaction mixture was poured into 1 N sodium hydroxide and the resulting mixture was extracted with EtOAc (50 mL). The EtOAc layer was washed sequentially with IN HCl (50 mL), saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved by warming in toluene (70 mL) and the solution was cooled to room temperature and upon addition of hexanes (200 mL), a solid precipitate appeared. The solid precipitate was filtered, washed using hexanes (50 mL) and dried in a vacuum oven at 50°C for 72 h to provide Compound 31 as a yellow powder. Yield = 33 mg (6.7 %).
y) Preparation of 6.H,llH-thia-6-aza-benzo[a]fluorene-5-one (40a)
Figure imgf000094_0001
40a
From homophthalic anhydride: A solution of 2-mercaptobenzonitrile (39a, i.e. Scheme 9, compound 39, wherein R7-Rιo are hydrogen) (1.35 g, 10 mmol) and homophthalic anhydride (lib) (1.6 g, 10.0 mmol, 1.0 eq) in acetonitrile (150 mL) under inert atmosphere was warmed with stirring until all reactants were in solution. Triethylamine (6.9 mL, 50 mmol, 5.0 eq) was added and the reaction was heated at reflux for 72 hours, then cooled to room temperature. After cooling, the reaction mixture was filtered, and the collected solid was washed using methanol (3 x 50 mL), then dried in a vacuum oven at 50°C to provide Compound 40a as a white solid. Yield = 225 mg (9 %).
From a-bromodimethylhomophthalate: A solution of 2-mercaptobenzonitrile (39a) (1.35 g, 10 mmol) and α-bromodimethylhomophthalate (20a) (2.87 g, 10.0 mmol, 1.0 eq) in acetonitrile (150 mL) under inert atmosphere was warmed with stirring until all reactants were in solution. Triethylamine (6.9 mL, 50 mmol, 5.0 eq) was added and the reaction was heated at reflux for 72 hours, then cooled to room temperature. After cooling, the reaction mixture was filtered, and the collected solid was washed using methanol (3 x 50 mL), then dried in a vacuum oven at 50°C to provide Compound 40a as a white solid. Yield = 250 mg (10 %).
z) Preparation of 5,6-Dihydro-5-oxo-9-nitro-indeno[l,2-c]isoquinoline (53a).
Figure imgf000095_0001
53a To a refluxing mixture of 2-methyl-4-nitro-benzonitrile (32.4 g, 0.2 mol) and NBS (44.470 g, 0.25 mol) in CC14 (300 ml) was added AIBN (0.325 g) and the resultant reaction mixture was refluxed for 4 hours. The reaction mixture was treated with AIBN (0.325 g, 31 mmol) and refluxed further for 4 hours. The reaction mixture was filtered, and the filtered succinimide was washed with CC14. The filtrate was concentrated in vacuo to provide a bromo compound (46 g). The bromo compound was dissolved in MeCN (200 ml), and to the reaction mixture was added homophthalic anhydride (30.780 g, 0.19 mol) at room temperature and under inert atmosphere. The reaction mixture was then treated with a solution of triethylamine (84 ml, 0.6 mol) in acetonitrile (100 ml). The reaction mixture was refluxed for 8 hours. The precipitate that formed was removed by filtration and washed with MeCN (100 ml). The washed precipitate was suspended in DMF (300 ml), which was heated at 130 °C, then cooled and filtered. The resultant solid was washed with DMF (100 ml) and dried under vacuum to provide Compound 53a as a pale yellow solid (18.310 g, 33%). 1H-NMR (DMSO-d6): δ, 4.09 (s, 2H), 7.56 (m, IH), 7.81 - 7.82 (m, 2H), 8.17 (d, J = 8.4 Hz, IH), 8.26 - 8.34 (m, 2H), 8.44 (s, IH), 12.47 (s, IH).
aa) Preparation of 5,6-Dihydro-5-oxo-9-amino-indeno[l,2-c]isoquinoline (54a).
Figure imgf000096_0001
54a To a suspension of Compound 53a (5.3 g, 0.019 mol) and ammonium formate (5.985 g, 0.095 mol) in DMF (100 ml) was added Pd-C (5%, 100 mg) at 80 °C. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction mixture became clear, it was filtered through the pad of celite. The celite was washed with DMF. The filtrate was then diluted with ice, and the resultant solid was filtered, washed with water and dried at 80 °C under vacuum to provide Compound 54a (3.2 g, 68%). 1H-NMR (DMSO-d6): δ, 3.89 (s, 2H), 7.18 (d, J = 8.4 Hz, IH), 7.40 - 7.45 (m, 2H), 7.66 - 7.72 (m, 2H), 7.94 (d, J = 8.1 Hz, IH), 8.21 (d, J = 8.1 Hz, IH), 12.28 (s, IH).
bb) Preparation of N-[5,6-Dihydro-5-oxo-indeno[l,2-c]isoquinoIin-9-yl]-4-bromo- butylamide (55a).
Figure imgf000096_0002
55a To a suspension of Compound 54a (1.5 g, 0.006 mol) in saturated NaHCO3 (150 ml) and ethyl acetate (100 ml) was added 4-bromobutyryl chloride (5 eq). The reaction mixture was stirred at room temperature for 1 hour. The resultant solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to provide Compound 55a (1.625 g, 68%). 1H-NMR (DMSO-d6): δ, 2.09 - 2.13 (m, 2H), 2.47 - 2.52 (m, 2H), 3.58 (t, I = 6.6 Hz, 2H), 3.85 (s, 2H), 7.40 (t, J = 6.3 Hz, IH), 7.50 (d, J = 8.4 Hz, IH), 7.66 - 7.71 (m, 2H), 7.86 (d, J = 8.4 Hz, IH), 7.92 (s, IH), 8.20 (d, J = 8.1 Hz, IH), 10.10 (s, IH), 12.24 (s, IH).
cc) Preparation of N-[5,6-Dihydro-5-oxo-indeno[l,2-c]isoquinoIin-9-yl]-4-chIoro- butylamide (55b).
Figure imgf000097_0001
55b As set forth above for Compound 55a, Compound 55b (N-[5,6-dihydro-5-oxo- indeno[l,2-c]isoquinolin-9-yl]-4-chloro-butylamide) was prepared from the amino compound 54a using chlorobutyryl chloride in the presence of aqueous NaHCO3 and ethyl acetate. 1H-NMR (DMSO-d6): δ, 1.99 - 2.08 (m, 2H), 2.47 - 2.52 (m, 2H), 3.70 (t, J = 6.6 Hz, 2H), 3.86 (s, 2H), 7.38 - 7.44 (m, IH), 7.50 (d, J = 8.1 Hz, IH), 7.66 - 7.71 (m, 2H), 7.86 (d, J = 8.1 Hz, IH), 7.95 (s, IH), 8.21 (d, I = 8.1 Hz, IH), 10.09 (s, IH), 12.24 (s, IH). dd) Preparation of N-[5,6-Dihydro-5-oxo-indeno[l,2-c]isoquinolin-9-yl]-2-chloro- acetamide (55c).
Figure imgf000098_0001
55c To a suspension of Compound 54a (1.5 g, 0.0060 mol) in saturated NaHCO3 (250 ml) and ethyl acetate (250 ml) was added chloroacetyl chloride (5 eq). The reaction mixture was stirred at room temperature for 1 hour. The resultant solid was isolated by filtration; washed sequentially with ethyl acetate, water and methanol; and dried under vacuum to provide Compound 55c (1.6 g, 82%). 1H-NMR (DMSO-d6): δ, 3.89 (s, 2H), 4.27 (s, 2H), 7.40 - 7.45 (dd, J = 6.3 and 8.1 Hz, IH), 7.52 (d, J = 8.1 Hz, IH), 7.67 - 7.75 (m, 2H), 7.90 (d, J = 8.4 Hz, IH), 7.94 (s, IH), 8.21 (d, J = 8.1 Hz, IH), 10.43 9s, IH), 12.28 (s, IH).
ee) Preparation of N-[5,6-Dihydro-5-oxo-indeno[l,2-c]isoquinolin-9-yl]-4- morpholino-butylamide (73).
Figure imgf000098_0002
73 To a suspension of Compound 55a (1.625 g, 0.004 mol) in DMF (25 ml) was added triethyl amine (5 ml) followed by morpholine (5 ml). The reaction mixture was heated at 140 to 155 °C for 1 hour, cooled to room temperature and allowed to stir overnight. The resultant solid precipitate was filtered; washed sequentially with DMF, water and methanol; and dried under vacuum to provide the free base of Compound 73 (1.380 g, 85%o). 1H-NMR (DMSO-d6): δ, 1.72 - 1.76 (dd, I = 6.9 and 7.2 Hz, 2H), 2.26 - 2.37 (m, 8H), 3.51 - 3.54 (t, J = 4.2 Hz, 4H), 3.86 (s, 2H), 7.39 - 7.43 (dd, I = 6.3 and 6.6 Hz, IH), 7.51 (d, J = 6.6 Hz, IH), 7.66 - 7.74 (m, 2H), 7.86 (d, J = 8.4 Hz, IH), 7.96 (s, IH), 8.20 (d, I = 8.1 Hz, IH), 10 .0 (s, IH), 12.25 (s, IH).
ff) Preparation of the camphor sulfonic acid salt of 73. To a suspension of the Compound 73 (free base) (0.403 g, 0.001 mol) in MeOH (20 ml) was added camphor sulfonic acid (255 mg, 0.0011 mol). The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo, and the resultant residue was dissolved in distilled, deionized water (40 ml); treated with decolorising charcoal (0.5 g); and stirred at 90 to 100 °C for 30 min. The resultant solution was filtered through the pad of celite, and the celite was washed with water. The filtrate was lyopholized to provide the camphor sulfonic acid salt of 73 (0.450 g, 71%). 1H-NMR (DMSO-d6): d, 0.72 (s, 3H), 1.02 (s, 3H), 1.20 - 1.30 (m, 2H), 1.76 (d, J = 18Hz, IH), 1.82 - 1.86 (m, IH), 1.89 - 1.97 (m, 3H), 1.99 - 2.25 (m, IH), 2.35 (d, J = 14.7 Hz, IH), 2.43 - 2.48 (m, 2H), 2.64 - 2.71 (dd, J = 11.7 and 14.7 Hz, IH), 2.85 (d, J = 14.7 Hz, IH), 3.05 - 3.13 (m, 4H), 3.46 (d, J = 11.7 Hz, 2H), 3.64 (t, J = 12 Hz, 2H), 3.86 (s, 2H), 3.97 (d, J = 12.3 Hz, 2H), 7.39 - 7.44 (dd, J = 7.8 and 8.1 Hz, IH), 7.52 (d, I = 8.1 Hz, IH), 7.67 - 7.75 (m, 2H), 7.87 (d, J = 8.1 Hz, IH), 7.96 (s, IH), 8.21 (d, J = 8.1 Hz, IH), 9.57 (s, IH), 10.15 (s, IH), 12.25 (s, IH).
gg) Preparation of 2-Dimethylamino-N-(5,6-Dihydro-5-oxo-indeno[l,2- c]isoquinolin-9-yl)-acetamide (43).
Figure imgf000099_0001
43 A suspension of Compound 55c (1.6 g, 0.0049 mol) and dimethyl amine in ethanol (2N, 200 ml) was refluxed for 24 h. Additional solution of dimethyl amine in ethanol (2N, 200ml) was added. The reaction mixture was refluxed further for 24 hours and allowed to cool to room temperature. The resultant solid was filtered, washed with ethanol, and dried under vacuum to provide Compound 43 (1.510 g, 92%). 1H-NMR (DMSO-d6): δ, 2.27 (s, 6H), 3.07 (s, 2H), 3.85 (s, 2H), 7.38 - 7.43 (m, IH), 7.58 (d, J = 8.1 Hz, IH), 7.66 - 7.73 (m, 2H), 7.87 (d, J = 8.1Hz, IH), 8.02 (s, IH), 8.20 (d, I = 8.1 Hz, IH), 9.82 (s, IH), 12.21 (s, IH); MS (ES+): m/z 334.01 (M +1).
hh) Preparation of camphorsulfonic acid salt of 43. To a suspension of Compound 43 (free base) (0.1.250 g, 0.0037 mol) in MeOH
(200 ml) was added camphor sulfonic acid (0.915 g, 0.0039 mol). The reaction mixture was allowed to at room temperature for 1 hour, and concentrated in vacuo. The resultant residue was dissolved in distilled, deionized water (300 ml); filtered; treated with decolorising charcoal (1 g); and allowed to stir at 100 to 105 °C for 30 minutes. The resultant solution was filtered through a pad of celite, and the celite was washed with water. The filtrate was lyophilized to provide the camphor sulfonic acid salt of Compound 43 (1.660 g, 75%). 1H-NMR (DMSO-d6): δ, 0.72 (s, 3H), 1.02 9s, 3H), 1.20 - 1.30 (m, 2H), 1.74 - 1.92 (m, 3H), 2.17 - 2.25 (m, IH), 2.35 (d, I = 14.7 Hz, IH), 2.64 (t, J = 9.9 Hz, IH, 2.80 (d, J = 14.7 Hz, IH), 3.90 (s, 2H), 4.16 (s, 2H), 7.41 - 7.46 (dd, J = 6.3 and 8.1 hz, IH), 7.53 (d, J = 8.1 Hz, IH), 7.68 - 7.73 (m, 2H), 7.92 - 7.94 (m, 2H), 8.22 (d, J= 8.1 Hz, IH), 9.77 (s, IH), 10.68 (s, IH), 12.29 (s, IH).
Example 2. Effect of Illustrative Isoquinoline Derivatives on PARS activity in cultured macrophages, using a whole-cell based assay and a purified enzyme assay. Demonstration of illustrative Isoquinoline Derivatives' ability to inhibit PARS and prevent peroxynitrite induced cytotoxicity was shown using methods described in Virag et al., Br. J. Pharmacol. 1999, 126(3):769-77; and Immunology 1998, 94(3):345- 55. Raw mouse macrophages were cultured in DMEM medium with high glucose and supplemented with 10 % fetal bovine serum. Cells were used at 80 % confluence in 12- well plates. Cells were pretreated with various concentrations (100 nM -1 gM) of an Isoquinoline Derivative for 10 min. Peroxynitrite, a prototypical oxidant which induces DNA single strand breakage, was used to induce PARS activation. Peroxynitrite was diluted in phosphate buffered saline (PBS) (pH 11.0) and added to the cells in a bolus of 50 μl. Cells were then incubated for 20 min. Peroxynitrite was decomposed by incubation for 30 min at pH 7.0, used as a control, and failed to influence the parameter studied. After the 20 min incubation, the cells were spun, the medium was aspirated and the cells were resuspended in 0.5 ml assay buffer (56 mM HEPES pH 7.5, 28 mM KCl, 28 mM NaCl, 2 mM MgCl2, 0.01 % w/v digitonin and 0.125 μM NAD+ and 0.5 μCi/ml 3H-NAD+). Following an incubation in assay buffer, (10 min at 37°C), PARS activity was measured as follows: 200 μl ice cold 50 % w/v TCA was added and the samples were incubated for 4 hours at 4°C. Samples were then spun (10 min @ 10,000 g) and pellets washed twice with ice cold 5 % w/v TCA and solubilized overnight in 250 μl 2 % w/v SDS/0.1 N NaOH at 37°C. The contents of the tubes were added to 6.5 ml ScintiSafe Plus scintillation liquid (Fisher Scientific) and radioactivity was determined using a liquid scintillation counter (Wallac, Gaithersburg, MD). The results shown in Table 3 demonstrate that the illustrative Isoquinoline Derivatives significantly and dose- dependently inhibit the activation of PARS in the macrophage assay.
Table 3. Inhibitory effect of various novel substituted isoquinolines on PARS activation in cultured murine macrophages.
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
NT - Not Tested *tested in purified enzyme assay The potency of inhibition on purified PARS enzyme was subsequently determined for selected Isoquinoline Derivatives, and the potency was compared with that of 3-aminobenzamide, a prototypical benchmark PARS inhibitor. The assay was performed in 96 well ELISA plates according to instructions provided with a commercially available PARS inhibition assay kit (Trevigen, Gaithersburg, MD). Briefly, wells were coated with 1 mg/mL histone (50 μl/well) at 4°C overnight. Plates were then washed four times with PBS and then blocked by adding 50 μl Strep-Diluent (supplied with the kit). After incubation (lh, room temperature), the plates were washed four times with PBS. Appropriate dilutions of PARS inhibitors were combined with 2x PARS cocktail (1.95 mM NAD+, 50 μM biotinylated NAD+ in 50 mM TRIS pH 8.0, 25 mM MgCl2) and high specific activity PARS enzyme (both were supplied with the kit) in a volume of 50 μl. The reaction was allowed to proceed for 30 min at room temperature. After 4 washes in PBS, incorporated biotin was detected by peroxidase-conjugated streptavidin (1:500 dilution) and TACS Sapphire substrate. The assay confirmed the results of the macrophage-based PARS assay. For example, the PARS inhibitor 81 (mesylate salt) exerted 50 % inhibition of PARS activity in this assay at 3 nM, and thus was approximately 50,000 times more potent than the reference compound 3-aminobenzamide. Example 3: Effect of Illustrative Isoquinoline Derivatives on PARS activity using cell protection assay The ability of illustrative Isoquinoline Derivatives to inhibit PARS and prevent peroxynitrite induced cytotoxicity was measured in a cell protection assay using the methods described in Jagtap et al., Bioorg. &Med. Chem. Letters 14 (2004) 81-85. Briefly, raw mouse macrophages were cultured then treated with an illustrative Isoquinoline Derivative at various concentrations ranging from 10 nM to 10 μM for about 15 minutes. Peroxynitrite (750 μM) was then added to the treated macrophages for a 15 minute incubation period to induce PARS activation. The media was removed and replaced with 0.5 mL HEPES (pH 7.5) containing 0.01% digitonin and 3H-NAD (0.5 μCi/mL, final concentration of NAD+ in buffer is 20 nM/L) and the resultant mixture was allowed to stand for 20 minutes. The cells were then scraped from the wells and placed in Eppendorf tubes containing 50% (w/v) of ice-cold TCA (200 μL). The tubes were maintained at 4 °C for four hours, centrifuged at 1800g for 10 minutes, and the supernatant removed. The resultant pellets were washed with 5% (w/v) TCA (200 μL, 2x), then solubilized overnight in 2 % (w/v) SDS/0.1 N NaOH (250 μl) at 37 °C. The contents of the tubes were then added to ScintiSafe Plus scintillation liquid (6.5 ml, Fisher Scientific) and radioactivity was measured using a liquid scintillation counter (Wallac, Gaithersburg, MD). The results shown in Table 4 demonstrate that the illustrative Isoquinoline Derivatives dose-dependently inhibit the activation of PARS. Table 4. Inhibitory effect of illustrative Isoquinoline Derivatives on cell protection
Figure imgf000105_0001
Example 4: Effects of illustrative Isoquinoline Derivatives in various disease models a: Effects of illustrative Isoquinoline Derivatives on in vitro cell disease models In additional in vitro studies in isolated thymocytes, cells were exposed to peroxynitrite or hydrogen peroxide (toxic oxidant species) to induce cytotoxicity. In this system the toxicity is, at least in part, related to activation of the nuclear enzyme PARS. In this oxidant-stimulated thymocyte assay (described, in detail, in Virag et al., Immunology 94(3):345-55, 1998), the compounds tested prevented the oxidant-induced suppression of the viability of the cells and did so at the low nanomolar concentration range. An example of this response (Compound 81, mesylate salt) is shown in Table 4. This assay represents an in vitro model of cells dying because of exposure to pro-oxidant species, as it occurs in during the reperfusion of ischemic organs.
Table 5. Reduction of peroxynitrite induced cytotoxicity by 30 nM - 3 μM of the Isoquinoline Derivative 81 (mesylate salt).
Figure imgf000106_0001
b: Effect of illustrative Isoquinoline Derivatives on in vivo models of inflammatory diseases In order to substantiate the efficacy of the compounds in inflammatory diseases, the effect of illustrative Isoquinoline Derivatives was demonstrated in a systemic inflammatory model induced by bacterial lipopolysaccharide (LPS), which is reported to be responsible for causing reperfusion injuries and inflammatory diseases such as septic shock and systemic inflammatory response syndrome in animals (see Parrillo, N. Engl J. Med., 328:1471-1478 (1993) and Lamping, J. Clin. Invest. 101:2065-2071 (1998). In a series of experiments, mice were pretreated with intraperitoneal injection of 0.1 and 1 mg/kg of compounds 81 (mesylate salt), 8p and 8j, and LPS at 10 mg/kg was injected i.p., and TΝF-alpha was measured in the plasma at 90 minutes. As shown in Table 5, all compounds substantially reduced TΝF production, indicative of the compounds' anti- inflammatory activity.
Table 5. Reduction of LPS induced TNF production by 0.1-1 mg/kg intraperitoneal injection of the PARS inhibitor compounds 81 (mesylate salt), 8p and 8j in mice in vivo
Figure imgf000107_0001
All compounds markedly suppressed LPS induced TNF production when compared to control. At high doses, LPS causes multiple organ dysfunction resembling of septic shock, and ultimately death (in part because of the early release of TNF-alpha). Similarly, in a model induced by cecal ligation and puncture (CLP), the live bacteria that derive from the intestinal flora induce systemic inflammation and shock. Agents that inhibit inflammatory mediator production, PARS activation, and cell death in this model prevent mortality induced by LPS or CLP. In experiments with Balb/c mice, injection of 100 mg/kg LPS intraperitoneally caused death in 50 % of the animals over 24 h, whereas treatment of the animals with 3 mg/kg/day of compound 81 (mesylate salt) reduced the endotoxin-induced mortality to 10 % under the same experimental conditions. In response to CLP induced shock, compound 81 (mesylate salt) (3 mg/kg/day) caused a reduction in the mortality from 100 % death to 60 % death over 24 h. The data demonstrating the reduction of TNF production by illustrative Isoquinoline Derivatives in animals subjected to an inflammation model, coupled with the fact that TNF production is an important trigger of inflammation in various inflammatory diseases (such as, for example, colitis, arthritis and neuroinflammation and shock) indicate that the Isoquinoline Derivatives have therapeutic effects in various systemic and local inflammatory diseases, including the rejection of transplanted organs, which entails both an inflammatory disease component and a reperfusion injury component and, accordingly, are useful for treating or preventing an inflammatory disease or a reperfusion injury. c: Effect of illustrative Isoquinoline Derivatives on in vivo models of reperfusion injury In order to substantiate the efficacy of the Isoquinoline Derivatives in ischemia-reperfusion conditions, the effect of an illustrative Isoquinoline Derivative in a mouse model of ischemic and reperfused gut was tested. The superior mesenteric artery was occluded for 45 min, followed by a reperfusion for 1 h. Following the end of the reperfusion, gut permeability was measured with the FD4 method in evened gut sacks (Liaudet et al., Shock 2000, 14(2): 134-41). Ischemia-reperfusion increased the permeability of the gut from ll ± 4 to 216 ± 27 ml min/cm2, indicative of severe damage of the reperfused gut. Treatment with Compound 81 (mesylate salt) (3 mg/kg i.v., injected 10 min prior to initiation of reperfusion) reduced the increase in the permeability of the gut by approximately 73 %, indicating a marked maintenance of the gut function. The ischemia-reperfusion studies in the gut were associated with a 80 % mortality over 12 hours, whereas only 15 % mortality was noted in the animals treated with 81 (mesylate salt). In another set of experiments, the effect of Compound 81 (mesylate salt) in a rat model of middle cerebral artery occlusion/reperfusion was assayed as described in Abdelkarim et al, Int JMol Med. 2001, 7(3):255-60. Occlusion lasted for 2 hours, followed by reperfusion for 24 hours. Infarct size was quantified with tetrazolium staining. Compound 81 (mesylate salt) was administered at 3 mg/kg/day in 3 divided intraperitoneally injected doses, the first dose being administered 10 min prior to the initiation of reperfusion. There was an approximately 80 % reduction in the degree of cortical necrosis and neuronal death in the animals administered with 81 (mesylate salt), when compared to vehicle-treated controls. This protection also translated into functional benefit, such as neurological improvements in the PARS inhibitor treated group. These data indicate that the Isoquinoline Derivatives have therapeutic effects in various systemic and local conditions of reperfusion injuries, including the rejection of transplanted organs, which entails both an inflammatory disease component and a reperfusion injury component and, accordingly, are useful for treating or preventing an inflammatory disease or a reperfusion injury or reoxygenation injury resulting from organ transplantation. d: Effect of illustrative Isoquinoline Derivatives in a diabetes model PARS inhibitors and PARS deficiency are known to reduce the development of diabetes and the incidence of diabetic complications (Mabley et al., Br J Pharmacol. 2001, 133(6):909-9; and Soriano et al., Nat Med. 2001, 7(1): 108-13). In order to substantiate the efficacy of the Isoquinoline Derivatives in a diabetes model, a single high-dose streptozotocin model of diabetes was conducted as previously described. Briefly, 160 mg/kg streptozotocin was injected to mice treated with vehicle or with illustrative Isoquinoline Derivatives intraperitoneally (3 mg/kg) and 3 days later blood sugar levels were determined using a blood glucose meter. The data shown in Table 6 demonstrate that the illustrative Isoquinoline Derivatives attenuate the streptozotocin- induced onset of diabetes as they reduce the hyperglycemia.
Table 6. Reduction of streptozotocin (STZ) induced hyperglycemia by 3 mg/kg mtraperitoneal injection of the PARS inhibitor compounds 81 (mesylate salt), 8p and 8j in mice in vivo
Figure imgf000109_0001
Accordingly, the Isoquinoline Derivatives are useful for treating or preventing diabetes or a diabetic complication. e: Effects of illustrative Isoquinoline Derivatives in overcoming temozolomide resistance in a mismatch repair deficient malignant glioma xenograft Temozolomide (TMZ) is a methylating agent used in the treatment of malignant gliomas. DNA is methylated by TMZ primarily at the O6 and N7 positions of guanine and N3 of adenine. The cytotoxicity of TMZ is attributed to futile attempts by the mismatch repair system (MMR) to process O6-methylguanine. Tumor cells deficient in MMR are resistant to TMZ. The N-methylpurine adducts are efficiently removed by base excision repair (BER). Cells that are deficient in BER have heightened sensitivity to methylating agents. One of the components of BER is the enzyme PARP. Inhibition of PARP was examined to determine whether it increases the cytotoxicity of TMZ, particularly in MMR-deficient cells. Groups of ten mice bearing procarbazine resistant xenograft tumors, which are cross-resistant to TMZ, were randomly assigned to one of four separate treatment arms. The four treatment arms were: 1) control arm (5% dextrose in sterile water); 2) compound 81 (mesylate salt) alone; 3) TMZ alone; and 4) combination of compound 81 (mesylate salt) and TMZ. Treatments were administered when the tumor volumes reached the size of 100-500 mm on Day 1 only, by mtraperitoneal injections as set forth below. The tumors were subsequently measured twice weekly with hand-held vernier calipers and tumor volumes were calculated as follows: (width2 x length)/2. Animals tested out of the study when the tumor volume exceeded 1000 mm3 and when tumor volume was greater than five times the tumor volume at the time of initial treatment. Athymic mice, transplanted with MMR proficient (D-245 MG) or deficient (D- 245 MG (PR) xenografts were treated with a combination of TMZ and Compound 81 (mesylate salt). For the tumors deficient in MMR, the most effective dose of compound 81 (mesylate salt) was found to be 150 mg/kg, administered i.p. three times at 4 hr intervals with the first injection in combination with 262.5 mg/kg TMZ (0.75 LD10). This dose of TMZ induced no partial regressions and approximately a 4-day tumor- control growth delay in two experiments. The combination therapy increased the growth delay by 21.6 and 9.7 days (P=0.001 and P=0.006, respectively) with partial regressions observed in 4 of 8 and 3 of 9 mice. The addition of compound 81 (mesylate salt) also increased the tumor growth delay in MMR proficient xenografts. In these experiments, mice were treated with 200 mg/kg of compound 81 (mesylate salt) in combination with 88 mg/kg TMZ. The tumor growth delay for TMZ alone in these mice was 43.1 and 39.2 days, in two sets of experiments. The combination therapy resulted in a modest increase in growth delay to 48.9 and 45.7 days (P=0.001 and P=0.003, respectively). These results indicate that inhibition of PARP by Compound 81 (mesylate salt), an illustrative
Isoquinoline Derivative, increases the efficacy of TMZ in treatment of malignant gliomas, particularly in tumors deficient in MMR. As shown in Figure 1, compound 81 (mesylate salt) markedly enhances the anti- tumor effects of TMZ in vivo. Accordingly, Compound 81 (mesylate salt), an illustrative Isoquinoline Derivative, is useful for treating or preventing cancer, such as CNS and brain cancers, including gliomas. The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparant to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.

Claims

What is claimed is
1. A method for treating cancer, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (I):
Figure imgf000112_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C C5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)„-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRnRi2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -( -C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); Rπ and R12 are independently -hydrogen or - -Cio alkyl, or N, Rπ and R are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, ~Cι-C10 alkyl, -halo-substituted Ci-Cs alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ^, -(C1-C5 alkylene)-NZbZ2, -amino-substituted Ci-C5 alkyl, -( -C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2. -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-Cs alkyl), -halo, -hydroxy, -NO2, -CN, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -Cι-C10 alkyl, -C2-Cio alkenyl, -C2-Cι0 alkynyl, -aryl, -benzyl, -C(O)OH, -CI-CS alkylene-C(O)O-(Ci-C5 alkyl) or -Ci-C5 alkylene-OC(O)-(Ci-C5 alkyl); R2, R3, Rt, R , R8, R9 and R10 are independently -hydrogen, -halo, -hydroxy, -O-(Ci-C5 alkyl), -Ci-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted Cι-C5 alkyl, -C(O)OH, -C(O)O(Ci-C5 alkyl), -OC(O)(Ci-C5 alkyl), -NO2 or -A-B; Zi and Z are independently -H or -Ci-Cu) alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -Ci-Cs alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH ; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
2. A method for treating cancer, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (II):
Figure imgf000113_0001
(II) or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or Ci-Cs alkyl; Ri is -hydrogen, -halo, -Ci- o alkyl, -halo-substituted Ci-Cs alkyl, -C2-Cio alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(0)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CONCCj-Cs alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -Ci-Cio alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted C1-C5 alkyl, -(Ci-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZiZ2; R2, R3, R4, R , R8, R and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Ci-C5 alkyl), -C1-C10 alkyl, -halo-substituted -C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted Ci-Cs alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Ci-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -Ci-Cio alkyl, -C2-Cio alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(Ci-Cs alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Ci-C5 alkyl), -C(O)O-phenyl or -NZ1Z2; and Zi and Z2 are independently -H or -Ci-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -Ci-Cs alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
3. A method for treating cancer, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (III):
Figure imgf000114_0001
(III) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted Ci-Cs alkyl,
-hydroxy, -O-(C C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl,
Figure imgf000115_0001
-3- to 7-membered monocyclic heterocycle, or -7- to
10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted C1-C5 alkyl, -amino-substituted C1-C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -C1-C10 alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and Z2 are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
4. A method of for treating cancer, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (IV):
Figure imgf000115_0002
(IV) or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the RM and Rι5 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH ; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
5. The method of claim 1, wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, skin cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, testicular cancer, bladder cancer, kidney cancer, liver cancer, breast cancer, prostate cancer, head and neck cancer, brain cancer, cancer of the central nervous system, uterine cancer, cervical cancer, or ovarian cancer.
6. The method of claim 2, wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, skin cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, testicular cancer, bladder cancer, kidney cancer, liver cancer, breast cancer, prostate cancer, head and neck cancer, brain cancer, cancer of the central nervous system, uterine cancer, cervical cancer, or ovarian cancer.
7. The method of claim 3, wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, skin cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, testicular cancer, bladder cancer, kidney cancer, liver cancer, breast cancer, prostate cancer, head and neck cancer, brain cancer, cancer of the central nervous system, uterine cancer, cervical cancer, or ovarian cancer.
8. The method of claim 4, wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, skin cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, testicular cancer, bladder cancer, kidney cancer, liver cancer, breast cancer, prostate cancer, head and neck cancer, brain cancer, cancer of the central nervous system, uterine cancer, cervical cancer, or ovarian cancer.
9. The method of claim 1, wherein the cancer is melanoma, metastatic brain cancer, or glioma.
10. The method of claim 2, wherein the cancer is melanoma, metastatic brain cancer, or glioma.
11. The method of claim 3, wherein the cancer is melanoma, metastatic brain cancer, or glioma.
12. The method of claim 4, wherein the cancer is melanoma, metastatic brain cancer, or glioma.
13. The method of claim 9, wherein the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme.
14. The method of claim 10, wherein the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme.
15. The method of claim 11 , wherein the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme.
16. The method of claim 12, wherein the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme.
17. The method of claim 1, further comprising administering an effective amount of temozolomide, procarbazine, dacarbazine, irinotecan, Interleukin-2, or a combination thereof.
18. The method of claim 17, wherein the compound is
Figure imgf000118_0001
or a pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the pharmaceutically acceptable salt is mesylate.
20. The method of claim 2, further comprising administering an effective amount of temozolomide, procarbazine, dacarbazine, irinotecan, Interleukin-2, or a combination thereof.
21. The method of claim 3, further comprising administering an effective amount of temozolomide, procarbazine, dacarbazine, irinotecan, Interleukin-2, or a combination thereof.
22. The method of claim 4, further comprising administering an effective amount of temozolomide, procarbazine, dacarbazine, irinotecan, Interleukin-2, or a combination thereof.
23. A composition comprising an effective amount of temozolomide, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (I):
Figure imgf000119_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-,
-NH-, -S-, -CH(NRΠR12)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(Cι-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R11 and Rι2 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl,
-C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ1Z2,
-(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZιZ2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZiZ^, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -Ci-Cio alkyl, -C2-Cι0 alkenyl, -C2-Cι0 alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 alkylene-C(O)O-(C,-C5 alkyl) or -C1-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R3, t, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(d-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and X_ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
24. A composition comprising an effective amount of temozolomide, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (II):
Figure imgf000120_0001
(II) or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or C1-C5 alkyl; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C -Qo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-Cs alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -Ci-Cio alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZιZ2; R2, R3, t, R7, R8, R9 and Rι0 are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted -C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(C Cs alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZιZ2; and Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z ), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH ; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z^ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
25. A composition comprising an effective amount of temozolomide, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000121_0001
(IH) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted Q-Cs alkyl,
-hydroxy, -O-(d-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZιZ2, -3- to 7-membered monocyclic heterocycle, or -7- to
10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted C1-C5 alkyl, -amino-substituted Q-C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -C1-C10 alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and Z2 are independently hydrogen or -Q-Q alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; or N, Zi and 7χ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
26. A composition comprising an effective amount of temozolomide, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (IV):
Figure imgf000122_0001
(IV) or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Rι4 and Rι5 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z^ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
27. A composition comprising an effective amount of procarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (I):
Figure imgf000123_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRnRι2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(Q-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R11 and Rι2 are independently -hydrogen or -C1-Q0 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -Ci-Cio alkyl, -halo-substituted Cι-C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ1Z2, -(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZιZ2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-Cs alkyl), -halo, -hydroxy, -NO2, -CN, -NZιZ2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -C1-C10 alkyl, -C2-Cιo alkenyl, -C2-Cιo alkynyl, -aryl, -benzyl, -C(O)OH, -d-Cs alkylene-C(O)O-(Ci-C5 alkyl) or -C1-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R , t, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy,
-O-(Ci-C5 alkyl), -C1-Q0 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cι0, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(C C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-Q0 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -Q-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z^ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
28. A composition comprising an effective amount of procarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (II):
Figure imgf000125_0001
(II) or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or Ci-C5 alkyl; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Ci-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -C1-C10 alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZiZ^; R2, R3, R4, R , R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Ci-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZfe and Zi and Z2 are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z ), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
29. A composition comprising an effective amount of procarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000126_0001
(HI) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted C1-C5 alkyl, -hydroxy, -O-(C C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZ1Z2, -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted Q-C5 alkyl, -amino-substituted C1-C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -Ci-Qo alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and TL are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen-containing-3 - to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
30. A composition comprising an effective amount of procarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (IV):
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Rι4 and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and 7Aι are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
31. A composition comprising an effective amount of dacarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (I):
Figure imgf000128_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 al yl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)„-, -CH(OH), -CH(-aryl)-, -O-,
-NH-, -S-, -CH(NRπRι2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -( -C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R11 and R12 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1- 0 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl,
-C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZ1Z2,
-(C1-C5 alkylene)-NZ1,Z2, -amino-substituted C1-C5 alkyl, -( -C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZ1Z2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -Ci-Cio alkyl, -C2-C10 alkenyl, -C2-Cι0 alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 alkylene-C(O)O-(Cι-C5 alkyl) or -Cι-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R3, t, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted Ci-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
32. A composition comprising an effective amount of dacarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (II):
Figure imgf000129_0001
(ID or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or Cι-C5 alkyl; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted -C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -Ci-Cio alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -arnino- substituted C1-C5 alkyl, -(Cι-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C C5 alkyl), -C(O)O-phenyl or -NZ1Z2; R2, R3, Rt, R , R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(C C5 alkyl), -OC(O)(C C5 alkyl), -NO2 or -A-B ; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZιZ2; and Zi and Z2 are independently -H or -C1- 0 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Tχ are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
33. A composition comprising an effective amount of dacarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000130_0001
(HI) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted C1-C5 alkyl,
-hydroxy, -O-(Cι-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-C C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZιZ2, -3- to 7-membered monocyclic heterocycle, or -7- to
10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted C1-C5 alkyl, -amino-substituted -C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -C1-C10 alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and 7 _ are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3 - to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
34. A composition comprising an effective amount of dacarbazine, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (IV):
Figure imgf000131_0001
(IV) or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the R14 and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
35. A composition comprising an effective amount of irinotecan, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (I):
Figure imgf000132_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 alkyl, X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)„-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRιιRι2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); Rπ and Rι are independently -hydrogen or -C1- 0 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZιZ2, -(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZιZ2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -C1-C10 alkyl, -C2-C10 alkenyl, -C2-Cι0 alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 alkylene-C(O)O-(Cι-C5 alkyl) or -C1-C5 alkylene-OC(O)-(Ci-C5 alkyl); R2, R3, Rt, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
36. A composition comprising an effective amount of irinotecan, a pharmacologically acceptable vehicle or carrier, and an. effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (II):
Figure imgf000134_0001
(II) or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or C1-C5 alkyl; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -C1-C10 alkyl, -C2-C10 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C!-C5 alkyl), -C(O)O-phenyl or -NZiZ2; R2, R3, Rt, R , R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1- 0 alkyl, -halo-substituted Cι-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted Cι-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(d-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZ1Z2; and Zi and Z2 are independently -H or -Ci-Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z ), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH ; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
37. A composition comprising an effective amount of irinotecan, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000135_0001
(III) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted C1-C5 alkyl, -hydroxy, -O-(Cι-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZιZ2, -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted -C5 alkyl, -amino-substituted C1-C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with - -C10 alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and ϊ_ are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3 - to 7-membered monocyclic heterocycle; or N, Zi and Zj are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
38. A composition comprising an effective amount of irinotecan, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (IV):
Figure imgf000136_0001
or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Ri and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or - -Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
39. A composition comprising an effective amount of Interleukin-2, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (I):
Figure imgf000137_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-,
-NH-, -S-, -CH(NRΠRI2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R11 and Rι2 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1- 0 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl,
-C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZιZ2,
-(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZιZ2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -Ci-Cio alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 alkylene-C(O)O-(Cι-C5 alkyl) or -C1-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R3, Rt, R7, R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-Cι0, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z ), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
40. A composition comprising an effective amount of Interleukin-2, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (II):
Figure imgf000138_0001
(ID or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or C1-C5 alkyl; Ri is -hydrogen, -halo, -Ci- o alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -Ci-Cio alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -arnino- substituted C1-C5 alkyl, -( -C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(C C5 alkyl), -C(O)O-phenyl or -~ Z _\ R2, R3, R4, R , R8, R and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B ; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZ1Z2; and Zi and Z2 are independently -H or - -Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
41. A composition comprising an effective amount of Interleukin-2, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000139_0001
(HI) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted -C5 alkyl,
-hydroxy, -O-(d-C5 alkyl), -Cι-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl,
Figure imgf000140_0001
-3- to 7-membered monocyclic heterocycle, or -7- to
10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted -C5 alkyl, -amino-substituted -C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with - -C10 alkyl or -hydroxy-substituted Cι-C5 alkyl; and Zi and Z are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
42. A composition comprising an effective amount of Interleukin-2, a pharmacologically acceptable vehicle or carrier, and an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (IV):
Figure imgf000140_0002
(IV) or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the RJ4 and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
43. A method for treating a vascular disease other than a cardiovascular disease, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (I):
Figure imgf000141_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-C5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRΠRI2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); R11 and Rι2 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, -
7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZiZj, -(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZ1Z2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -C1-C10 alkyl, -C2-Cιo alkenyl, -C2-Cιo alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 arkylene-C(O)O-(Cι-C5 alkyl) or -Cι-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R3, Rt, R7, R8, R and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -Cι-C10 alkyl, -halo-substituted -C5 alkyl, -C2-Cι0, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
44. A method for treating a vascular disease other than a cardiovascular disease, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (II):
Figure imgf000143_0001
(II) or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or Cι-C5 alkyl; Ri is -hydrogen, -halo, - -Cio alkyl, -halo-substituted C1-C5 alkyl, -C -Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted -C5 alkyl, -C(O)OH, -C(O)O(C C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -amino- substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(d-C5 alkyl), -C(O)O-phenyl or - L&_\ R2, R3, Rt, R , R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted C C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH , -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cι0 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZ1Z2; and Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
45. A method for treating a vascular disease other than a cardiovascular disease, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (III):
Figure imgf000144_0001
(III) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R3 are independently -hydrogen, -halo, -halo-substituted -C5 alkyl, -hydroxy, -O-(d-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZ1Z2, -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted -C5 alkyl, -amino-substituted -C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -Ci-Cio alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and Z2 are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen-containing-3 - to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
46. A method for treating a vascular disease other than cardiovascular disease, comprising administering to an animal in need thereof, an effective amount of a having the formula (IV):
Figure imgf000145_0001
(IV) or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the RJ4 and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
47. The method of claim 43, wherein the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, or lipedema.
48. The method of claim 44, wherein the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, or lipedema.
49. The method of claim 45, wherein the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, or lipedema.
50. The method of claim 46, wherein the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, or lipedema.
51. A method for treating renal failure, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (I):
Figure imgf000146_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R5 is O, NH or S; R6 is -H or -C1-Q5 alkyl X is -C(O)-, -CH2-, -CH(halo)-, -CH(OH)-(CH2)n-, -CH(OH), -CH(-aryl)-, -O-, -NH-, -S-, -CH(NRΠRI2)- or -N(SO2Y)-, wherein Y is -OH, -NH2 or -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle); RH and Rι2 are independently -hydrogen or -C1-C10 alkyl, or N, Rπ and Rι2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; Ri is -hydrogen, -halo, -C1-C10 alkyl, -halo-substituted -C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -arnino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A-B; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-,
-CON(Cι-C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -NZιZ2, -(C1-C5 alkylene)-NZι,Z2, -amino-substituted C1-C5 alkyl, -(C1-C5 alkyl)-(-3- to 7- membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH,
-C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -C(NH)NH2, each of which, other than -NZ1Z2, -C(O)OH, or -C(NH)NH2, is unsubstituted or substituted with one or more of -O-(Cι-C5 alkyl), -halo, -hydroxy, -NO2, -CN, -NZ1Z2, -nitrogen-containing-3- to 7-membered monocyclic heterocycle, -C1- 0 alkyl, -C2-Cιo alkenyl, -C2-C10 alkynyl, -aryl, -benzyl, -C(O)OH, -C1-C5 alkylene-C(O)O-(Cι-C5 alkyl) or -C1-C5 alkylene-OC(O)-(Cι-C5 alkyl); R2, R3, Rt, R , R8, R and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), - -C10 alkyl, -halo-substituted C1-C5 alkyl, -C2-C10, alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH , -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
52. A method for treating renal failure, comprising administering to an animal in need thereof, an effective amount of a compound having the formula (II):
Figure imgf000148_0001
(ID or a pharmaceutically acceptable salt thereof, wherein: R6 is -H or C1-C5 alkyl; Ri is -hydrogen, -halo, -Ci- o alkyl, -halo-substituted C1-C5 alkyl, -C2-Cιo alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -NO2 or -A'-B'; A' is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -CO-, -C(O)O-, -CONH-, -CON(C C5 alkyl)-, -NH-, -(CH2)-, -S- or -C(S)-; B' is -C1-C10 alkyl, -C2-Cιo alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -arnino- substituted -C5 alkyl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZιZ2; R2, R3, Rt, R , R8, R9 and Rio are independently -hydrogen, -halo, -hydroxy, -O-(Cι-C5 alkyl), -C1-C10 alkyl, -halo-substituted Cι-C5 alkyl, -C2-Cι0 alkenyl, -C3-C8 monocyclic cycloalkyl, -aryl, -NH2, -amino-substituted C1-C5 alkyl, -C(O)OH, -C(O)O(Cι-C5 alkyl), -OC(O)(Cι-C5 alkyl), -NO2 or -A-B ; A is -SO2-, -SO2NH-, -NHCO-, -NHCONH-, -O-, -CO-, -OC(O)-, -C(O)O-, -CONH-, -CON(Cι-C5 alkyl)-, -NH-, -CH2-, -S- or -C(S)-; B is -C1-C10 alkyl, -C2-C10 alkenyl, -3- to 7-membered monocyclic heterocycle, - 7- to 10-membered bicyclic heterocycle, -C3-C8 monocyclic cycloalkyl, -aryl, -(C1-C5 alkyl)-(-3- to 7-membered monocyclic heterocycle), -H2NC(O)-substituted aryl, -C(O)OH, -C(O)O-(Cι-C5 alkyl), -C(O)O-phenyl or -NZjZ2; and Zi and Z2 are independently -H or - -Cio alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and TJI are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
53. A method for treating renal failure, comprising administering to an animal in need thereof, an effective amount of a compound or pharmaceutically acceptable salt of a compound having the formula (III):
Figure imgf000149_0001
(III) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -O-; R2 and R are independently -hydrogen, -halo, -halo-substituted C1-C5 alkyl, -hydroxy, -O-(Cι-C5 alkyl), -C1-C5 alkyl, -NO2, -NH2, -CONH2, -C(O)OH, -OC(O)-Cι-C5 alkyl or -C(O)O-Cι-C5 alkyl; R8 and R9 are independently -hydrogen or -A-B; A is -SO2-, -SO2NH- or -NHCO-; B is -C1-C5 alkyl, -NZ1Z2, -3- to 7-membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of -hydroxy-substituted C1-C5 alkyl, -amino-substituted -C5 alkyl, -3- to 7- membered monocyclic heterocycle, or -7- to 10-membered bicyclic heterocycle, each unsubstituted or substituted with -Ci- o alkyl or -hydroxy-substituted C1-C5 alkyl; and Zi and Z^ are independently hydrogen or -Cι-C8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle.
54. A method of for treating renal failure, comprising administering to an animal in need thereof, an effective amount of a having the formula (IV):
Figure imgf000150_0001
or a pharmaceutically acceptable salts thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Ru and Rι5 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -C1-C10 alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or -C1-C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH2; or N, Z3 and Z are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
55. The method of claim 51, wherein the renal failure is chronic renal failure or acute renal failure.
56. The method of claim 52, wherein the renal failure is chronic renal failure or acute renal failure.
57. The method of claim 53, wherein the renal failure is chronic renal failure or acute renal failure.
58. The method of claim 54, wherein the renal failure is chronic renal failure or acute renal failure.
59. A compound of the Formula (IV):
Figure imgf000151_0001
or a pharmaceutically acceptable salt thereof, wherein: Rι3 and Rι6 are hydrogen; one of the Rι and R15 groups is -NHC(O)-(CH2)n-NZιZ2, and the other group is - hydrogen; Zi and Z2 are independently -H or -Ci- o alkyl, which is unsubstituted or substituted with one or more of -halo, -OH or -N(Z3)(Z4), where Z3 and Z4 are independently, -H or - -C5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or -NH ; or N, Z3 and Z4 are taken together to form a nitrogen- containing-3- to 7-membered monocyclic heterocycle; or N, Zi and Z2 are taken together to form a nitrogen-containing-3- to 7-membered monocyclic heterocycle; and n is an integer ranging from 0-5.
60. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein Rι4 is -NHC(O)-(CH2)n-NZιZ2 and Rι3, R15, and Rι6 are each hydrogen.
61. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein Rι5 is -NHC(O)-(CH2)n-NZιZ2 and Rι3, Rι4, and Rι6 are each hydrogen.
62. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein n is 1.
63. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein n is 2.
64. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein n is 3.
65. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein n is 4.
66. The compound or pharmaceutically acceptable salt of the compound of claim 59, wherein n is 5.
67. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of the compound of claim 59.
68. A method of treating a reperfusion injury, comprising administering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
69. The method of claim 68, wherein the reperfusion injury is stroke or myocardial infarction.
70. A method of treating an inflammatory disease, comprising admininstering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
71. The method of claim 70, wherein the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock, or chemotherapeutic shock.
72. A method of treating diabetes or a diabetic complication, comprising admininstering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
73. The method of claim 72, wherein the diabetes is type I diabetes or type H diabetes.
74. A method of treating an ischemic condition, comprising admininstering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
75. The method of claim 74, wherein the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease, or cerebral ischemia.
76. A method of treating a reoxygenation injury resulting from organ transplantation, comprising administering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
77. A method of treating Parkinson's disease, comprising admininstering to an animal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 59.
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