US 2002/0165218 A1Published application

Materials and methods to potentiate cancer treatment

AssigneeICOS Corporation

InventorsJames Halbrook, Edward A. Kesicki, Laurence E. Burgess, Stephen T. Schlachter, Charles T. Eary, Justin G Schiro, Hongmei Huang, Michael Evans, Yongxin Han

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Abstract

Compounds that inhibit DNA-dependent protein kinase, compositions comprising the compounds, methods to inhibit the DNA-PK biological activity, methods to sensitize cells the agents that cause DNA lesions, and methods to potentiate cancer treatment are disclosed.

Claims37

Dependent claims

A DNA-PK inhibitor having a formula

146
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer 0 through 4;
Z, independently, is CR3 or N;
A is an optionally substituted four- to seven-membered aliphatic ring containing 0, 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O, and S;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, N(Rh)2, ORh, carboxyl, carboxy, nitro, hydrazono, hydroxyamino, cyano, aldehyde, carboxamide, thiocarboxamide, acyl, mercapto, sulfonyl, trifluoromethyl, heteroaryl, and substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, carbamoyl, carboxamide, N(Rh)2, carboxy, ORh, sulfamyl, nitro, phosphate, and sulfonamido;
or
R1 and R2 are taken together with the carbon atoms to which each is attached to form a 5-, 6-, or 7-membered ring, wherein 1, 2, or 3 carbon atoms of R1 and R2 optionally are a heteroatom selected from the group consisting of O, N, S, and P, said ring optionally substituted with one or more ═O, ═S, ═NH, ORb, N(Rh)2, carboxyl, carboxy, alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, said heteroatom optionally substituted with a group selected from the group consisting of aryl, substituted aryl, alkyl, alkyl substituted with acyl, and acyl;
R3, independently, is selected from the group consisting of hydrogen, halo, aldeyhde, ORh, nitro, N(Rh)2, carboxyl, carboxy, sulfonamido, sufamyl, and sulfo or a halide derivative thereof,
wherein Rh, independently, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
and
R4, independently, is selected from the group consisting of ORh, halo, N(Rh)2, aldehyde, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
with the proviso that when A is morpholinyl, R2 and R4 are hydrogen, and ZR3 is CH at each occurrence, then R1 is different from —(CO)—CH3, (C═CH2)-phenyl, and nitro;
and with the proviso that when A is morpholinyl, R4 is hydrogen, and Z is nitrogen at each occurrence, then R1 and R2, when taken together, is different from triazole.

12 more elements

A DNA-PK inhibitor having a formula:

149
or a pharmaceutically acceptable salt thereof, wherein:
Z, independently, is CR7 or N;
L is selected from the group consisting of alkylene, substituted alkylene, carbonyl, carbamoyl, NRh, oxy (—O—), thio (—S—), thionyl (—SO—), and sulfonyl;
A is absent, or A is an optionally substituted four- to seven-membered aliphatic ring containing 0, 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O, and S;
R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, N(Rh)2, ORh, carboxyl, carboxy, nitro, hydrazono, hydroxyamino, cyano, aldehyde, carboxamide, thiocarboxamide, acyl, mercapto, sulfonyl, trifluoromethyl, heteroaryl, and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, carbamoyl, carboxamide, N(Rh)2, carboxy, ORh, sulfamyl, nitro, phosphate, and sulfonamido;
or
R5 and R6 are taken together with the carbon atoms to which each is attached to form a 5-, 6-, or 7-membered ring, wherein 1, 2, or 3 carbon atoms of R5 and R6 optionally are a heteroatom selected from the group consisting of O, N, S, and P, said ring optionally substituted with one or more of ═O, ═S, ═NH, ORh, N(Rh)2, carboxyl, carboxy, alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and said heteroatom optionally substituted with a substituent selected from the group consisting of aryl, substituted aryl, alkyl, alkyl substituted with acyl, and acyl;
R7, independently, is selected from the group consisting of hydrogen, halo, aldehyde, ORh, nitro, N(Rh)2, carboxyl, carboxy, sulfamyl, sulfonamido, and sulfo or a halide derivative thereof,
wherein Rh, independently, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
and
R8, independently, is selected from the group consisting of ORh, halo, N(Rh)2, aldehyde, alkyl, subtituted alkyl, acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

10 more elements

A DNA-PK inhibitor selected from the group consisting of:

benzyl 2-((4-benzyl)carbonyl)-5-morpholin-4-yl-benzene phosphate;
4-methylphenyl 4-morpholin-4-yl-2-(phosphonooxy)phenyl methanone disodium salt;
5-morpholin-4-yl-2-nitrophenylamine;
5-(4-methyl-piperazin-1-yl)-2-nitrophenylamine;
2-hydroxymethyl-5-morpholin-4-yl-phenol;
2-nitro-5-thiomorpholin-4-yl-phenylamine;
N1-morpholin-4-yl-4-nitrobenzene-1,3-diamine;
1-(3-amino-4-nitrophenyl)-piperidin-4-ol;
2-nitro-5-piperidin-1-yl-phenylamine;
5-(4-acetyl-piperazin-1-yl)-2-nitrophenylamine;
2-nitro-5-piperazin-1-yl-phenylamine;
1-(3-amino-4-nitrophenyl)-piperidin-3-ol;
N1-(2-morpholin-4-yl-ethyl)-4-nitrobenzene-1,3-diamine;
5-(4-(2-methoxyphenyl)-piperazin-1-yl]-2-nitrophenylamine;
5-(cis-2,6-dimethylmorpholin-4-yl)-2-nitrophenylamine;
2-nitro-5-(4-pyridin-2-yl-piperazin-1-yl)-phenylamine;
N1-(3-morpholin-4-yl-propyl)-4-nitrobenzene-1,3-diamine;
2-hydroxy-4-morpholin-4-yl-benzonitrile;
(5-morpholin-4-yl-2-nitrophenyl)-methanol;
2-hydroxy-4-morpholin-4-yl-benzoic acid;
2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester;
5-morpholin-4-yl-2-nitro-benzamide;
2-hydroxy-4-morpholin-4-yl-benzaldehyde;
5-morpholin-4-yl-2-nitro-phenol;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-propan-1-one;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-3-methyl-butan-1-one;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-phenyl-methanone;
2,2,2-trifluoro-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
4-amino-2-morpholin-4-yl-pyrimidine-5-carboxylic acid;
1-(5-bromo-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(3-bromo-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(3,5-dichloro-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(3-chloro-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(5-fluoro-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(3-fluoro-2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(2-hydroxy-4-(tetrahydropyran-4-yloxy)-phenyl]-ethanone;
5-(morpholin-4-yl)-1,3-dihydro-benzimidazol-2-one;
2-methoxy-4-morpholin-4-yl-benzaldehyde;
4-methoxy-6-morpholin-4-yl-benzene-1,3-dicarbaldehyde;
2-hydroxy-5-morpholin-4-yl-benzoic acid methyl ester;
2-((hydroxyimino)methyl)-5-morpholin-4-yl-phenol;
2-hydrazonomethyl-5-morpholin-4-yl-phenol;
2-hydroxy-4-((1-morpholin-4-yl-methanoyl)-amino]-benzoic acid;
2-hydroxy-4-morpholin-4-ylmethyl-benzoic acid methyl ester hydrochloride;
2-hydroxy-4-morpholin-4-ylmethyl-benzoic acid trifluoroacetate;
2-hydroxy-4-morpholin-4-ylmethyl benzoic acid hydrochloride;
4-amino-2-hydroxy-benzoic acid methyl ester;
2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester;
2-hydroxy-N-methyl-4-morpholin-4-yl-benzamide;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-morpholin-4-yl-methanone;
2-hydroxy-4-morpholin-4-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-benzyl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-phenyl-benzamide;
N-cyclopropyl-2-hydroxy-4-morpholin-4-yl-N-phenyl-benzamide;
2-hydroxy-N-(2-methoxy-ethyl)-4-morpholin-4-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-methoxy-N-methyl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-(3-dimethylamino-propyl)-benzamide;
2-hydroxy-N-methoxy-4-morpholin-4-yl-benzamide;
2-hydroxy-N-(2-methanesulfonyl-ethyl)-4-morpholin-4-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-pyridin-3-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-pyridin-4-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-thiazol-2-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-( 1,4-thiazin-2-yl)-benzamide;
2,N-dihydroxy-4-morpholin-4-yl-benzamide;
2-hydroxy-4-morpholin-4-yl-N-(4-pyridylmethyl)-benzamide;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-(4-phenylpiperizin-1-yl)-methanone;
2-hydroxy-4-morpholin-4-yl-benzoic acid;
N-carboxymethyl-2-hydroxy-4-morpholin-4-yl-phenyl)-carboxamide methyl ester;
N-carboxymethyl-2-hydroxy-4-morpholin-4-yl-phenyl-carboxamide;
2-hydroxy-4-morpholin-4-yl-thiobenzamide;
2-(4-ethylphenyl)-4-imino-7-morpholin-4-yl-benzo(e)-1,3,2-oxathiaphos-phane-2-thione;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-phenyl-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-(4-trifluoromethylphenyl)-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-(o-tolyl)-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-(4-methoxyphenyl)-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-pyridin-3-yl-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-pentan-1-one;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-2-phenyl-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-thiophen-2-yl-methanone;
2-hydroxy-4-morpholin-4-yl-phenyl-1,3-thiazol-2-yl ketone;
1-(3-chlorophenyl)-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-methanone;
2-chloro-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-2-morpholin-4-yl-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-2-imidazol-1-yl-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-pyrrolidin-1-yl-methanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-1-(4-methylpiperazin-1-yl)-methanone;
2-hydroxy-4-morpholin-4-yl-phenyl-1-piperidin-1-yl-methanone;
2-(benzyl-methyl-amino)-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
2-acetylthio-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
1-(2-hydroxy-4-morpholin-4-yl-phenyl)-2-mercapto-ethanone;
6-morpholin-4-yl-2-hydrobenzo[b]furan-3-one;
4-(2-methyl-4-morpholin-4-yl-phenyl)-2-(3-pyridyl)-1,3-thiazole;
5-morpholin-4-yl-2-(2-phenylamino-1,3-thiazol-4-yl)-phenol;
3-methoxy-1-morpholin-4-yl-benzene;
4-methoxy-2-morpholin-4-yl-benzenesulfonic acid;
4-methoxy-2-morpholin-4-yl-benzenesulfonyl chloride;
4-methoxy-N-methyl-2-morpholin-4-yl-benzenesulfonamide;
4-methoxy-2-morpholin-4-yl-N-benzyl-benzenesulfonachide;
4-methoxy-2-morpholin-4-yl-N-cyclopropylmethyl-benzenesulfonamide;
NN diethyl(3 morpholin-4-yl-phenoxy)carboxamide;
N,N-diethyl-(2-benzenesulfonyl-5-morpholin-4-yl-phenoxy)carboxamide;
2-benzenesulfonyl-5-morpholin-4-yl-phenol;
3-nitro-1-morpholin-4-yl-benzene;
3-morpholin-4-yl-phenylamine;
1-(2-amino-4-morpholin-4-yl-phenyl)-2-chloro-ethanone;
2-amino-4-morpholin-4-yl-N-benzyl-N-methyl-benzamide;
1-(2-amino-4-morpholin-4-yl-phenyl)-1-pyrrolidin-1-yl-methanone;
(2-amino-4-morpholin-4-yl-phenyl)-1-piperidin-1-yl-methanone;
2-amino-4-fluorobenzoic acid methyl ester;
4-fluoro-2-(2,2,2-trifluoroacetylamino)-benzoic acid methyl ester;
4-morpholin-4-yl-2-(2,2,2-trifluoroacetylamino)-benzoic acid methyl ester;
2-amino-4-morpholin-4-yl-benzoic acid;
2-methylsulfonylamino-4-morpholin-4-yl-benzoic acid;
4-morpholin-4-yl-2-(2,2,2-trifluoroacetylamino)-N-benzyl-benzamide;
N,N-dimethyl-4-morpholin-4-yl-2-(2,2,2-trifluoroacetylamino)-benzamide;
2-amino-4-morpholin-4-yl-N,N-dimethyl-benzamide;
N-methyl-4-morpholin-4-yl-2-(2,2,2-trifluoroacetylamino)-benzamide;
2-amino-4-morpholin-4-yl-benzoic acid methyl ester;
2-acetylamino-4-morpholin-4-yl-benzoic acid methyl ester;
2-acetylamino-4-morpholin-4-yl-benzoic acid;
2-methanesulfonylamino-4-morpholin-4-yl-benzoic acid methyl ester;
(2-N-methyl-N-(2,2,2-trifluoroacetyl)amino)-4-morpholin-4-yl-benzoic acid methyl ester;
2-methylamino-4-morpholin-4-yl-benzoic acid methyl ester;
2-methylamino-4-morpholin-4-yl-benzoic acid;
2-chloro-1-(2-acetamido-4-morpholin-4-yl-phenyl)-ethanone;
1-acetyl-6-morpholin-4-yl-1,2-dihydro-indol-3-one;
4-morpholin-4-yl-2-nitro-benzoic acid methyl ester;
4-morpholin-4-yl-2-nitro-benzoic acid;
4-morpholin-4-yl-2-nitrophenyl)N(methylcarboxymethyl)benzamide;
5-hydroxy-7-morpholin-4-yl-2-phenyl-chromen-4-one;
5-hydroxy-2-phenyl-7-piperidin-1-yl-chromen-4-one;
trifluoromethanesulfonic acid 3,5-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester;
3,5-dihydroxy-7-morpholin-4-yl-2-phenyl-chromen-4-one;
trifluoromethanesulfonic acid 4-acetyl-3,5-dihydroxy-phenyl ester;
1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone;
4-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile;
3-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile;
5-hydroxy-2-(4-methoxyphenyl)-7-morpholin-4-yl-chromen-4-one;
5-hydroxy-7-morpholin-4-yl-2-pyridin-3-yl-chromen-4-one;
2-hydroxy-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone;
and
2-hydroxy-1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone.

140 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/941,897Filed 28 Aug 2001
Priority: 1 Sep 2000
Published: 7 Nov 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents
C07C 309/66
Of a saturated carbon skeleton: methanesulfonates

Family

Application60/229,899Us provisional application · filed 1 Sep 2000
US 7,179,912 B2Related patent
US 2002/0165218 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A DNA-PK inhibitor having a formula

146
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer 0 through 4;
Z, independently, is CR3 or N;
A is an optionally substituted four- to seven-membered aliphatic ring containing 0, 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O, and S;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, N(Rh)2, ORh, carboxyl, carboxy, nitro, hydrazono, hydroxyamino, cyano, aldehyde, carboxamide, thiocarboxamide, acyl, mercapto, sulfonyl, trifluoromethyl, heteroaryl, and substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, carbamoyl, carboxamide, N(Rh)2, carboxy, ORh, sulfamyl, nitro, phosphate, and sulfonamido;
or
R1 and R2 are taken together with the carbon atoms to which each is attached to form a 5-, 6-, or 7-membered ring, wherein 1, 2, or 3 carbon atoms of R1 and R2 optionally are a heteroatom selected from the group consisting of O, N, S, and P, said ring optionally substituted with one or more ═O, ═S, ═NH, ORb, N(Rh)2, carboxyl, carboxy, alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, said heteroatom optionally substituted with a group selected from the group consisting of aryl, substituted aryl, alkyl, alkyl substituted with acyl, and acyl;
R3, independently, is selected from the group consisting of hydrogen, halo, aldeyhde, ORh, nitro, N(Rh)2, carboxyl, carboxy, sulfonamido, sufamyl, and sulfo or a halide derivative thereof,
wherein Rh, independently, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
and
R4, independently, is selected from the group consisting of ORh, halo, N(Rh)2, aldehyde, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
with the proviso that when A is morpholinyl, R2 and R4 are hydrogen, and ZR3 is CH at each occurrence, then R1 is different from —(CO)—CH3, (C═CH2)-phenyl, and nitro;
and with the proviso that when A is morpholinyl, R4 is hydrogen, and Z is nitrogen at each occurrence, then R1 and R2, when taken together, is different from triazole.

12 more elements

Facts

Application

09/941,897Filed 28 Aug 2001

Priority

1 Sep 2000

Published

7 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents
C07C 309/66
Of a saturated carbon skeleton: methanesulfonates