IP Library › Granted Patent US 8,802,712
Granted Patent B2
US 8,802,712 · App. 13/807,954 · Granted Aug 12, 2014

Pyrazoloquinolines

Inventors: Thomas Fuchss (Bensheim-Auerbach, DE); Werner Mederski (Zwingenberg, DE); Frank Zenke (Darmstadt, DE)
Assignee: Merck Patent GmbH
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Quick Facts
Patent No.
US 8,802,712
App. No.
13/807,954
Granted
Aug 12, 2014
Kind
B2
Abstract

The invention relates to compounds of the formulae (I), (II) and (III), and/or physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. The compounds of the formula (I) can be used for the inhibition of serine/threonine protein kinases and for the sensitisation of cancer cells to anticancer agents and/or ionising radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumours, metastases or angiogenesis disorders, in combination with radiotherapy and/or an anticancer agent. The invention furthermore relates to a process for the preparation of the compounds of the formula (I) by reaction of compounds of the formula (II) or (III) and optionally conversion of a base or acid of the compounds of the formula (I) into one of its salts

Claims (233)

1. A compound of formula (I)

in which

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R3 denotes H, Hal, CN, -Alk-CN, -Alk-NYY, Het 1 or Het 2 ,

R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO—NYY or

Het 1 ,

R5 denotes Hal, Y, OY, NYY, —NY—COY, COOY, —CO—NYY, —CO—NY-Alk-OY, -Alk-CO—NYY, -Alk-OY, -Alk-NYY, Ar, Het 1 or Het 2 ,

or

R3, R5 together denote -Alk-CO—NY—,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

X denotes CH 2 , O, S or Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Cyc denotes cyclic alkyl having 3-7 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I, or a pharmaceutically acceptable salt or tautomer thereof.

2. A compound according to claim 1 , which is of formula (IA)

in which

R1, R4 denote Y,

R2 denotes Y or —CH(R6)(R7),

R5 denotes Hal, Y, COOY, Alk-OA or Het 2 ,

R6 denotes —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY or —CO—NY-Alk-OY,

R7 denotes Ar or Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-4 C atoms, in which, independently of one another, 1-3 H atoms are optionally replaced by Hal,

Alk denotes alkylene having 1-3 C atoms, in which 1-2 H atoms are optionally replaced by Hal and/or OH,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-3 N and/or S atoms, which may be unsubstituted or monosubstituted by Hal, A, CN or NYY,

Het 2 denotes a monocyclic saturated heterocycle having 3-5 C atoms and1-2 N and/or O atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I, or a pharmaceutically acceptable salt or tautomer thereof.

3. A compound according to claim 1 , which is one of the following compounds

or a pharmaceutically acceptable salt or tautomer thereof.

4. A compound of formula (II)

in which

R8 denotes CN or ═O,

R9 denotes NO 2 or NYY,

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R5 denotes Hal, Y, OY, NYY, —NY—COY, COOY, —CO—NYY, —CO—NY-Alk-OY, -Alk-CO—NYY, -Alk-OY, -Alk-NYY, Ar, Het 1 or Het 2 ,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

or a pharmaceutically acceptable salt or tautomer thereof.

5. A compound according to claim 4 , which is of formula (IIA)

in which

R1, R2, independently of one another, denote A or -Alk-Ar,

Alk denotes alkylene having 1-3 C atoms, in which 1-2 H atoms are optionally replaced by Hal,

R5 denotes Hal, Y, COOY, Alk-OA or Het 2 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-4 C atoms, in which, independently of one another, 1-3 H atoms are optionally replaced by Hal,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal,

Het 2 denotes a monocyclic saturated heterocycle having 3-5 C atoms and 1-2 N and/or O atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

or a pharmaceutically acceptable salt or tautomer thereof.

6. A compound of formula (III)

in which

R10 denotes H or Hal,

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO—NYY or Het 1 ,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Cyc denotes cyclic alkyl having 3-7 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

or a pharmaceutically acceptable salt or tautomer thereof.

7. A compound according to claim 6 , in which

R1, R2, independently of one another, denote A or -Alk-Ar,

R10 denotes Hal,

Alk denotes alkylene having 1-3 C atoms, in which 1-2 H atoms are optionally replaced by Hal,

R4 denote Y,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-4 C atoms, in which, independently of one another, 1-3 H atoms are optionally replaced by Hal,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, and

Hal denotes F, Cl, Br or I,

or a pharmaceutically acceptable salt or tautomer thereof.

8. A process for preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising

(a) reacting a compound of formula (IIA)

in which

R1, R2, independently of one another, denote A or -Alk-Ar,

Alk denotes alkylene having 1-3 C atoms, in which 1-2 H atoms are optionally replaced by Hal,

R5 denotes Hal, Y, COOY, Alk-OA or Het 2 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-4 C atoms, in which, independently of one another, 1-3 H atoms are optionally replaced by Hal,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal,

Het 2 denotes a monocyclic saturated heterocycle having 3-5 C atoms and 1-2 N and/or O atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

in an acidic medium with a reducing agent and with a compound E-NO 2 , in which E denotes an element from the 1st main group,

to give a compound of formula (IB)

in which R1, R2 and R5 have the meaning indicated for the compound of formula (IIA),

and optionally

(b′) reacting the compound of formula (IB) with a compound Hal-R4, in which

R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO—NYY or Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Cyc denotes cyclic alkyl having 3-7 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY, and

Hal denotes F, Cl, Br or I,

to give a compound of formula (IC)

in which R1, R2 and R5 have the meaning indicated for the compound of formula (IIA), and R4 has the meaning indicated for the compound Hal-R4,

(b″) converting a group R1, —O—R2, R4, R5 and/or the CN group of the compound of formula (IC) to give a compound of formula (IE)

in which

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R3 denotes H, Hal, CN, -Alk-CN, -Alk-NYY, Het 1 or Het 2 ,

R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO—NYY or Het 1 ,

R5 denotes Hal, Y, OY, NYY, —NY—COY, COOY, —CO—NYY, —CO—NY-Alk-OY, -Alk-CO—NYY, -Alk-OY, -Alk-NYY, Ar, Het 1 or Het 2 ,

Or

R3, R5 together denote -Alk-CO—NY—,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

X denotes CH 2 , O, S or Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Cyc denotes cyclic alkyl having 3-7 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

and/or

(b″) converting a base or acid compound of formula (IE), (IB) or (IC) into one of its pharmaceutically acceptable salts,

or

(a) reacting a compound of formula (III)

in which

R1, R2, independently of one another, denote A or -Alk-Ar,

R10 denotes Hal,

Alk denotes alkylene having 1-3 C atoms, in which 1-2 H atoms are optionally replaced by Hal,

R4 denote Y,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-4 C atoms, in which, independently of one another, 1-3 H atoms are optionally replaced by Hal,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, and

Hal denotes F, Cl, Br or I,

with a compound of formula (IV)

in which

D denotes boric acid, boric ester, organotin compound or boron trifluoromethanesulfonate, and

R3 denotes H, Hal, CN, -Alk-CN, -Alk-NYY, Het 1 or Het 2 ,

R5 denotes Hal, Y, OY, NYY, —NY—COY, COOY, —CO—NYY, —CO—NY-Alk-OY, -Alk-CO—NYY, -Alk-OY, -Alk-NYY, Ar, Het 1 or Het 2 ,

or

R3, R5 together denote -Alk-CO—NY—,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

to give a compound of formula (ID)

in which R1, R2 and R4 have the meaning indicated for the compound of formula (III),

and R3 and R5 have the meaning indicated for the compound of formula (IV),

and optionally

(b′) converting a group R1, —O—R2, R3, R4 and/or R5 of the compound of formula (ID) to give a compound of formula (I)

and/or

(b″) converting a base or acid compound of formula (I) or (ID) into one of its phyarmaceutically acceptable salts.

9. A process for preparing a compound of claim 4 or a pharmaceutically acceptable salt thereof, comprising

(a) reacting a compound of formula (V)

in which

Hal denotes F, Cl, Br or I,

R9 denotes NO 2 or NYY,

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY, and

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A,

with a compound of formula (VI)

in which

R8 denotes CN or ═O,

R5 denotes Hal, Y, OY, NYY, —NY—COY, COOY, —CO—NYY, —CO—NY-Alk-OY, -Alk-CO—NYY, -Alk-OY, -Alk-NYY, Ar, Het 1 or Het 2 ,

and Hal, Y, Alk, Ar, Het 1 or Het 2 , have the meanings indicated for the compound of formula (V),

to give a compound of formula (II)

and optionally

(b) converting a base or acid compound of formula (II) into one of its salts.

10. A process for preparing a compound of claim 6 or a pharmaceutically acceptable salt thereof, comprising

(a) reacting a compound of formula (VII)

in which

R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar,

R2 denotes Y, -Alk-OY, -Alk-NYY, —C(Y)(R6)(R7), —C(Hal)(R6)(R7), —SO 2 A, —SO 2 —Ar or —POOH—Ar,

R6 denotes Hal, Y, —COOY, —CO—NYY, —CO—NY—OY, —CO—NY—C(═NH)—NYY, —CO—NY-Alk-OY, —CO—NY-Alk-NYY, —CO—NY-Alk-SO 2 —NYY, —CO—NY-Alk-Ar, —CO—NY-Alk-Het 2 or —CO—NY—O-Alk-CN,

R7 denotes Ar, Het 1 or -Het 1 -Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, Het 1 , Het 2 , -Alk-OY, -Alk-NYY, -Alk-Het 1 or Alk-Het 2 ,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY,

Het 2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by A, and

Hal denotes F, Cl, Br or I,

in an acidic medium with a compound E-NO 2 , in which E denotes an element from the 1st main group,

to give a compound of formula (IIIA)

in which R1 and R2 have the meaning indicated for the compound of formula (VII),

and optionally

(b′) halogenating the compound of formula (IIIA) to give a compound of formula (IIIB)

in which R1, R2 and Hal have the meaning indicated for the compound of formula (VII),

(b″) reacting a compound of formula (IIIA) or (IIIB) with a compound Hal-R4, in which

R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO—NYY or Het 1 ,

Y denotes H or A,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which, independently of one another, 1-7 H atoms may be replaced by Hal, and/or in which, independently of one another, one or two adjacent CH 2 groups are optionally replaced by a —CH═CH— and/or —C≡C— group,

Alk denotes alkylene having 1-6 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Cyc denotes cyclic alkyl having 3-7 C atoms, in which, independently of one another, 1-4 H atoms are optionally replaced by Hal and/or OY,

Het 1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, —NY—COY, COOY, -Alk-OY or -Alk-NYY, and

Hal denotes F, Cl, Br or I,

to give a compound of formula (III)

and/or

(b″) converting a base or acid compound of formula (III) into one of its salts.

11. A method for sensitizing cancer cells to anticancer agents and/or ionising radiation, comprising bringing together an effective amount of a compound of claim 1 with said cancer cells with the proviso that the sensitisation does not take place in vivo on the human body.

12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition according to claim 12 , further comprising an anticancer agent other than a compound of formula (I).

14. A method of sensitizing progress and control of cancer, a tumor, metastases and/or angiogenesis disorder to radiotherapy, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with radiotherapy and/or with an anticancer agent other than a compound of formula (I).

15. A method for sensitizing cancer cells to anticancer agents and/or ionising radiation, comprising bringing together an effective amount of a compound of claim 1 with said cancer cells.

16. A method for inhibiting DNA-PK, comprising bringing together an effective amount of a compound of claim 1 with said DNA-PK.

17. A method according to claim 14 , wherein the cancer, tumour, metastases and/or angiogenesis disorder is colon cancer.

18. A method according to claim 14 , wherein the cancer, tumour, metastases and/or angiogenesis disorder is squamous epithelium, a tumor of the lung, small-cell lung carcinoma, pancreatic cancer or a tumor of the oesophagus.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 2, 2013
From: FUCHSS, THOMAS; MEDERSKI, WERNER; ZENKE, FRANK
To: MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG
Reel/Frame 029552/0757 →
Priority Claims (1)
DE 10 2010 025 786 · Jul 1, 2010 · national
Continuity (1)
Related Publication 20130150359A1 · Jun 13, 2013