Benzonaphthyridinamines as autotaxin inhibitors

1. A compound of formula (I)

in which:

D denotes Ar or Het,

Ar denotes unsubstituted or mono- or polysubstituted phenyl, indanyl, naphthyl or biphenyl,

Het denotes a mono- or bicyclic saturated, partially unsaturated or aromatic heterocycle having 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or mono- or polysubstituted,

X, Y each, independently of one another, is absent, denotes —CH 2 —, —(CH 2 ) 2 —, —C(O)—, —CHOH— or —CH 2 OC(O)—, where only one of the radicals X or Y may be absent,

R in each case, independently of one another, denote H, A, Cyc, (CH 2 ) g Ar or (CH 2 ) q Het and may be mono- or polysubstituted by R 6 , where in A and Cyc, the C chain and C ring respectively may also be interrupted by O,

R 1 in each case, independently of one another, denote R, F, Cl, Br, I, OH, ═O, CN, NO 2 , NRR, NHC(O)R, NHSO 2 R, OR, C(O)R, C(O)NRR, CF 3 , OCF 3 , SCF 3 , SO 2 CH 3 , SO 3 R, SO 2 R, SO 2 NR, SR, OA, A, phenyl and may be mono- or polysubstituted by R 6 ,

R 2 , R 3 each, independently of one another, denote R, where R 2 and R 3 may alternatively together also form Cyc or Het, each of which may in turn be mono- or polysubstituted by R 6 ,

R 4 in each case, independently of one another, denote R, F, Cl, Br, I, OH, ═O, CN, NO 2 , NRR, NHC(O)R, NHSO 2 R, OR, C(O)R, C(O)NRR, CF 3 , OCF 3 , SCF 3 , SO 2 CH 3 , SO 3 R, SO 2 R, SO 2 NR, SR, OA, A, phenyl and may be mono- or polysubstituted by R 6 ,

R 5 in each case, independently of one another, denote R, F, Cl, Br, I, OH, ═O, CN, NO 2 , NRR, NHC(O)R, NHSO 2 R, OR, C(O)R, C(O)NRR, CF 3 , OCF 3 , SCF 3 , SO 2 CH 3 , SO 3 R, SO 2 R, SO 2 NR, SR, OA, A, phenyl and may be mono- or polysubstituted by R 6 ,

R 6 in each case, independently of one another, denote R, F, Cl, Br, I, OH, ═O, CN, NO 2 , NRR, NHC(O)R, NHSO 2 R, OR, C(O)R, C(O)NRR, CF 3 , OCF 3 , SCF 3 , SO 2 CH 3 , SO 3 R, SO 2 R, SO 2 NR, SR, OA, A, phenyl and, so long as a substitution is chemically possible, may be mono- or polysubstituted by R, F, Cl, Br, I, OH, ═O, CN, NO 2 , NRR, NHC(O)R, NHSO 2 R, OR, C(O)R, C(O)NRR, CF 3 , OCF 3 , SCF 3 , SO 2 CH 3 , SO 3 R, SO 2 R, SO 2 NR, SR, OA, A, phenyl,

A denotes linear or branched alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced by OR, CN, NRR, F and/or Cl and/or in which one or two non-adjacent CH 2 groups may be replaced by O, NH, S, SO, SO 2 and/or by CH═CH groups,

Cyc denotes cyclic alkyl having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms,

m denotes 0, 1, 2, 3, 4, or 5,

n denotes 0, 1, 2, or 3,

p denotes 0, 1, 2, 3, or 4,

q denotes 0, 1, or 2,

or pharmaceutically usable salts, solvates or stereoisomers thereof, including mixtures thereof in all ratios.

2. A compound according to claim 1 in which

D denotes Ar,

Ar denotes unsubstituted or mono- or polysubstituted phenyl,

X, Y each, independently of one another, denote —CH 2 —, —C(O)— or —CH 2 OC(O)—,

R 1 in each case, independently of one another, denote F, Cl, OA or OCH 3 ,

R 2 , R 3 each, independently of one another, denote H, Ar, Ar monosubstituted by OA, Het, Het monosubstituted by A, CH 2 -Het, A, A monosubstituted by OH or by NRR or by CO—NRR or by Het or by CO—R, or each, independently of one another, denote 1-methylpiperidin-4-yl, 2-hydroxyethyl, 2-dimethylaminoethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, 1H-benzimidazol-2-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-oxo-2-piperidin-1-ylethyl, 2-morpholin-4-yl-2-oxoethyl, cyclohexylcarbamoylmethyl, 2-(4-methylpiperazin-1-yl)-2-oxo-ethyl, 2-(4-isopropylpiperazin-1-yl)-2-oxoethyl, diethylcarbamoylmethyl, 2-(4-benzylpiperazin-1-yl)-2-oxoethyl, 3-oxo-3-piperidin-1-ylpropyl, pyridin-4-yl, pyridin-3-yl, phenyl, pyridin-2-yl or 4-methoxyphenyl, where R 2 and R 3 may alternatively together also form 4-(2-hydroxyethyl)-piperazin-1-yl,

m denotes 2,

n denotes 0,

p denotes 0,

q denotes 0 or 1,

Het, R, R 6 , A and Cyc have the meanings indicated in claim 1 ,

or pharmaceutically usable salts, solvates and or stereoisomers thereof, including mixtures thereof in all ratios.

3. A compound according claim 1 ,

Compound

No.

Chemical Structure

Chemical Name

 1

N-(5-Chloro-2- methoxyphenyl)-2-[10- (1-methylpiperidin-4- ylamino)-3,4-dihydro- 1H-benzo[b]-1,6-naph- thyridin-2-yl]acetamide

 2

2-(10-Amino-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl)- N-(5-chloro-2-methoxy- phenyl)acetamide

 3

2-(10-Amino-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl)- N-(2,5-dichlorophenyl)- acetamide

 4

N-(5-Chloro-2- methoxyphenyl)-2-[10- (2-hydroxyethylamino)- 3,4-dihydro-1H- benzo[b]-1,6-naph- thyridin-2-yl]acetamide

 5

N-(5-Chloro-2- methoxyphenyl)-2-[10- (2-dimethylaminoethyl- amino)-3,4-dihydro-1H- benzo[b]-1,6-naph- thyridin-2-yl]acetamide

 6

10-(2-Dimethylamino- ethylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridine-2- carboxylic acid (5- chloro-2-methoxy- phenylcarbamoyl)methyl ester

 7

10-(2-Hydroxy- ethylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridine-2- carboxylic acid (5- chloro-2-methoxy- phenylcarbamoyl)methyl ester

 8

N-(5-Chloro-2- methoxyphenyl)-2-[10- (methylcarbamoyl- methylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

 9

N-(5-Chloro-2- methoxyphenyl)-2-[10- (dimethylcarbamoyl- methylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

10

N-(5-Chloro-2- methoxyphenyl)-2-[10- [4-(2-hydroxyethyl)- piperazin-1-yl]-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

11

2-{10-[(1H- Benzimidazol-2- ylmethyl)amino]-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- N-(5-chloro-2-methoxy- phenyl)acetamide

12

N-(5-Chloro-2- methoxyphenyl)-2-[10- (2-oxo-2-pyrrolidin-1-yl- ethylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

13

N-(5-Chloro-2- methoxyphenyl)-2-[10- (2-oxo-2-piperidin-1-yl- ethylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

14

N-(5-Chloro-2- methoxyphenyl)-2-[10- (2-morpholin-4-yl-2- oxoethylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

15

N-(5-Chloro-2- methoxyphenyl)-2-[10- (cyclohexylcarbamoyl- methylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

16

N-(5-Chloro-2- methoxyphenyl)-2-{10- [2-(4-methylpiperazin-1- yl)-2-oxoethylamino]- 3,4-dihydro-1H- benzo[b]-1,6-naph- thyridin-2-yl}acetamide

17

N-(5-Chloro-2- methoxyphenyl)-2-{10- [2-(4-isopropyl- piperazin-1-yl)-2-oxo- ethylamino]-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl}- acetamide

18

N-(5-Chloro-2- methoxyphenyl)-2-[10- (diethylcarbamoyl- methylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

19

2-{10-[2-(4-Benzyl- piperazin-1-yl)-2-oxo- ethylamino]-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl}- N-(5-chloro-2-methoxy- phenyl)acetamide

20

N-(5-Chloro-2- methoxyphenyl)-2-[10- (pyridin-4-ylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

21

N-(5-Chloro-2- methoxyphenyl)-2-[10- (pyridin-3-ylamino-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

22

N-(5-Chloro-2- methoxyphenyl)-2-(10- phenylamino-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl)- acetamide

23

N-(5-Chloro-2- methoxyphenyl)-2-[10- (pyridin-2-ylamino)-3,4- dihydro-1H-benzo[b]- 1,6-naphthyridin-2-yl]- acetamide

24

N-(5-Chloro-2- methoxyphenyl)-2-[10- (4-methoxyphenyl- amino)-3,4-dihydro-1H- benzo[b]-1,6-naph- thyridin-2-yl]acetamide

or pharmaceutically usable salts, solvates or stereoisomers thereof, including mixtures thereof in all ratios.

4. A process for preparation of compounds of the formula (I) according to claim 1 or pharmaceutically usable salts, solvates or stereoisomers thereof, comprising reacting a compound of formula (II)

in which D, X, Y, R, R 1 , R 4 , R 5 , m, n and p have the meanings indicated and L is a halogen, tosylate, mesylate or triflate,

with a compound of formula (III)

H—NR 2 R 3   (III)

in which R 2 , R 3 have the meanings indicated,

and/or converting a base or acid of the resultant compounds of the formula (I) into one of its salts,

or

reacting a compound of formula (IV)

in which D, X, Y, R, R 1 and m have the meanings indicated and L represents a halogen, tosylate, mesylate, triflate or a free or reactively modified OH group,

with a compound of formula (V)

in which R 2 , R 3 , R 4 , R 5 , n and p have the meanings indicated,

and/or converting a base or acid of the resultant compounds of the formula (I) into one of its salts,

or

first reacting a compound of formula (VI)

in which D, X, R, R 1 and m have the meanings indicated,

with a carbonylation agent,

and then reacted with a compound of the formula (V)

in which R 2 , R 3 , R 4 , R 5 , n and p have the meanings indicated,

and/or a base or acid of the resultant compounds of the formula (I) is converted into one of its salts.

5. A method of inhibiting an autotaxin comprising inhibiting said autotaxin with a compound according to claim 1 .

6. A pharmaceutical composition comprising at least one compound of the formula (I) according to claim 1 and/or pharmaceutically usable salts, solvates or stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

7. A method for treating physiological and/or pathophysiological conditions in which inhibition, regulation and/or modulation of phosphodiesterase or lysophospholipase autotaxin plays a role, comprising administering an effective amount of a compound according to claim 1 .

8. A method for treating glioblastomas, neuroblastomas, kidney cell carcinomas, prostate carcinomas, thyroid cancer, lung cancer, breast cancer, lymphomas or angiogenesis, mediated by autotaxin, said method comprising administering an effective amount of a compound according to claim according to claim 1 .

9. A pharmaceutical composition according to claim 6 , further comprising at least one additional pharmacologically active substance.

10. A method according to claim 7 , wherein said compound is administered before and/or during and/or after the treatment with at least one additional pharmacologically active substance.

11. A kit comprising a therapeutically effective amount of at least one compound according to claim 1 and a therapeutically effective amount of at least one additional pharmacologically active substance which does not correspond to a compound according to claim 1 .