HETEROCYCLIC COMPOUNDS AS AUTOTAXIN INHIBITORS

• US 20120115852A1
• Filed: 06/17/2010
• Published: 05/10/2012
• Est. Priority Date: 07/16/2009
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Schultz, Melanie, Schiemann, Kai, Staehle, Wolfgang
• Application Number:
  US13/383,908
• Publication Number:
  US 20120115852A1
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds of the formula (I), in which R, R¹, R², X, X₁, Y, Y₁, Q, E, n1 and n2 have the meanings indicated in claim 1, are autotaxin inhibitors and can be employed for the treatment of tumours.

Claims

1. Compounds of the formula I

2. Compounds according to claim 1 in which

R² denotes H, (CH₂)_n3NH₂, (CH₂)_n3NHA, (CH₂)_n3NA₂, (CH₂)_n3OH, (CH₂)_n3OA, (CH₂)_n3Het², CH₂COHet², CH₂CONH₂, CH₂CONHA, CH₂CONA₂ or methyl,

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

3. Compounds according to claim 1 in which

X, X₁ each, independently of one another, denote CO or CH₂,

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

4. Compounds according to claim 1 in which

Y, Y₁ denote CH,

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

5. Compounds according to claim 1 in which

A denotes unbranched or branched alkyl having 1-10 C atoms,

in which 1-7H atoms may be replaced by F and/or Cl,

or

cyclic alkyl having 3-7 C atoms,

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

6. Compounds according to claim 1 in which

Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂, NHA and/or NA₂,

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

7. Compounds according to claim 1 in which

Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, Het², OH, NH₂, NHA and/or NA₂,

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

8. Compounds according to claim 1 in which

Het¹ denotes a mono-, bi- or tricyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by A and/or Hal,

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

9. Compounds according to claim 1 in which

R denotes Hal, Ar or Het'"'"',

R¹ denotes SO₂A, COOA, COOH, Cyc, Het, Ar, COHet, CONHHet, CONHAr, CHO, CONH₂, CONHA, CONA₂, (CH₂)_n2OH, (CH₂)_n2OA, OAr, NHAr, (CH₂)_n2NH₂, (CH₂)_n2NHA, (CH₂)_n2NA₂ or A,

R² denotes H, (CH₂)_n3NH₂, (CH₂)_n3NHA, (CH₂)_n3NA₂, (CH₂)_n3OH, (CH₂)_n3OA, (CH₂)_n3Het², CH₂COHet², CH₂CONH₂, CH₂CONHA, CH₂CONA₂ or methyl,

X, X₁ each, independently of one another, denote CO or CH₂,

Y, Y₁ denote CH,

Q denotes CO, SO₂ or COO,

E denotes CO, CH(OH), CA(OH), CH(OA), CA(OA), CH(NH₂), Alk,

10. Compounds according to claim 1 selected from the group

11. Medicaments comprising at least one compound of the formula I according to claim 1 or a compound “

B1”

-“

B27” and

/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

12. Compounds of the formula I and the compounds “

B1”

-“

B27” and

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

for treatment and/or prophylaxis of tumours, tumour diseases and cancer diseases.

13. Compounds according to claim 12, where the cancer diseases are selected from the group of tumours of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the stomach, of the larynx and/or of the lung.

14. Compounds according to claim 12, where the tumour originates from the group monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, ovarian carcinoma, glioblastomas and breast carcinoma and colon carcinoma.

15. Compounds according to claim 12, where the disease to be treated is a tumour of the blood and immune system.

16. Compounds according to claim 12, where the tumour originates from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

17. The compound 4′

-chloro-4-({(R)-4-[(S)-3,3-dimethyl-2-(piperidin-4-ylamino)butyryl]piperazin-2-carbonyl}amino)-2′

-fluorobiphenyl-3-carboxylic acid (“

47”

) and salts thereof.