Macrocyclic pyridazinone derivatives

Patent metadata

Field	Value
Publication number	US-9550794-B2
Application number	US-201414766291-A
Country	US
Kind code	B2
Filing date	Feb 7, 2014
Priority date	Feb 7, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to compounds of formula (I) Wherein R1, R2, R3, R4, L and Z have the meaning given in claim 1 , and their use in the prophylaxis and treatment of diseases.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
R1, R3 denote each, independently of one another H, (CH 2 ) p CON(R5) 2 , OA, Hal, COOH, COOA, (CH 2 ) p NHCOA, (CH 2 ) p Het1, (CH 2 ) p NR2R5, or OH;
R2 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms, wherein one or two H atoms of the alkyl group are optionally replaced by OR6, NR5R6, NHCOR5, CONR5R6;
R4 denotes H or A;
R5 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;
R6 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;
Z is absent or denotes Ar-diyl or Het-diyl;
L denotes (CH 2 ) n wherein one or two CH 2 groups are optionally replaced by O and/or a CH═CH-group, and/or wherein one or two H atoms are optionally replaced by OR2, NR2R5 or Het1;
Ar-diyl denotes 1,2-, 1,3- or 1,4-phenylen optionally substituted with from 1 to 5 groups independently selected from the group consisting of Hal, CN, —CF 3 , —OCF 3 , OH, O-A, SO 2 -A, COOH, COOA, —CO-A, O-phenyl, SO 2 -phenyl, SO 2 —CF 3 , Het2 and A;
Het-diyl denotes an unsaturated, saturated or aromatic 5- or 6-membered heterocycle having 1 to 2 N, O and/or S atoms, which are optionally unsubstituted or mono-, di- or trisubstituted by Hal, CN, —CF 3 , —OCF 3 , O-A, SO 2 -A, COOH, COOA, —CO-A, O-phenyl, SO 2 -phenyl, SO 2 —CF 3 , Het2 and/or A;
A denotes an unbranched or branched alkyl having 1 to 10 C atoms, in which 1 to 5 H atoms are optionally replaced by F and/or in which one or two non-adjacent CH 2 groups are optionally replaced by O;
Het1 denotes morpholinyl, piperidinyl or pyrrolidinyl;
Het2 denotes morpholinyl, piperidinyl or pyrrolidinyl;
Hal denotes F, Cl, Br, I;
n denotes 1, 2, 3, 4, 5 or 6;
p denotes 0, 1 or 2
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R4 is H or methyl.

3. The compound of claim 1 , wherein Het-diyl denotes pyridine-diyl, pyrimidine-diyl, pyridazin-diyl, pyrazol-diyl, imidazol-diyl, piperidin-diyl or pyrrolidin-diyl, each of which is unsubstituted or disubstituted by A.

4. The compound of claim 1 , wherein Z is 1,3-phenylen, which is unsubstituted or monosubstituted by A, Hal, OH, or OA.

5. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising: the compound of claim 1 and at least one pharmaceutically acceptable carrier or excipient.

7. A kit consisting of separate packs of:
(a) an effective amount of the compound of claim 1 , and
(b) an effective amount of a further medicament active ingredient.

8. The pharmaceutical composition of claim 6 , further comprising: a medicament effective for treatment of an inflammatory disease or an immune disorder.

9. The pharmaceutical composition of claim 8 , further comprising an immunomodulating agent.

10. A process for synthesizing the compound of claim 1 , the process comprising:
macrocyclizing a compound of formula (II) to obtain the compound of claim 1 , wherein R1, R2, R3, R4, Z and L are the same as in claim 1 and A1 is H, Li, Na or K:

Assignees

• Merck Patent Gmbh

Inventors

• Jorand-Lebrun Catherine
• Kulkarni Santosh
• Christmann-Franck Serge

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title