4-amino substituted condensed pyrimidine compounds as PDE4 inhibitors

Patent metadata

Field	Value
Publication number	US-9505724-B2
Application number	US-201514817683-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Feb 4, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The invention relates to novel substituted condensed pyrimidine compounds of general formula (I)

in which the chemical groupings, substituents and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

First claim

The invention claimed is:

1. Pyrimidine compounds of general formula (I)

in which
G denotes a phenyl optionally substituted with at least one substituent Z or a 6-membered heteroaromatic optionally substituted with at least one substituent Z; or denotes a phenyl optionally substituted with at least one substituent Z or a 6-membered heteroaromatic optionally substituted with at least one substituent Z, being part of a 8- to 10-membered heterocyclic condensed ring containing at least one heteroatom selected from N, O, and S;
Z independently of one another denotes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —S(C 1 -C 6 ) alkyl, halogen, hydroxyl or cyano, wherein aforementioned alkyls are branched or straight-chain and can be substituted;
Q denotes a phenyl, pyrimidyl, or pyrazinyl substituted with a substituent X 1 and optionally substituted with at least one substituent X;
X independently of one another denotes (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) cycloalkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, hydroxyl, cyano, carboxyl, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —NH—C(O)—(C 1 -C 6 ) alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 6 ) alkyl, —C(O)—N((C 1 -C 6 ) alkyl) 2 , —S(O) 2 —NH 2 , —S(C 1 -C 6 ) alkyl, —S(O)—(C 1 -C 6 ) alkyl, or —S(O) 2 —(C 1 -C 6 ) alkyl, wherein the aforementioned alkyl chains are branched or straight-chain and can be substituted;
X 1 denotes an L-CO 2 R 2 group;
L denotes a bond, (C 1 -C 6 ) alkylene, (C 2 -C 6 ) alkenylene, —O—(C 1 -C 4 )alkylene, —NH—(C 1 -C 4 ) alkylene, or —NR 3 —(C 1 -C 4 ) alkylene, wherein aforementioned alkylenes or alkenylenes can each be substituted with one or more halogen atoms or wherein aforementioned alkylenes or alkenylenes can be substituted with one or more (C 1 -C 6 ) alkyl groups, or wherein in aforementioned alkylenes or alkenylenes a CH 2 unit can be replaced by an oxygen atom;
R 1 denotes hydrogen or a branched or straight-chain (C 1 -C 6 ) alkyl;
R 2 and R 3 , independently of each other denotes hydrogen or a branched or straight-chain (C 1 -C 6 ) alkyl;
n denotes 1 or 2;
K denotes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, hydroxyl or cyano; and
m denotes 0, 1, 2, 3 or 4,
as well as pharmacologically tolerable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

2. The pyrimidine compounds according to claim 1 , wherein
Z independently of one another denotes CH3, OCH3, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, SCH3, Cl, F, OH or CN;
X1 denotes an L-CO2R2 group;
L denotes a bond or methylene, wherein the methylene can be substituted with one or two halogen atoms; and
R1 denotes hydrogen or a branched or straight-chain (C1-C4) alkyl;
R2 denotes hydrogen or a branched or straight-chain (C1-C4) alkyl;
K denotes (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, fluorine, chlorine, bromine, hydroxyl or cyano.

3. The pyrimidine compounds according to claim 1 , wherein
G denotes a phenyl optionally substituted with at least one substituent Z or a 6-membered heteroaromatic optionally substituted with at least one substituent Z, selected from the following groups G1 to G9;

in which the site marked with an asterisk (*) indicates the binding site at position 2 of the pyrimidine ring;
k denotes 0, 1 or 2; and
Q is selected from the following groups Q1 to Q13,

in which the site marked with an asterisk (*) indicates the binding site at the nitrogen and
p denotes 0, 1, 2, 3 or 4;
X independently of one another denotes (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C3-C6) cycloalkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, hydroxyl, cyano, carboxyl, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —NH—C(O)—(C1-C6) alkyl, —C(O)—NH2, —C(O)—NH(C1-C6) alkyl, —C(O)—N((C1-C6) alkyl)2, —S(O)2-NH2, —S(C1-C6) alkyl, —S(O)—(C1-C6) alkyl, or —S(O)2-(C1-C6) alkyl, wherein the aforementioned alkyl chains are branched or straight-chain and can be substituted;
L denotes a bond or methylene, wherein the methylene can be substituted with one or two halogen atoms.

4. The pyrimidine compounds according to claim 1 , wherein n denotes 1.

5. The pyrimidine compounds according to claim 1 , wherein n denotes 2.

6. The pyrimidine compounds according to claim 1 , wherein m denotes 0.

7. The pyrimidine compounds according to claim 1 , wherein p denotes 0 or 1.

8. The pyrimidine compounds according to claim 3 , wherein
G denotes a phenyl optionally substituted with at least one substituent Z or a 6-membered heteroaromatic optionally substituted with at least one substituent Z, selected from G1, G2, G3 or G4; and
Q denotes a chemical grouping Q2, Q3, Q8 or Q9.

9. The pyrimidine compounds according to claim 3 , wherein
G denotes a phenyl G1 optionally substituted with at least one substituent Z; and
Q denotes a chemical grouping Q1, Q2 or Q3.

10. The pyrimidine compounds according to claim 3 , wherein
G denotes a phenyl G1 optionally substituted with at least one substituent Z; and
Q denotes a chemical grouping Q2.

11. The pyrimidine compounds according to claim 3 , wherein
G denotes a phenyl G1 optionally substituted with at least one substituent Z; and
Q denotes a chemical grouping Q3.

12. A pharmaceutical composition comprising at least one compound as defined in claim 1 .

13. A method of treating conditions or diseases responsive to the inhibition of PDE4-enzyme, said method comprising administering to a patient in need thereof an effective amount of one or more compounds as defined in claim 1 , or a physiologically tolerable salt thereof, or a pure stereoisomer thereof, wherein said conditions or diseases are selected from the following group:
inflammatory diseases of the joints selected from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis (Bechterew's disease), gout and osteoarthritis;
inflammatory diseases of the skin selected from psoriasis, atopic dermatitis and lichen planus;
inflammatory diseases of the eyes selected from uveitis;
gastrointestinal diseases and complaints selected from inflammatory diseases of the digestive organs, Crohn's disease, ulcerative colitis, and acute and chronic inflammations of the gall bladder, bile ducts, pseudopolyps and juvenile polyps;
inflammatory diseases of the internal organs selected from SLE (systemic lupus erythematosus), lupus nephritis, chronic prostatitis and interstitial cystitis;
hyperplastic diseases selected from benign prostatic hyperplasia;
respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract selected from: COPD (chronic obstructive pulmonary disease), chronic bronchitis, asthma, pulmonary fibrosis, allergic and non-allergic rhinitis, obstructive sleep apnoea, cystic fibrosis, chronic sinusitis, emphysema, cough, alveolitis, ARDS (acute respiratory distress syndrome), pulmonary oedema, bronchiectasis and

Assignees

• Gruenenthal Gmbh

Inventors

• Konetzki Ingo
• Jakob Florian
• Craan Tobias
• Hesslinger Christian

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P37/02

  Immunomodulators · CPC title