TECHNICAL FIELD

This invention relates to substituted amino-quinazolinones and their use as R-secretase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases and conditions in which the use of therapeutic effective amounts of compounds inhibiting Î²-secretase display a therapeutic benefit, e.g. in Alzheimer's disease.

BACKGROUND ART

EP 652 009 A1 describes inhibitors of aspartate protease which inhibit the production of beta-amyloid peptides in cell culture and in vivo.

WO 00/69262 discloses a beta-secretase and the use thereof in assays for finding potential active substances for the treatment of AD.

WO 01/00663 discloses memapsin 2 (human beta-secretase) as well as a recombinant catalytically active enzyme. Methods of identifying inhibitors of memapsin 2 are also described.

WO 01/00665 discloses inhibitors of memapsin 2 for the treatment of AD.

WO 03/057721 discloses substituted aminocarboxamides for the treatment of AD.

WO 05/004802 discloses substituted benzyl substituted N-alkyl-phenylcarboxamides for the treatment of AD.

The International patent applications WO 06/024932, WO 06/017836 and WO 06/017844 disclose substituted amino-quinazolines and their use as Î²-secretase inhibitors for the treatment of Alzheimer's disease.

At present there are no effective treatment methods capable of preventing, stopping or reversing AD.

Surprisingly, it has been found that the compounds of the present invention inhibit beta secretase-mediated cleavage of APP, are weakly basic, are only partially protonated at physiological conditions, show a high ability to overcome the blood/brain barrier and show improved selectivity against a variety of other biological targets.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to substituted amino-quinazolinones of general formula 1

wherein

- A is selected from the group GA.1 consisting of
  - a C₁-C₃-alkylene bridge, aryl-, heteroaryl- and heterocyclyl-, wherein the above-mentioned members of the group GA.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, R¹⁴â€”Oâ€”C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-Oâ€”, F₃Câ€”Oâ€”, HF₂Câ€”Oâ€”, FH₂Câ€”Oâ€”, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)₂â€”Nâ€”COâ€”,
- R¹is selected from the group GR1.1 consisting of Hâ€”, HOâ€”, methyl-, ethyl-, F₃Câ€”, F₃Câ€”CH₂â€”, H₃Câ€”Oâ€”, H₃Câ€”CH₂â€”Oâ€”, H₃Câ€”C(O)â€”, (CH₃)₃Câ€”Oâ€”C(O)â€” and HC(O)â€”,
- R²is selected from the group GR2.1 consisting of
  - Hâ€”, fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, F₃Câ€”Oâ€”, HF₂Câ€”Oâ€”, FH₂Câ€”Oâ€”, C_1-6-alkyl-, C_1-6-alkyl-Sâ€”, C_1-6-alkyl-Sâ€”C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-, aryl-C_1-6-alkyl-, heterocyclyl-, heterocyclyl-C_1-6-alkyl-, heteroaryl-, heteroaryl-C_1-6-alkyl-, R¹⁴â€”Oâ€”, R¹⁴â€”Oâ€”C_1-3-alkyl-, (R¹³)₂Nâ€”, (R¹³)₂â€”Nâ€”COâ€”, R¹³â€”COâ€”(R¹³)Nâ€”, (R¹³)₂â€”Nâ€”COâ€”(R¹³)Nâ€”, R¹³â€”SO₂â€”(R¹³)Nâ€”, (R¹³)₂Nâ€”SO₂â€” and R¹³â€”SO₂â€”,
  - wherein the above-mentioned members of the group GR2.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-Oâ€”, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)₂Nâ€”COâ€”,
- R³is selected from the group GR3.1 consisting of
  - Hâ€”, fluorine, chlorine, bromine, HOâ€”, NCâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, F₃Câ€”Oâ€”, HF₂Câ€”Oâ€”, FH₂Câ€”Oâ€”, C_1-6-alkyl-, C_1-6-alkyl-Sâ€”, C₂-C₆-alkenyl, C_1-6-alkyl-Sâ€”C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-, aryl-C_1-6-alkyl-, heterocyclyl-, heterocyclyl-C_1-6-alkyl-, heteroaryl-, heteroaryl-C_1-6-alkyl-, R¹²â€”Oâ€”, R¹²â€”Oâ€”C_1-3-alkyl-, R¹²â€”Sâ€”, R¹²â€”COâ€”, (R¹³)₂Nâ€”, (R¹³)₂â€”Nâ€”COâ€”, R¹³â€”COâ€”(R¹³)Nâ€”, (R¹³)₂Nâ€”COâ€”(R¹³)Nâ€”, R¹³â€”SO₂â€”(R¹³)Nâ€”, (R¹³)₂Nâ€”SO₂â€” and R¹³â€”SO₂â€”,
  - wherein the above-mentioned members of the group GR3.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, R¹⁴â€”Oâ€”, R¹⁴â€”Oâ€”C_1-6-alkyl-, C_1-6-alkyl-, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)₂â€”Nâ€”COâ€”,
- R⁴is selected from the group GR4.1 consisting of
  - Hâ€”, fluorine, NCâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, C_1-6-alkyl-, C₂-C₆-alkenyl, C_1-6-alkyl-Sâ€”, C_1-6-alkyl-Sâ€”C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-, aryl-C_1-6-alkyl-, heterocyclyl-, heterocyclyl-C_1-6-alkyl-, heteroaryl-, heteroaryl-C_1-6-alkyl-, R¹⁴â€”Oâ€”, and R¹⁴â€”Oâ€”C_1-3-alkyl-, wherein the above-mentioned members of the group GR4.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-Oâ€”, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)2â€”Nâ€”COâ€”,
- R⁵is selected from the group GR5.1 consisting of
  - R⁶R⁷Nâ€”COâ€”, R⁸â€”COâ€”(R⁹)Nâ€”, and R¹⁰R¹¹â€”Nâ€”COâ€”(R⁹)Nâ€”,
- R⁶, R⁷are selected from the group GR6/11.1 consisting of
- R⁸, R⁹Hâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, C_1-6-alkyl-, C₂-C₆-alkenyl, C_1-6-alkyl-Sâ€”
- R¹⁰, R¹¹C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-, aryl-C_1-6-alkyl-, heterocyclyl-, heterocyclyl-C_1-6-alkyl-, heteroaryl-, heteroaryl-C_1-6-alkyl-, and
  - R¹⁴â€”Oâ€”C_1-3-alkyl-,
  - wherein, if R⁶and R⁷or R¹⁰and R¹¹are C_1-6-alkyl groups, those two C_1-6-alkyl groups bound to the same nitrogen atom of R⁵may be joined together forming, together with the nitrogen atom to which they are bound, a 3 to 7 membered heterocyclic ring, and wherein one of the â€”CH₂-groups of the heterocyclic ring formed by the R⁶and R⁷or R¹⁰and R¹¹C_1-6-alkyl groups and the nitrogen atom of R⁵may be replaced by â€”Oâ€”, â€”Sâ€”, Nâ€”H, â€”N(C_3-6-cycloalkyl)-, â€”N(C_3-6-cycloalkyl-C_1-4-alkyl)- or â€”N(C_1-4-alkyl)- and
  - wherein the above-mentioned members of the group GR6/11.1 including the the heterocyclic ring formed by the R⁶and R⁷or R¹⁰and R¹¹C_1-6-alkyl groups and the nitrogen atom of R⁵may optionally be substituted independently of one another by one or more substituents selected from group GR6/11.S1 consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-Oâ€”, aryl-, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)₂Nâ€”COâ€”
  - wherein the above-mentioned aryl of group GR6/11.S1 may optionally be substituted independently of one another by one or more substituents selected from group consisting of
  - fluorine, chlorine, bromine, NCâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, and C_1-6-alkyl-Oâ€”,
- R¹²is selected from the group GR12.1 consisting of
  - F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, C_1-6-alkyl-, C_3-6-alkenyl-, C_1-6-alkyl-Sâ€”C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-, aryl-C_1-6-alkyl-, heterocyclyl-, heterocyclyl-C_1-6-alkyl-, heteroaryl-, and heteroaryl-C_1-6-alkyl-, wherein the above-mentioned members of the group GR12.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, R¹⁴â€”Oâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, R¹⁴â€”Oâ€”C_1-6-alkyl-, C_1-6-alkyl-, (R¹³)₂Nâ€”, (R¹³)₂Nâ€”C_1-3-alkyl-, and (R¹³)₂Nâ€”COâ€”.

R¹³is selected from the group GR13.1 consisting of

- - Hâ€”, F₃Câ€”CH₂â€”, C_1-6-alkyl-, C_2-6-alkenyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, aryl-, aryl-C_1-3-alkyl-, heterocyclyl-, heterocyclyl-C_1-3-alkyl-, heteroaryl-, and heteroaryl-C_1-3-alkyl-,
  - wherein two C_1-6-alkyl groups bound to the same nitrogen atom may be joined together forming, together with the nitrogen atom to which they are bound, a 3 to 7 membered heterocyclic ring, and wherein one of the â€”CH₂â€” groups of the heterocyclic ring formed may be replaced by â€”Oâ€”, â€”Sâ€”, Nâ€”H, â€”N(C_3-6-cycloalkyl)-, â€”N(C_3-6-cycloalkyl-C_1-4-alkyl)- or â€”N(C_1-4-alkyl)- and
  - wherein the above-mentioned members of the group GR13.1 including the the heterocyclic ring formed may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, and C_1-6-alkyl-Oâ€”.
- R¹⁴is selected from the group GR14.1 consisting of
  - Hâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, C_1-6-alkyl-, C_2-6-alkenyl-,C_3-7-cycloalkyl-, C_3-7-cyclyoalkyl-C_1-3-alkyl-, aryl-, aryl-C_1-3-alkyl-, heterocyclyl-, heterocyclyl-C_1-3-alkyl-, heteroaryl- and heteroaryl-C_1-3-alkyl-,
  - wherein the above-mentioned members of the group GR14.1 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, HOâ€”, NCâ€”, O₂Nâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, and C_1-6-alkyl-Oâ€”,
    and pharmaceutically acceptable salts thereof.

In a preferred embodiment of the present invention

- A is selected from the group GA.2 consisting of
  - â€”CH2-, â€”CH2-CH2-, â€”CH2-CH2-CH2-, aryl-, and heteroaryl-,
  - wherein the above-mentioned members of the group GA.2 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, bromine, NCâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, F₃Câ€”Oâ€”, HF₂Câ€”Oâ€”, FH₂Câ€”Oâ€”, H₃Câ€”Oâ€”C_1-6-alkyl-, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-, and C_1-6-alkyl-Oâ€”.

In another preferred embodiment the present invention

- A is selected from the group GA.3 consisting of
  - â€”CH2-CH2-, â€”CH2-CH2-CH2-, phenyl-, and pyridyl-,
  - wherein the above-mentioned members of the group GA.3 may optionally be substituted independently of one another by one or more substituents selected from the group consisting of
  - fluorine, chlorine, NCâ€”, F₃Câ€”, HF₂Câ€”, FH₂Câ€”, F₃Câ€”CH₂â€”, F₃Câ€”Oâ€”, HF₂Câ€”Oâ€”, FH₂Câ€”Oâ€”, H₃Câ€”, and H₃Câ€”Oâ€”.