Tetrahydroisoquinoline derivatives, pharmaceutical compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-9340510-B2
Application number	US-201514855668-A
Country	US
Kind code	B2
Filing date	Sep 16, 2015
Priority date	Sep 17, 2014
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

The invention relates to new pyrrolidine derivatives of the formula

wherein R 1 to R 6 , n and m are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is selected from a group consisting of:
halogen, CN, OH, C 1-6 -alkyl, C 3-7 -cycloalkyl, —(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O—(C 1-6 -alkyl), —O—(C 3-7 -cycloalkyl), —O—(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O-phenyl, —O—(C 1-3 -alkyl)-phenyl, —COOH, —COO(C 1-4 -alkyl), —CO—NH—(C 1-3 -alkyl)-phenyl, —CO—NH—(C 1-6 -alkyl), —NH—(C 1-6 -alkyl), —NH—(C 3-7 -cycloalkyl), —NH—[(C 1-3 -alkyl)-(C 3-7 -cycloalkyl)] and NH—(C 1-3 -alkyl)-phenyl,
wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from F and CF 3 ; and
wherein the hydrogen atom in each NH group is optionally replaced with C 1-6 -alkyl;

or, if two R 1 -groups are attached to adjacent carbon atoms of the phenyl moiety of the tetrahydroisoquinolinyl group, they may be linked with each other and together form a C 3-5 -alkylene bridging group in which 1 or 2 —CH 2 -groups may independently of each other be replaced by —O—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —NH— or —N(C 1-4 -alkyl)-;
n is 0, 1, 2 or 3;
R 2 is selected from a group consisting of: H, C 1-6 -alkyl, C 3-7 -cycloalkyl, NH 2 , —NH—(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , —O—(C 1-6 -alkyl), heterocyclyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from O, S, N and NH, 6-membered heteroaryl containing one or two nitrogen atoms, and —(C 1-3 -alkyl)-(6-membered heteroaryl containing one or two nitrogen atoms);
wherein each alkyl group is optionally substituted with one or more substituents selected from F, CN, CONH 2 , CONH(C 1-3 -alkyl), CON(C 1-3 -alkyl) 2 , NH 2 and OH,
wherein each cycloalkyl group is optionally substituted with one or more substituents selected from F, CN, OH, NH 2 , NH(CO)OC 1-6 -alkyl, C 1-3 -alkyl and CF 3 ,
wherein each heteroaryl group is optionally substituted with one or more substituents selected from F, Cl, C 1-3 -alkyl, NH 2 and —NH—C(O)—(C 1-3 -alkyl), and
wherein the heterocyclyl group is selected from a group consisting of 2-oxo-pyrrolidinyl, 2-oxo-dihydrofuranyl and morpholinyl;

R 3 is H or C 1-4 -alkyl;
R 4 is H or C 1-4 -alkyl;
R 5 is H or C 1-3 -alkyl;
R 6 is F, OH or —O—(C 1-4 -alkyl),
or, if m is 2, both R 6 groups together with the carbon atom, to which they are attached, may form a carbonyl group; and
R 7 is H, C 1-4 -alkyl, —COOH or —COO(C 1-4 -alkyl), and
m is 0, 1 or 2;

wherein each of the above-mentioned alkyl and —O-alkyl groups may be substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein
R 3 is H,
R 4 is CH 3 and
R 5 is H,
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein
n is 1 or 2 and
R 1 is independently of one another selected from a group consisting of:
F, Cl, Br, C 1-3 -alkyl, —O—(C 1-6 -alkyl), —O—(C 3-7 -cycloalkyl), —O—(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O—(C 1-3 -alkyl)-phenyl, —COOH, —COO(C 1-4 -alkyl), and —CO—NH—(C 1-3 -alkyl)-phenyl,
wherein each alkyl and cycloalkyl is optionally substituted with one to three F or one CF 3 ; and
wherein the hydrogen atom in each NH group is optionally replaced with C 1-4 -alkyl;

or, if two R 1 -groups are attached to adjacent carbon atoms of the phenyl moiety of the tetrahydroisoquinolinyl group, they may be linked with each other and together form a C 3-5 -alkylene bridging group in which 1 or 2 —CH 2 -groups may independently of each other be replaced by —O—,
or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 , wherein
R 2 is selected from a group consisting of:
C 1-3 -alkyl, C 3-5 -cycloalkyl, —O—(C 1-3 -alkyl), NH 2 , —NH—(C 1-3 -alkyl), —N(C 1-3 -alkyl) 2 , —(C 1-2 -alkyl)-pyrimidinyl, pyrimidinyl, 2-oxo-pyrrolidinyl, 2-oxo-dihydrofuranyl, morpholinyl and a heteroaryl group selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiatolyl, imidazolyl and 1H-pyrazolyl;
wherein each alkyl group is optionally substituted with one to three substituents selected from F, CN, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , NH 2 and OH;
wherein each cycloalkyl group is optionally substituted with one or two substituents selected from F, CN, OH, NH 2 , —NH(CO)—O(C 1-4 -alkyl), C 1-3 -alkyl and CF 3 ;
wherein each heteroaryl group is optionally substituted with one or more substituents selected from Cl, CH 3 , NH 2 and —NH—C(O)—(C 1-2 -alkyl),

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 , wherein
R 2 is CH 3 , CH 2 CH 3 , CH 2 CN, CH 2 OH, cyclopropyl, cyclobutyl or

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 , wherein
m is 0 or 1, and R 6 is F, OH, or OCH 3 ; or
m is 2 and R 6 is F; or
m is 2 and both R 6 together with the carbon atom, to which they are attached, form a carbonyl group, and
R 7 is H, CH 3 , COOH or COOCH 3 ,
or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 having the formula

wherein
R 1a is selected from the group consisting of Cl, CF 3 , —O—(C 3-4 -alkyl), —O-cyclo-butyl, —O—(C 1-2 -alkyl)-(C 3-4 -cycloalkyl), —O—CH 2 -phenyl, —COOCH 3 , and —CO—NH—CH 2 -phenyl,
wherein each alkyl and cycloalkyl is optionally substituted with one to three F or one CF 3 ;

R 1b is H, F, Cl, Br or —OCH 3 ;
R 2 is selected from the group consisting of:
C 1-2 -alkyl, C 3-4 -cycloalkyl, —O—CH 3 , —NH—(C 1-2 -alkyl), —N(C 1-2 -alkyl) 2 , —CH 2 -pyrimidinyl, pyrimidinyl, 2-oxo-pyrrolidinyl, 2-oxo-dihydrofuranyl, morpholinyl and a heteroaryl group selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiatolyl, imidazolyl and 1H-pyrazolyl;
wherein each alkyl group is optionally substituted with one to three substituents selected from F, CN, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , NH 2 and OH;
wherein each cycloalkyl group is optionally substituted with one or two substituents selected from F, CN, OH, NH 2 , —NH(CO)—O—C(CH 3 ) 3 , CH 3 and CF 3 ;
wherein each heteroaryl group is optionally substituted with one or more substituents selected from Cl, CH 3 , NH 2 and —NH—C(O)—(C 1-2 -alkyl);

R 6 is selected from the group consisting of: F, OH, and —O—CH 3 ,
or, if m is 2, both R 6 groups together with the carbon atom, to which they are attached, may form a carbonyl group;
R 7 is selected from the group consisting of: H, CH 3 , —COOH and —COOCH 3 ; and
m is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 having one of the formula

wherein
R 1a is Cl, CF 3 , —O—(C 3-4 -alkyl), —O-cyclobutyl, —O—(C 1-2 -alkyl)-(C 3-4 -cycloalkyl) or —O—CH 2 -phenyl,
wherein each alkyl and cycloalkyl is optionally substituted with one to three F or one CF 3 ;

R 1b is H, Cl, Br or —OCH 3 ;
R 2 is selected from the group consisting of:

and
R 6 is H, F, —OH, or —OCH 3 ;
m is 0 or 1 or, if R 6 is F, m may also be 2;
R 7 is H or —CH 3 ;
or a pharmaceutically acceptable salt thereof.

9. A compound according to clai

Assignees

• Boehringer Ingelheim Int

Inventors

• Roth Gerald Juergen
• Fleck Martin
• Haebel Peter Wilhelm
• Heimann Annekatrin
• Heine Niklas

Classifications

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title