ARYL-SUBSTITUTED POLYCYCLIC AMINES, METHOD FOR THE PRODUCTION THEREOF, AND USE THEREOF AS A MEDICAMENT

• US 20070299077A1
• Filed: 02/13/2007
• Published: 12/27/2007
• Est. Priority Date: 08/16/2004
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: GOSSEL, Matthias, STENGELIN, Siegfried, HESSLER, Gerhard, SCHWINK, Lothar, LENNIG, Petra
• Granted Patent: US 7,838,547 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The invention relates to aryl-substituted polycyclic amines of formula I, especially bicyclic amines, and to the physiologically tolerated salts and physiologically functional derivatives thereof; where the symbols and radicals are explained in the description, as well as to pharmaceutical compositions containing them and to methods of treatment using them.

Claims

1. A compound of formula I

2. A compound as claimed in claim 1,

in which

Q is selected from:

wherein

W1, W2, W3, W4, W5, W6, W7, W8, W9, W10, W11, W12, W13, and W14 are,

independently of one another, a bond, C═

C, a 1 to 4-membered alkylene or alkylidene chain in which 1 carbon atoms outside a double bond present in the alkylidene chain may be replaced by a member selected from the group consisting of N(R90), O and S;

where the carbon atoms in the groups of the formulae (II), (III) and (IV) may be substituted with a substituent selected from H, F, OH, oxo, (C₁-C₆)-alkyl, O—

(C₁-C₆)-alkyl, and (CR52R53)_oR54;

R87, R88, and R90 are selected from;

H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R51), (CR52R53)_o—

R54, and CO(CR52R53)_p—

R55;

R51 is H, or (C₁-C₈)-alkyl;

R52, and R53 are,

independently of one another, H, (C₁-C₈)-alkyl, OH, (C₃-C₈)-cycloalkyl, or (C₁-C₄)-alkoxy-(C₁-C₄)alkyl;

o, and p are, independently of one another, 0, 1, 2, 3, 4, 5, or 6;

R54, and R55 are,

independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R56)(R57), N(R58)CO(R59), N(R60)(R61), CO₂(R62), SO₂Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group of N, O and S, which may be substituted by one or more of the following substituents;

F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R63), oxo, and OH;

R56, R57, R58, R59, R62, and R63 are,

independently of one another, H, or (C₁-C₈)-alkyl;

or, alternatively,

R56 and R57, form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R60, and R61 are,

independently of one another, H, (C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R64), (CR65R66)_q—

R67, or CO(CR68R69)_r—

R70;

or, alternatively, R60 and R61 form, together with the nitrogen atom to which they are bonded, a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, comprises 0 to 3 additional heteroatoms selected from the group consisting of N, O and S and may additionally be substituted by one or more of the following substituents;

F, Cl, Br, CF₃, O—

(C₁-C₈)-alkyl, (C₁-C₆)-alkyl, CO(R71), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, CON(R72)(R73), N(R74)CO(R75), N(R76)(R77), CO₂(R78), and SO₂Me;

R64, R65, R66, R68, R69, R71, R72, R73, R74, R75, R76, R77, and R78 are,

independently of one another, H, or (C₁-C₈)-alkyl;

or, alternatively,

R76 and R77 form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatoms selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

q, and r are, independently of one another, 0, 1, 2, 3, 4, 5, or 6;

R67, and R70 are,

independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R79)(R80), N(R81)CO(R82), N(R83)(R84), CO₂(R85), SO₂Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group of N, O and S, which may be substituted by one or more of the following substituents;

F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R86), oxo, and OH;

R79, R80, R81, R82, R83, R84, R85, and R86 are,

independently of one another, H, or (C₁-C₈)-alkyl;

or, alternatively,

R79 and R80, R83 and R84

form, independently of one another, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

or an N-oxide thereof or a physiologically tolerated salts thereof.

3. A compound as claimed in claim 2, in which Q is selected from:

4. A compound as claimed in claim 1, wherein

A, B, D, and G are,

independently of one another, N or C(R3), and the total number of nitrogen atoms in this ring is 0-2.

5. A compound as claimed in claim 1, wherein

K is a bond, O, CO, OCH₂, CH₂O, N(R36)CO, CON(R37), (C(R38)(R39))₂, (R31)C═

C(R32), C≡

C, SCH₂, SO₂CH₂, particularly preferably OCH₂, CH₂O, N(R36)CO, CON(R37), (C(R38)(R39))₂, (R31)C═

C(R32), C≡

C, SCH₂, SO₂CH₂, very particularly preferably OCH₂, CH₂O, CON(R37), (C(R38)(R39))₂, C≡

C, or SCH₂;

where

R31, R32, R36, R37, R38, and R39

are, independently of one another, H or (C₁-C₈)-alkyl.

6. A compound as claimed in claim 1, wherein

R2 is (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may include 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted with one or more of the following substituents:

F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R41), CON(R42)(R43), hydroxy, N(R45)CO(C₁-C₆)-alkyl, N(R46)(R47) SO₂CH₃ (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or bicyclic ring which may include 0 to 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted with one or more of the following substituents;

F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl, oxo, CO(R41), CON(R42)(R43), N(R45)CO(C₁-C₆)-alkyl and SO₂CH₃;

R41, R42, R43, R45, R46, and R47 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R42 and R43, R46 and R47

form, independently of one another, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom-containing members selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur.

7. A compound as claimed in claim 1, wherein

A, B, D, and G are C(R3), wherein

R3 is H, F, Cl, Br, CF₃, CN, O—

(C₁-C₆)-alkyl, O—

(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—

(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl, O—

(C₀-C₈)-alkylene-aryl, N(R4)(R5), SO₂—

CH₃, CON(R6)(R7), N(R8)CO(R9), CO(R12), (CR13R14)_x—

O(R15);

R4, R5, R6, R7, and R8 are,

independently of one another, H, or (C₁-C₈)-alkyl;

or, alternatively,

R4 and R5, R6 and R7,

independently of one another, optionally together with the nitrogen atom to which they are bonded, form a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R9 and R12 are,

independently of one another, H or (C₁-C₈)-alkyl;

R13 and R14 are each H;

R15 is H or (C₁-C₆)-alkyl;

X is 0, 1 or 2.

8. A compound as claimed in claim 1 wherein

Q is a bi-, tri- or spirocyclic saturated or partially unsaturated ring structure having one nitrogen atom and 0-3 further heteroatoms selected from the group consisting of N, O and S, where the rings of the structure may be spiro-linked, fused or bridged, and where the ring system may be substituted with one or more of the following substituents:

F, OH, CF₃, CN, OCF₃, O—

(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R51), (CR52R53)_o—

R54, and CO(CR52R53)_p—

R55;

R51 is H or (C₀-C₈)-alkyl;

R52 and R53 are,

independently of one another, H, (C₁-C₈)-alkyl, OH, (C₃-C₈)-cycloalkyl, or (C₁-C₄)-alkoxy-(C₁-C₄)alkyl;

o and p are, independently of one another, 0, 1, 2, 3, 4, 5, 6;

R54 and R55 are,

independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R56)(R57), N(R58)CO(R59), N(R60)(R61), CO₂(R62), SO₂Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group of N, O and S, which may be substituted by one or more of the following substituents;

F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R63), OH;

R56, R57, R58, R59, R62, and R63 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R56 and R57

form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R60 and R61 are,

independently of one another, H, (C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R64), (CR65R66)_q—

R67, or CO(CR68R69)_r—

R70;

or, alternatively, R60 and R61 form, together with the nitrogen atom to which they are bonded, a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, comprises 0 to 3 additional heteroatoms selected from the group consisting of N, O and S and may additionally be substituted with one or more of the following substituents;

F, Cl, Br, CF₃, O—

(C₁-C₈)-alkyl, (C₁-C₆)-alkyl, CO(R71), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, CON(R72)(R73), N(R74)CO(R75), N(R76)(R77), CO₂(R78), and SO₂Me;

R64, R65, R66, R68, R69, R71, R72, R73, R74, R75, R76, R77, and R78 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R76 and R77 form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

q and r are, independently of one another, 0, 1, 2, 3, 4, 5 or 6;

R67 and R70 are,

independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R79)(R80), N(R81)CO(R82), N(R83)(R84), CO₂(R85), SO₂Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, which may be substituted with F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R86), oxo, or OH;

R79, R80, R81, R82, R83, R84, R85 and R86 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R79 and R80, R83 and R84 form, independently of one another, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur.

9. A compound as claimed in claim 1 wherein

Q is a bi-, tri- or spirocyclic saturated ring structure having one nitrogen atom and 0-3 further heteroatoms selected from the group consisting of N, O and S, where the rings of the structure may be spiro-linked, fused or bridged, and where the ring system may be substituted with one or more of the following substituents:

F, OH, CF₃, CN, OCF₃, oxo, O—

(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R51), (CR52R53)_o—

R54, and CO(CR52R53)_p—

R55;

R51 is H or (C₁-C₈)-alkyl;

R52 and R53 are,

independently of one another, H, (C₁-C₈)-alkyl, OH, (C₃-C₈)-cycloalkyl, or (C₁-C₄)-alkoxy-(C₁-C₄)alkyl;

o and p are, independently of one another, 0, 1, 2, 3, 4, 5, or 6;

R54 and R55 are,

independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R56)(R57), N(R58)CO(R59), N(R60)(R61), CO₂(R62), SO₂Me, CN, a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, which may be substituted with F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R63), oxo, or OH;

R56, R57, R58, R59, R62, and R63 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R56 and R57 form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R60 and R61 are,

independently of one another, H, (C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R64), (CR65R66)_q—

R67, or CO(CR68R69)_r—

R70;

or, alternatively, R60 and R61 form, together with the nitrogen atom to which they are bonded, a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, comprises 0 to 3 additional heteroatoms selected from the group consisting of N, O and S and may additionally be substituted with one or more of the following substituents;

F, Cl, Br, CF₃, O—

(C₁-C₈)-alkyl, (C₁-C₆)-alkyl, CO(R71), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, CON(R72)(R73), N(R74)CO(R75), N(R76)(R77), CO₂(R78), and SO₂Me;

R64, R65, R66, R68, R69, R71, R72, R73, R74, R75, R76, R77, and R78 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R76 and R77 form, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur;

q and r are, independently of one another, 0, 1, 2, 3, 4, 5 or 6;

R67 and R70 are, independently of one another, OH, O—

(C₁-C₈)-alkyl, CON(R79)(R80), N(R81)CO(R82), N(R83)(R84), CO₂(R85), SO₂Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, which may be substituted with one or more of the following substituents;

F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—

(C₁-C₈)-alkyl, CO(R86), oxo, and OH;

R79, R80, R81, R82, R83, R84, R85, and R86 are,

independently of one another, H or (C₁-C₈)-alkyl;

or, alternatively,

R79 and R80, R83 and R84 form, independently of one another, optionally together with the nitrogen atom to which they are bonded, a 5-6 membered ring which, apart from the nitrogen atom, may also include 1 further heteroatom selected from the group consisting of NH, N—

(C₁-C₆)-alkyl, oxygen and sulfur.

10. A compound as claimed in claim 1 wherein W3 in formula II and W8 in formula III are each a bond.

11. A compound as claimed in claim 9, in which Q is selected from the group consisting of:

12. A compound as claimed in claim 1, wherein X is a bond or N(R16), in which R16 is H or (C₁-C₈)-alkyl.

13. A medicament comprising one or more of the compounds of formula I as claimed in claim 1.

14. A medicament comprising one or more of the compounds of formula I as claimed in claim 1 and one or more active ingredients which have beneficial effects on metabolic disturbances or disorders associated therewith.

15. A medicament comprising one or more of the compounds of formula I as claimed in claim 1 and one or more antidiabetics.

16. A medicament comprising one or more of the compounds of formula I as claimed in claim 1 and one or more lipid modulators.

17. A method for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

18. A method the treatment and/or prevention of disorders in which insulin resistance is involved which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

19. A method. for the treatment and/or prevention of diabetes mellitus and the sequelae associated therewith which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

20. A method for the treatment and/or prevention of dyslipidemias and the sequelae thereof which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

21. A method for the treatment and/or prevention of conditions associated with the metabolic syndrome which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

22. A method for the treatment and/or prevention of obesity and sequelae associated therewith which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1.

23. A method for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1 in combination with at least one further active ingredient.

24. A method for the treatment and/or prevention of disorders in which insulin resistance is involved which comprises administering to a patient in need thereof an effective amount of a medicament comprising one or more of the compounds of formula I as claimed in claim 1 in combination with at least one further active ingredient.