ARYL-SUBSTITUTED POLYCYCLIC AMINES, METHOD FOR THE PRODUCTION THEREOF, AND USE THEREOF AS A MEDICAMENT
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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;
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Citations
24 Claims
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1. A compound of formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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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.
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3. A compound as claimed in claim 2, in which Q is selected from:
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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;
whereR31, R32, R36, R37, R38, and R39 are, independently of one another, H or (C1-C8)-alkyl.
- C(R32), C≡
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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.
- F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—
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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.
- (C1-C6)-alkyl, O—
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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.
- F, OH, CF3, CN, OCF3, O—
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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.
- F, OH, CF3, CN, OCF3, oxo, O—
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10. A compound as claimed in claim 1 wherein W3 in formula II and W8 in formula III are each a bond.
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11. A compound as claimed in claim 9, in which Q is selected from the group consisting of:
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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.
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13. A medicament comprising one or more of the compounds of formula I as claimed in claim 1.
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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.
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15. A medicament comprising one or more of the compounds of formula I as claimed in claim 1 and one or more antidiabetics.
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16. A medicament comprising one or more of the compounds of formula I as claimed in claim 1 and one or more lipid modulators.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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2. A compound as claimed in claim 1,
Specification
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Current AssigneeSanofi-Aventis Deutschland GmbH (Sanofi )
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Original AssigneeSanofi-Aventis Deutschland GmbH (Sanofi )
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InventorsGOSSEL, Matthias, STENGELIN, Siegfried, HESSLER, Gerhard, SCHWINK, Lothar, LENNIG, Petra
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/249
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CPC Class CodesA61P 25/00 Drugs for disorders of the ...A61P 25/18 Antipsychotics, i.e. neurol...A61P 25/22 AnxiolyticsA61P 25/24 AntidepressantsA61P 3/00 Drugs for disorders of the ...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/06 AntihyperlipidemicsA61P 3/08 for glucose homeostasis pan...A61P 3/10 for hyperglycaemia, e.g. an...A61P 7/02 Antithrombotic agents; Anti...A61P 9/04 Inotropic agents, i.e. stim...A61P 9/10 for treating ischaemic or a...A61P 9/12 AntihypertensivesC07D 471/04 Ortho-condensed systemsC07D 471/08 Bridged systemsC07D 487/04 Ortho-condensed systems