Substituted N-aryl heterocycles, process for their preparation and their use as medicaments

• US 7,223,788 B2
• Filed: 02/17/2004
• Issued: 05/29/2007
• Est. Priority Date: 02/14/2003
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Schwink, Lothar, Hessler, Gerhard, Stengelin, Siegfried, Gossel, Matthias, Gretzke, Dirk, Stahl, Petra, Boehme, Thomas
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US10/779,853
• Publication Number:
  US 20040220191A1
• Time in Patent Office: 1,197 Days
• Field of Search: 548/557, 546/306, 546/279.1, 546/304, 514/326, 514/329, 514/429, 514/218, 514/318, 514/426
• US Class Current: 514/426
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/26 2-Pyrrolidones
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof.

Compounds of the formula I

in which the radicals have the stated meanings, the N-oxides and the physiologically tolerated salts thereof and process for the preparation thereof are described. The compounds are suitable for example as anorectic agents.

Claims

1. A compound of the formula I

2. The compound of claim 1 of formula 1:

3. The compound of claim 2 wherein

R1, R2 are each independently H, (C₁-C₈)-alkyl, —

(CH₂)_o—

R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, CO—

(C₁-C₈)-alkyl, —

CO—

(CH₂)_o—

R12, COCH═

CH(R13), COCC(R14), CO—

(C₁-C₄)-alkyl-S(O)_p—

(C₁-C₄)-alkyl, CO(C(R15)(R16))_qN(R17)(R18), CO(C(R19)(R20))_rCON(R21)(R22) or CO(C(R23)(R24))_sO(R25);

or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1 or 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃;

o 0, 1, 2, 3 or 4;

p 0, 1 or 2;

q, r, s are each independently 0, 1, 2 or 3;

R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally containing a further heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl;

R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33);

or

substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system which optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur and is optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—

(C₁-C₈)-alkyl;

R12 is OH or a 3-, 4-, 5-, 6, 7-, 8-, 9-, 10-, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, CF₃, CN, oxo, O—

(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—

(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═

CH(R36), (C(R37)(R38))_t(R39), CO(C(R37)(R38))_t(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40) or S(O)_u(R41);

t 0, 1, 2, 3 or 4;

u 0, 1 or 2;

R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl;

or

R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups;

R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl;

R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl;

R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing one or two heteroatoms selected from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—

(C₁-C₈)-alkyl;

R3 is H or (C₁-C₆)-alkyl;

R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—

(C₁-C₆)-alkyl or O—

CO(C₁-C₆)-alkyl;

R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl;

or

substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group;

n, m are each independently 0, 1 or 2;

A, B, D, G are each independently N or C(R42);

R42 is H, F, Cl, Br, CF₃, CN, O—

(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, (C₀-C₂)-alkylene-aryl, O—

(C₀-C₂)-alkylene-aryl, N(R43)(R44), SO₂—

CH₃, COO—

(C₁-C₆)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO₂(R50) or CO(R51);

R43, R44, R45, R46, R47, R49 are each independently H or (C₁-C₈)-alkyl;

or

substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl;

R10 is H or (C₁-C₈)-alkyl;

X is N(R52) or O;

R52 is H or (C₁-C₈)-alkyl;

E is a 3-, 4-, 5-, 6-, 7- or 8 membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3, or 4 heteroatoms from the group of N, O and S, and optionally substituted with H, F, Cl, CF₃, NO₂, OH, CN, O—

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

(C₀-C₈)-alkylene-aryl, N(R57)(R58), SO₂—

CH₃, COO—

(C₁-C₆)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65), and wherein said bivalent carbo-or heterocyclic ring is mono- or bicyclic;

R57, R58, R59, R60, R61, R63 are each independently H or (C₁-C₈)-alkyl;

or

substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl;

K is a bond, O, CH₂O, N(R66), (C(R69)(R70))_v or C≡

C;

v is 1 or 2;

R66, R67, R68, R69, R70 are each independently H or (C₁-C₈)-alkyl;

R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃;

R71, R72, R73, R74, R75, R76, R77 are each independently H or (C₁-C₈)-alkyl;

or

substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur.

4. The compound of claim 3, wherein

A, B, D, G are each independently N or C(R42), and the total number of nitrogen atoms in said ring is 0-2.

5. The compound of claim 4, wherein

n is 1 and

m is 1 or 2.

6. The compound of claim 1 wherein

R1, R2 are each independently H, (C₁-C₈)-alkyl, —

(CR78R79)_o-R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, CO—

(C₁-C₈)-alkyl, —

CO—

(CH₂)_o—

R12, CO-aryloxy-(C₁-C₄)-alkyl, COCH═

CH(R13), COCC(R14), CO(C(R15)(R16))_qN(R17)(R18), CO(C(R19)(R20))_rCON(R21)(R22), CO(C(R23)(R24))_sO(R25);

or R1 and R2, taken together with the nitrogen atom to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally comprises one or two additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—

(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃;

o is 0, 1, 2, 3, 4, 5 or 6;

q, r are independently of one another 1, 2 or 3;

s is 0, 1, 2, 3 or 4;

R13, R14 are each independently an aryl ring optionally comprising one nitrogen atom;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl;

R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33);

or

substituent pairs R17 and R18, R21 and R22, R27 and R28, R31 and R32,

independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains 1 further heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally comprising one additional heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—

(C₁-C₈)-alkyl;

R12 is OH, O—

(C₁-C₆)-alkyl, O—

(C₀-C₈)-alkylene-aryl, CN, S—

(C₁-C₆)-alkyl, COO(R80), CON(R81)(R82), or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, Br, OH, CF₃, CN, oxo, O—

(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, O—

(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═

CH(R36), (C(R37)(R38))_t(R39), CO(C(R37)(R38))_t(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40) or S(O)_u(R41);

t is 0, 1, 2, 3, 4, 5 or 6;

u is 0, 1 or 2;

R34, R35, R37, R38 are independently of one another H or (C₁-C₈)-alkyl;

or substituent pair R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups;

R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl or O—

(C₁-C₈)-alkyl;

R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl;

R41 is (C₁-C₆)-alkyl or a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl;

R78, R79 are independently of one another H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;

R80, R81 are independently of one another H or (C₁-C₈)-alkyl;

R3 is H or (C₁-C₆)-alkyl;

R4, R5 are independently of one another H, (C₁-C₆)-alkyl, OH, O—

(C₁-C₆)-alkyl, O—

CO(C₁-C₆)-alkyl or S—

(C₁-C₆)-alkyl;

R6, R7, R8, R9 is H;

or

substituent pairs R6 and R7, and R8 and R9, independently of one another, optionally form oxo;

n is 1;

m is 1 or 2;

A, B, D, G are independently of one another N or C(R42);

or

the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system;

R42 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(R43)(R44), SO₂—

CH₃, CON(R45)(R46), N(R47)CO(R48), CO(R51) or —

(CR84R85)_x—

O(R86);

R43, R44, R45, R46, R47 are independently of one another H, (C₁-C₈)-alkyl;

or

substituent pairs R43 and R44, and R45 and R46, independently of one another, taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl;

R84, R85 are H;

R86 is H or (C₁-C₆)-alkyl;

x is 0, 1 or 2;

R10 is H or (C₁-C₈)-alkyl;

X is N(R52) or a bond;

R52 is H or (C₁-C₈)-alkyl;

E is a 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—

(C₁-C₆)-alkyl, O—

(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—

(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—

(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—

(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—

CH₃, N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65) and wherein said carbo- or heterocyclic ring structure may be mono- or bicyclic;

R57, R58, R61, R63 are each independently H or (C₁-C₈)-alkyl;

R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl;

K is a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))_v, CO, C═

C, C≡

C, SCH₂ or SO₂CH₂;

v is 1, 2, 3 or 4;

R66, R67, R68, R69, R70 are independently of one another H or (C₁-C₈)-alkyl;

R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—

(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃;

R71, R72, R73, R74, R75, R76, R77 are independently of one another H or (C₁-C₈)-alkyl;

or

substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—

(C₁-C₆)-alkyl, oxygen and sulfur;

or

the N-oxides and the pharmaceutically acceptable salts thereof.

7. The compound of claim 6 having the formula Ia

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 further comprising one or more anorectic active ingredients.

10. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1.

11. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.

12. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1.

13. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.

14. A method of reducing weight in mammals comprising administering to a patient in need thereof a compound of claim 1.