EP1597228A2 - Substituierte n-arylheterozyklen, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel - Google Patents

Substituierte n-arylheterozyklen, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel

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Publication number
EP1597228A2
EP1597228A2 EP04710808A EP04710808A EP1597228A2 EP 1597228 A2 EP1597228 A2 EP 1597228A2 EP 04710808 A EP04710808 A EP 04710808A EP 04710808 A EP04710808 A EP 04710808A EP 1597228 A2 EP1597228 A2 EP 1597228A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently
another
group
apd62429pc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04710808A
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German (de)
English (en)
French (fr)
Inventor
Lothar Schwink
Siegfried Stengelin
Matthias Gossel
Thomas Böhme
Gerhard Hessler
Petra Stahl
Dirk Gretzke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Application filed by Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of EP1597228A2 publication Critical patent/EP1597228A2/de
Withdrawn legal-status Critical Current

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the invention relates to substituted N-Arylheterozyklen and their physiologically acceptable salts and physiologically functional derivatives.
  • the invention therefore relates to compounds of the formula I,
  • R 1, R 2 independently of one another are H, (C 1 -C 4 -alkyl, - (C R78 R 79) O -R 12, (CC 4 ) -
  • CO- (-C 8) -alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (CrC 4) alkyl, CO- (C 2 -C 8) - alkenyl, CO- (C 2 -C 8 ) alkynyl, COCH CH (R 13), COCC (R 14), CO- (CC 4 ) -alkyl-S (O) p - (CC 4 ) -alkyl, CO (C (R 15) (R 16)) q N (R17) (R18), CO (C (R19) (R20)) r CON (R21) (R22), CO (C (R23) (R24)) s O (R25); or R1 and R2 together with the nitrogen atom to which they are attached form a 4 to 10 membered mono-, bi- or spiro-cyclic ring which may contain, in addition to the nitrogen atom, 0 to 4 additional heteroatoms selected from the group consisting
  • q, r, s are independently 0, 1, 2, 3, 4;
  • R 13, R 14 independently of one another have a 5-10 membered aromatic ring system containing 0-2 further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , NO 2 , CN, (CC 6 ) -alkyl , O- (CC 8 ) -alkyl may be substituted;
  • R 15, R 16, R 17, R 19, R 20, R 21, R 22, R 23, R 24, R 25, R 26, R 27, R 28, R 29, R 30, R 31, R 32 independently of one another are H, (C 1 -C 6 ) -alkyl;
  • R18 H (d-CeJ-alkyl, CO (CC 6) -alkyl, CO (R33); or APD62429PC
  • R1 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (dC 6 ) - may include alkyl, oxygen and sulfur;
  • R33 is a 5-10 membered aromatic ring system containing 0-2 others
  • heteroatoms from the group nitrogen, oxygen and sulfur may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (-CC 6 ) alkyl, O- (CrC 8 ) alkyl;
  • R 12 is OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, S- (C 1 -C 6 ) -alkyl,
  • R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or APD62429PC
  • R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom 0-1 further heteroatoms from the group N include (dC 6) -alkyl, oxygen and sulfur and optionally may be substituted with 1 -2 oxo groups;
  • R36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system containing 0-2 further heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3, NO 2 , CN, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl may be substituted;
  • R 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
  • heteroatoms from the group nitrogen, oxygen and sulfur may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (dC 6 ) alkyl, O- (dC 8 ) alkyl;
  • R78, R79 independently of one another are H, (CC 8 ) -alkyl, hydroxy (C 1 -C 4 ) -alkyl, OH, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl;
  • R93 independently of one another are H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 1 -C 8 ) -alkylene
  • R82, R83 independently of one another are H, (C 1 -C 6 ) -alkyl; or R82 and
  • R83 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring which, in addition to the nitrogen atom, is still 0-1 APD62429PC
  • heteroatoms from the group N- (C 1 -C 6 ) -alkyl, oxygen and sulfur include and may optionally be substituted by 1-2 oxo groups;
  • R 3 is H, (C 1 -C 6 ) -alkyl
  • R4, R5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (D-)
  • R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl, or R6 and R7, R8 and R9 independently of one another are optionally oxo;
  • n, m are independently 0, 1, 2;
  • A, B, D, G are independently N, C (R42); or the groups A and B or the groups D and G are each C (R42) and together form a 5- or 6-membered carbocyclic or heterocyclic radical to give a total of a bicyclic system;
  • R 42 is H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (CC 6 ) -alkyl, O- (CC 4 ) -
  • R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (dC 6 ) -alkyl, May include oxygen and sulfur;
  • R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
  • R84, R85 independently of one another are H, (CC 8 ) -alkyl
  • R 86 is H, (C 1 -C 6 ) -alkyl, aryl;
  • R 10 is H, (CC 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
  • R52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl APD62429PC
  • R87, R88 independently of one another are H, (C 1 -C 4 ) -alkyl, where R 87 and R 88 in the y groups can each have the same or different meanings;
  • R89 is H, (C C ⁇ ) -alkyl
  • Heteroatoms from the group N, O and S which optionally have substituents from the group H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O- (CC 6 ) -alkyl, O- (dC 4) alkoxy- (C ⁇ -C4) alkyl, S- (dC 6) alkyl, (CC 6) alkyl, (C 2 - C 6) alkenyl, (C 3 -C 8 ) -Cycloalkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, O- (C 3 -C 8 ) -cycloalkenyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ), -alkylene-ary
  • R 57, R 58, R 59, R 60, R 61, R 63 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R 57 and R 58, R 59 and R 60 independently of one another, optionally together with the nitrogen atom to which they are bonded, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur;
  • R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; APD62429PC
  • K is a bond, O, OCH 2 , CH 2 O, S, SO, SO 2> N (R66), N (R67) CO,
  • R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl
  • Z is O, S, N (R92), CO, SO, SO 2;
  • R90, R91 independently of one another are H, (C 1 -C 8 ) -alkyl, hydroxy- (C 1 -C 4 ) -alkyl, hydroxy, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, where R 90 and R 91 in the z Groups may each have the same or different meanings;
  • R 92 is H, (C 1 -C 8 ) -alkyl
  • R11 H (CC 8) -alkyl, (dC 4) alkoxy- (C ⁇ -C4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
  • Alkynyl a 3 to 10-membered mono-, bi-, tri- or spiro-cyclic ring, which may include 0 to 4 heteroatoms selected from the group oxygen, nitrogen and sulfur, which ring system may additionally be substituted with F, Cl, Br, CF 3, NO 2, CN, (CC 6) -alkyl, O- (dC 8) - alkyl, (C ⁇ -C4) alkoxy (CrC 4) alkyl, (C 0 -C 8) -alkylene-aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, hydroxy- (CC 4) -alkyl, COO (R74), N (R75) CO (dC 6) -alkyl, N ( R76) (R77) or SO 2 CH 3, SCF 3;
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur; or
  • E, K and R11 together form a tricycle, wherein the rings independently of one another saturated, partially saturated or unsaturated and may each contain 3-8 ring atoms;
  • the invention therefore relates to compounds of the formula I
  • R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CH 2 ) 0 -R 12, (CC 4 ) -alkoxy
  • (dC 4) alkyl, (4 dC) alkyl aryloxy, (C 3 -C 8) -alkenyl, (C 3 -C 8) -alkynyl, CO- (dC 8) -alkyl, -CO- (CH 2 ) 0 -R12, CO-aryloxy- (C 1 -C 4 ) -alkyl, CO- (C 2 -C 8 ) -alkenyl, CO- (C 2 -C 8 ) -alkynyl, COCH CH (R 13), COCC ( R14), CO- (dC 4) - alkyl-S (O) p- (CrC 4) alkyl, CO (C (R15) (R16)) q N (R17) (R18), CO (C (R19) (R20)) r CON (R21) (R22), CO (C (R23) (R24)) s O (R25); or R1 and R2
  • heterocyclic ring system may additionally be substituted with F, Cl , Br, CF 3, NO 2, CN, (dC 6) -alkyl, O- (CC 8) -alkyl, (dC 4) alkoxy- (dC 4) alkyl, (C 0 -C 8) -alkylene-aryl, oxo, CO (R26), CON (R27) (R28), hydroxy, COO (R29), N (R30) CO (dC 6) -alkyl, N (R31) (R32) or SO 2 CH 3 ;
  • q, r, s are independently 0, 1, 2, 3, 4;
  • R 13, R 14 independently of one another have a 5-10 membered aromatic ring system containing 0-2 further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , NO 2 , CN, (CC 6 ) -alkyl , O- (C 1 -C 8 ) alkyl may be substituted;
  • R 15, R 16, R 17, R 19, R 20, R 21, R 22, R 23, R 24, R 25, R 26, R 27, R 28, R 29, R 30, R 31, R 32 independently of one another are H, (C 1 -C 6 ) -alkyl;
  • R 18 is H, (C 1 -C 6 ) alkyl, CO (CC 6 ) alkyl, CO (R 33);
  • R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N - (dC-6) - may include alkyl, oxygen and sulfur; APD62429PC
  • R33 is a 5-10 membered aromatic ring system containing 0-2 others
  • heteroatoms from the group nitrogen, oxygen and sulfur may be substituted by F, Cl, Br, CF 3 , NO 2 ( CN, (dC 6 ) alkyl, 0- (CC 8 ) alkyl;
  • R12 OH, 3-12 membered mono-, bi- or spiro-cyclic ring which may contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, J, OH , CF 3 , NO 2 , CN, OCF 3 , oxo, O- (C 1 -C 6 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, S- (C 1 -C 6 ) -alkyl, (dC 6) -alkyl, (C 2 -C 6) alkenyl, (C 3 -C 8) -cycloalkyl, O- (C 3 -C 8) - cycloalkyl, (C 3 -C 8) -cycloalkenyl, O- ( C 3 -C 8 ) -cycloalkenyl, (C 2
  • R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom 0-1 further heteroatoms from the group N include (dC 6) -alkyl, oxygen and sulfur and optionally may be substituted with 1-2 oxo groups;
  • R36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system containing 0-2 further heteroatoms from the group nitrogen, APD62429PC
  • R40 H (CC 8) -alkyl, (C 2 -C 6) alkenyl, (C 0 -C 8) -alkylene-aryl;
  • R 3 is H, (CC 6 ) -alkyl
  • R 4, R 5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, -O-CO (d-)
  • R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R6 and R7, R8 and R9 independently of one another optionally oxo
  • n, m are independently 0, 1, 2;
  • A, B, D, G are independently N, C (R42);
  • R 42 is H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (CC 6 ) -alkyl, O- (CC 4 ) -
  • R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl;
  • R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (dC 6 ) -alkyl, May include oxygen and sulfur;
  • R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
  • R 10 is H, (C 1 -C 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
  • R52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
  • Heteroatoms from the group consisting of N, O and S which optionally have substituents from the group consisting of H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, O-, (dC 4) alkoxy- (dC 4) alkyl, S- (dC 6) alkyl, (dC 6) alkyl, (C 2 -C 6) alkenyl, (C 3 -C 8) -cycloalkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, O- (C 3 -C 8 ) -cycloalkenyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -Alkylene-aryl, O- (C 0 -C 8 ) -
  • R 57 and R 58, R 59 and R 60 independently of one another, optionally together with the nitrogen atom to which they are bonded, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur;
  • R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
  • K is a bond, O, OCH 2 , CH 2 O, S, SO, SO 2, N (R66), N (R67) CO,
  • R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R11 H (CC 8) alkyl, (C ⁇ -C4) alkoxy (dC 4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
  • Alkynyl a 3 to 10-membered mono-, bi- or spiro-cyclic ring, which may include 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system may additionally be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, (C 0 -C 8 ) alkylene-aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (dC 6) -alkyl, N (R76) (R77) or SO 2 CH 3 ;
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (CC 8 ) -alkyl; APD62429PC
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur; or
  • E, K and R11 together form a tricycle, wherein the rings independently of one another saturated, partially saturated or unsaturated and may each contain 3-8 ring atoms;
  • the invention relates to compounds of the formula I, in the form of their racemates, enantiomerically enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • aryl is understood to mean in particular a phenyl or naphthyl group.
  • tricycle is meant three-membered structures joined by more than one bond, examples of which are fused-ring condensed systems and fused-ring spirocycles.
  • this ring may be substituted with one or more of the said substituents.
  • the bivalent carbo- or heterocyclic ring structure E also includes structures which are linked via one and the same atom to the two adjacent groups K and X.
  • Suitable pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and also organic acids, e.g.
  • the chloro salt is used in a particularly preferred manner.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in nontherapeutic, for example, in vitro applications.
  • physiologically functional derivative refers to any physiologically acceptable derivative of a compound of Formula I of the invention, for example, an ester which, when administered to a mammal, such as the human, in the APD62429PC
  • the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
  • prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
  • the compounds of the invention may also be present in different polymorphic forms, for. B. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
  • radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the meanings indicated and be identical or different.
  • the present invention relates to compounds of the formula I,
  • R 1, R 2 independently of one another are H, (C 1 -C 8 ) -alkyl, - (C 2 ) 0 -R 12, (CC 4 ) -alkoxy
  • q, r, s are independently 0, 1, 2, 3, preferably q, s are independently 1, 2, 3 and r is 0, 1, 2, 3;
  • R 13, R 14 are each independently a 5-10 membered aromatic ring system containing another heteroatom from the group consisting of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (dC 6 ) alkyl, O- (dC 8 ) alkyl ;
  • R29, R30, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl
  • Nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) - alkyl, oxygen and sulfur;
  • R33 is a 5-10 membered aromatic ring system containing another heteroatom selected from nitrogen, oxygen and sulfur and may be substituted with F, Cl, (dC 6 ) alkyl, O- (CC 8 ) alkyl;
  • R34, R35, R37, R38 independently of one another are H, (CC 8 ) -alkyl
  • R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom 0-1 further heteroatoms from the group N include (dC 6) -alkyl, oxygen and sulfur and optionally may be substituted with 1 -2 oxo groups;
  • R36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system containing a further heteroatom from the group nitrogen, APD62429PC
  • R 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
  • heteroatoms from the group nitrogen, oxygen and sulfur may be substituted by F, Cl, (CC 6 ) alkyl, O- (dC 8 ) alkyl;
  • R 3 is H, (C 1 -C 6 ) -alkyl
  • R4, R5 independently of one another are H, (CC 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (C
  • R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R6 and R7, R8 and R9 independently of one another optionally oxo
  • n, m are independently 0, 1, 2, preferably m is 0, 1, 2 and n is 1;
  • A, B, D, G are independently N, C (R42);
  • R 42 is H, F, Cl, Br, CF 3 , CN, O- (C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl,
  • R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
  • R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (dC 6 ) -alkyl , May contain oxygen and sulfur;
  • R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
  • R 10 is H, (CC 8 ) -alkyl
  • R52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R 57 and R 58, R 59 and R 60 independently of one another, optionally together with the nitrogen atom to which they are bonded, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur, wherein R59 and R60 are preferably not H at the same time;
  • R62, R64, R65 independently of one another are H, (CC 8 ) -alkyl, aryl;
  • K is a bond, O, CH 2 O, N (R66), (C (R69) (R70)) V , C ⁇ C, OCH 2 , CON (R68), preferably a bond, O, CH 2 O, (( CR69) (R70)) V , C ⁇ C, N (R66);
  • R66, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R 11 is H, (C 1 -C 8 ) -alkyl, (CC 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, (C 3 -C 8 ) -alkenyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may contain 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, which ring system may additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 ) -alkyl, O-, (CC 8 ) -alkyl, (CC 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (dC 6) -alkyl,
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur.
  • A, B, D, G independently of one another denote N or C (R42) and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1.
  • n 1 and m is 1 or 2.
  • A, B, D, G independently of one another denote N or C (R42) and the total number of nitrogen atoms in this ring 0-2 is preferably 0 or 1;
  • n 1 or 2.
  • the present invention relates to compounds of the formula I,
  • R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR 78 R 79) 0 -R 12, (dC 4 ) -
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4 to 10-membered mono- or bicyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may additionally be substituted by F, Cl, CF 3, (dC 6) -alkyl, O- (dC 4) -alkyl, (dC 4) alkoxy- (dC 4) alkyl, (C 0 - C 2 ) - alkylene-aryl, oxo, CO (R 26), hydroxy, N (R 31) (R 32) or SO 2 CH 3 ; particularly preferably independently of one another H, (-CC 8 ) -alkyl, - (CR78R79) 0 -R12
  • heterocyclic ring system may additionally be substituted by F, (C 1 -C 6 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, oxo, CO (R 26) , Hydroxy, N (R31) (R32);
  • q, r are independently 1, 2, 3; preferably q is 1 or 2;
  • s 0, 1, 2, 3, 4 preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
  • R 13, R 14 are each independently a phenyl ring which may contain 0-1 nitrogen atoms;
  • R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl;
  • R18 H, (dC 6) -alkyl, CO (dC 6) -alkyl, CO (R33); preferably H, (C 1 -C 12 -alkyl,
  • CO (dC 6 ) alkyl particularly preferably H, (C 1 -C 6 ) -alkyl; or
  • R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C 1 -C 6 ) - may include alkyl, oxygen and sulfur; preferably, the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine;
  • R33 is a 5-10 membered aromatic ring system which may contain another heteroatom selected from nitrogen, oxygen and sulfur and may be substituted with F, Cl, (dC 6 ) alkyl, O- (CC 8 ) alkyl; APD62429PC
  • R 12 is OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, S- (CC 6 ) -alkyl,
  • COO (R80), CON (R81) (R82), 3-12 membered mono-, bi- or spiro-cyclic ring which may contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, OH, CF 3, CN, oxo, O- (CC 6) alkyl, (dC 4) - alkoxy (dC 4) alkyl, (dC 6) alkyl- O- (C C 1 -C 8 ) -alkylene-aryl, (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35), COCH CH (R 36), (C (R 37) (R 38)) t (R 39) , CO (C (R37) (R38)) t (R39) (R41) may contain CO (CC 6) -alkyl, COCOO (dC 6) -alkyl, COO (R40
  • R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R34 and R35 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring which, in addition to the nitrogen atom, is still 0-1 APD62429PC
  • heteroatoms from the group consisting of N- (C 1 -C 6 ) -alkyl, oxygen and sulfur and may optionally be substituted with 1 -2 oxo groups;
  • R36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system that can contain 0-2 further heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, (CC 6) alkyl, O- (dC 8 ) -alkyl may be substituted;
  • R 40 is H, (CC 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
  • heteroatoms from the group nitrogen, oxygen and sulfur may be substituted by F, Cl, (CC 6 ) alkyl, O- (dC 8 ) alkyl;
  • R78, R79 are independently H, (CC 8 ) alkyl, hydroxy (C 1 -C 4 ) alkyl, OH, (CC 4 ) alkoxy (C 1 -C 4 ) alkyl;
  • R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R 3 is H, (CC 6 ) -alkyl; preferably H;
  • R 4, R 5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (D-)
  • C 6 ) alkyl, S (dC 6 ) alkyl preferably independently of one another are H, (CC 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (C 1 -C 6 ) -alkyl; particularly preferably independently of one another H, OH, O- (C 1 -C 6 ) -alkyl;
  • R6, R7, R8, R9 are H; n 1
  • n 1 or 2; preferably 1;
  • A, B, D, G are independently N, C (R42); or the groups A and B or D and G are each C (R42) and together form an ortho-phenylene unit to give a total of a 1,4-bis-substituted naphthalene system; are preferred
  • R 42 is H, F, Cl, Br, CF 3 , CN, O- (C 1 -C 6 ) -alkyl, O- (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, S--
  • R43, R44, R45, R46, R47 independently of one another are H, (C 1 -C 8 ) -alkyl; or R43 and R44, R45 and R46, independently of one another, optionally together with the nitrogen atom to which they are attached, form a 5-6 membered ring which except the
  • R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; preferably independently of one another H, (C 1 -C 8 ) -alkyl; R84, R85 H;
  • x 0, 1, 2; preferably 0, 1; more preferably 1;
  • R 10 is H, (C 1 -C 8 ) -alkyl
  • R89 is H, (C1-C8) -alkyl
  • R52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
  • Heteroatoms from the group N, O and S optionally substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (dC 6 ) alkyl, O- (d - C 4) alkoxy (dC 4) alkyl, S- (dC 6) alkyl, (CC 6) alkyl, (C 2 -C 6) -alkenyl, O- (C 3 -C 8) - Cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl, S- aryl, N (R57) (R58), SO 2 -CH 3, N (R61) CO (R62), N (R63) SO 2 (R64), CO (R
  • CO (R65) may carry e.g. E is selected from the group consisting of
  • R57, R58, R61, R63 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; preferably independently of one another H, (C 1 -C 8 ) -alkyl;
  • K is a bond, O, OCH 2 , CH 2 O, S, SO, SO 2 , N (R66), N (R67) CO,
  • CON (R68), (C (R69) (R70)) v, CO, C C, C ⁇ C, SCH 2, SO 2 CH 2; preferably a bond, O, OCH 2, CH 2 O, N (R66), CON (R68), (C (R69) (R70)) v, CO, CsC, SCH 2; particularly preferably a bond, O, OCH 2 , CH 2 O, CON (R68), (C (R69) (R70)) V , CO, C ⁇ C;
  • v 1, 2, 3, 4 preferably 1, 2, 3; more preferably 1, 2;
  • R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl
  • Alkynyl a 3 to 10-membered mono-, bi-, tri- or spiro-cyclic ring, which may include 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system additionally APD62429PC
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (C C6) -alkyl, May include oxygen and sulfur; or
  • A, B, G and D in formula I mean CH or: APD62429PC
  • E 1,4-phenylene
  • A, B, G and D furthermore preferably have the meanings given in Table I below:
  • E A, B, G and D furthermore preferably have the meanings listed in Table III below: APD62429PC
  • Table IV lists further preferred combinations for E and A, B, G and D.
  • radicals R11, K, X and E in formula I have, in a particularly preferred embodiment, one of the following meanings:
  • R 11 is preferably selected from the group consisting of: n-propyl, n-butyl, isobutyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex- (1) -enyl, phenyl, p-fluorophenyl, p- Chlorophenyl, p-bromophenyl, p-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-methylthiophenyl, o-fluorophenyl, o-chlorophenyl, o-cyanophenyl, m-fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4- methylphenyl, 2-nitro-4-methylphenyl, 2-amino-4-methylphenyl,
  • K is preferably selected from the group consisting of:
  • X is preferably selected from the group consisting of bond, NH and CH 2 .
  • E is preferably selected from the group consisting of: APD62429PC
  • E and R11 particularly preferably have the following meanings:
  • R11 is selected from the group consisting of: cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl , 3-fluoro-4-methylphenyl, o-cyanophenyl,
  • E R11 is selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl, o-fluorophenyl, phenyl and APD62429PC
  • R11 is selected from the group consisting of phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyl and p-fluorophenyl.
  • E and R11 more preferably have the following meanings:
  • E R11 is selected from the group consisting of: phenyl, p-fluorophenyl and p-chlorophenyl.
  • E and R 11 particularly preferably have the following meanings given in Table VII:
  • E and R 11 particularly preferably have the following meanings:
  • R11 is selected from the group consisting of: phenyl, cyclopropyl and cyclohexyl.
  • E and R11 particularly preferably have the following meanings given in Table VIII:
  • E and R 11 particularly preferably have the following meanings given in Table IX:
  • the compounds of the formula I are compounds of the formula Ia
  • R1, R2, R10, R11, R42 and groups X, E, K have the meanings given above and R42 'is defined as R42, where R42 and R42' in the compounds of the formula Ia may be identical or different, or their N-oxides and their physiologically acceptable salts.
  • APD62429PC in which the radicals R1, R2, R10, R11, R42 and groups X, E, K have the meanings given above and R42 'is defined as R42, where R42 and R42' in the compounds of the formula Ia may be identical or different, or their N-oxides and their physiologically acceptable salts.
  • radicals R1, R2, R10, R11, R42, R42 'and groups X, E, K have the following meanings:
  • R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR 78 R 79) 0 -R 12, (C 1 -C 4) -
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4 to 10-membered mono- or bicyclic ring which may contain, in addition to the nitrogen atom, 0 to 2 additional heteroatoms selected from the group consisting of oxygen and nitrogen, where the heterocyclic ring system may additionally be substituted by F, (C 1 -C 6 ) -alkyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, oxo, CO (R 26), hydroxy, N (R31) (R 32);
  • R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl; or
  • R 17 and R 18, R 27 and R 28, R 31 and R 32 independently of one another, optionally together with the nitrogen atom to which they are attached, form a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group consisting of C 6 ) - may include alkyl, oxygen and sulfur, preferably the ring is a pyrrolidine, piperidine, N-methylpiperazine, morpholine ring;
  • R 12 is OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 2 ) -alkylene-aryl, CN, S- (CC 6 ) -alkyl, 3-12 membered mono-, bi- or spirocyclic ring, which may contain 1 to 3 heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, OH, CF 3 , CN, oxo, (C 1 -C 6 ) -alkyl, (C 0 -C 2 ) - Alkylen-aryl, N (R34) (R35), COO (R40), CO (CC 6 ) alkyl may contain, preferably OH, O- (dC 6 ) alkyl, 3-10 membered mono- or bicyclic ring, 1-2 heteroatoms from the group N, O and S and may contain the 3-10 membered ring further substituents such as F
  • R34, R35 independently of one another are H, (C 1 -C 4 ) -alkyl
  • R 40 is H, (CC 6 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl;
  • R78, R79 are each independently H, (CC 8 ) alkyl, hydroxy (C 1 -C 4 ) alkyl, OH, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl;
  • R 42, R 42 'independently of one another are H, F, Cl, Br, CF 3 , CN, (CC 6 ) -alkyl; APD62429PC
  • R 10 is H, (CC 8 ) -alkyl
  • R52, R53, R54 independently of one another are H, (C 1 -C 8 ) -alkyl
  • Heteroatoms from the group N, O and S which optionally have substituents from the group H, F, Cl, Br, CF 3 , OH, CN, OCF 3 , NO 2 , O- (C 1 -C 6 ) -alkyl, (CC 6 ) Alkyl, SO 2 -CH 3 , CO (R 65);
  • E may be O, (CC 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, N (R 57) (R 58), SO 2 -CH 3 , CO (R 65) selected from the group consisting of
  • R65 is H, (C 1 -C 8 ) -alkyl
  • K is a bond, O, OCH 2 , CH 2 O, S, SO 2, N (R66), N (R67) CO, CON (R68),
  • R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R 11 (CC 8 ) -alkyl, (C 1 -C 4 ) -alkoxy (C 1 -C 4 ) -alkyl, a 3 to 10-membered mono-, bi-, tri- or spiro-cyclic ring which contain 0 to 4 heteroatoms may be selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may additionally be substituted with F, Cl, Br, CF 3 , CN, (CC 6 ) alkyl, O- (dC 8 ) alkyl, oxo, CO (R71), hydroxy, N (R75) CO (C ⁇ - C6) alkyl, or SO 2 CH 3; preferably (C 1 -C 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, a 3 to 10-membered mono- or bicyclic ring which may contain 0 to 2 heteroatoms selected from the group consisting of oxygen,
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8) -alkyl; or
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which except the APD62429PC
  • Nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) - alkyl, oxygen and sulfur.
  • the present invention relates to compounds of the formula Ia,
  • K is a bond, O or C (R69) (R70);
  • the present invention relates to compounds of the formula Ia
  • X is N (R52), preferably NH, or C (R53) (R54);
  • K is a bond, O or C (R69) (R70), preferably 0; preferably O
  • R1, R2, R10, R11, R42, R42 ', R52, R53, R54, R69 and R70 have the meanings given above with regard to the definition of the radicals of the compound of the formula Ia.
  • the compounds of the formula I are compounds of the formula Ib
  • radicals R1, R2, R10 and R11 and the groups E and D have the abovementioned meanings or their N-oxides and their physiologically acceptable salts.
  • radicals R1, R2, R10 and R11 have the following meanings:
  • R 1, R 2 independently of one another are H, (C 1 -C 8 ) -alkyl, - (C-R 8 R 79) 0 -R 12, (C 1 -C 4 ) -
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4 to 10 membered mono- or bicyclic ring which, in addition to the nitrogen atom, may contain from 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur the heterocyclic ring system may additionally be substituted by F, Cl, CF 3, (dC 6) -alkyl, O- (CC 4) -alkyl, (dC 4) -alkyl alkoxy (dC 4), (C 0 -C 2 ) - APD62429PC
  • R1 and R2 CO- (-C 8) -alkyl are not simultaneously; particularly preferably independently of one another are H, (C 1 -C 8 ) -alkyl, - (C-R 7 R 7) 0 -R 12, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, CO- (CC 8 ) -alkyl, -CO- (CH 2 ) 0 -R12, CO (C (R15) (R16)) q N (R17) (R18), or R1 and R2 form together with the nitrogen atom to which they are attached form a 4 to 10-membered mono- or bicyclic ring which may contain, in addition to the nitrogen atom, 0 to 2 additional heteroatoms selected from the group consisting of oxygen and nitrogen, where the heterocyclic ring system may additionally be substituted by F
  • q, r are independently 1, 2, 3; preferably q is 1 or 2;
  • s 0, 1, 2, 3, 4 preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
  • R 13, R 14 are each independently a phenyl ring which may contain 0-1 nitrogen atoms;
  • R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl;
  • R18 is H, (-CC 6 ) -alkyl, CO (CC 6 ) -alkyl, CO (R33); preferably H, (C 1 -C 6 ) -alkyl,
  • CO (dC 6 ) alkyl particularly preferably H, (C 1 -C 6 ) -alkyl; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 APD62429PC
  • a 5-6 membered ring which may contain, in addition to the nitrogen atom, 0-1 further heteroatoms from the group consisting of N- (C 6 -C 6) -alkyl, oxygen and sulfur; preferably, the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine;
  • R33 is a 5-10 membered aromatic ring system which may contain another heteroatom selected from nitrogen, oxygen and sulfur and may be substituted with F, Cl, (dC 6 ) alkyl, O- (dC 8 ) alkyl;
  • R 12 is OH, O- (CC 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, S- (CC 6 ) -alkyl,
  • R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R34 and R35 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group consisting of N- (CC 6 ) -alkyl, oxygen and
  • R36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system that can contain 0-2 further heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, (dC 6) alkyl, O- (CC 8 ) -alkyl may be substituted;
  • R 40 is H, (CC 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
  • R78, R79 independently of one another are H, (CC 8 ) -alkyl, hydroxy- (C 1 -C 4 ) -alkyl, OH, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl;
  • R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R 10 is H, (CC 8 ) -alkyl; APD62429PC
  • R57, R58, R61, R63 independently of one another are H, (C 1 -C 8 ) -alkyl
  • R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; preferably independently of one another H, (C 1 -C 8 ) -alkyl;
  • K is a bond, O, OCH 2 , CH 2 O, S, SO, SO 2 , N (R66), N (R67) CO,
  • CON (R68), (C (R69) (R70)) v, CO, C C, C ⁇ C, SCH 2, SO 2 CH 2; preferably a bond, O, OCH 2 , CH 2 O, N (R66), CON (R68), (C (R69) (R70)) V , CO, C ⁇ C, SCH 2 ; particularly preferably a bond, O, OCH 2 , CH 2 O, CON (R68), (C (R69) (R70)) V , CO, CsC;
  • v 1, 2, 3, 4 preferably 1, 2, 3; more preferably 1, 2;
  • R66, R67, R68, R69, R70 are independently H, (CC 8) alkyl
  • R11 H (C ⁇ -C8) alkyl, (dC 4) alkoxy- (CC 4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
  • Alkynyl a 3 to 10 membered mono-, bi-; tri- or spiro-cyclic ring which may contain 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, which ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C 1 -C 6 ) -alkyl, O- (C ⁇ -C8) alkyl, (C ⁇ -C4) alkoxy- (C ⁇ -C4) alkyl, hydroxy (C ⁇ -C 4) alkyl, (C 0 -C 8) -alkylene- aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (dC 6) - alkyl, N (R76) (R77) or SO 2 CH 3 SCF 3 ; preferably (CC 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -
  • ring system may additionally be substituted with F, Cl, Br, CF 3 , CN, (-CC 6 ) alkyl, O- (dC 8 ) alkyl, (C 0 -C 2 ) alkylene-aryl , oxo, CO (R71), CON (R72) (R73), hydroxy, N (R75) CO (CC 6) -alkyl, N (R76) (R77) or SO 2 CH 3; particularly preferably (C 1 -C 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, a 3 to 10-membered mono- or bicyclic ring which may contain 0 to 2 heteroatoms selected from the group oxygen , nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3, CN, (dC 6) -alkyl, O- (CC 8) -alkyl, o
  • R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
  • R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached, have a 5-6 membered ring which, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group consisting of N- (C 1 -C 6 ) -alkyl, May include oxygen and sulfur.
  • the present invention relates to compounds of formula Ib
  • the abovementioned groups optionally contain substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O- (C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, (C 2 -) C 6 ) alkenyl, N (R 57) (R 58), SO 2 - CH 3 , CO (R 65); preferably E means
  • R11 in the abovementioned compounds of the formula Ib is a substituted mono- or bicyclic ring system having 5-10 members, which may have 0-3 heteroatoms, in particular N, O and / or S, particularly preferably phenyl with 0-1 N-atom, cyclohexyl or a bicyclic system with 8-10 members and 1-2 heteroatoms, especially N, O and / or S.
  • the present invention relates to compounds of the formula Ib
  • K is CH 2, CH 2 CH 2, O, CH 2 O, OCH 2, CON (R68), N (R67) CO, S, SO 2, SCH 2, SO 2, SO 2 CH 2, CO or a triple bond; preferably CH 2 , O, CH 2 O, OCH 2 , CON (R68), SCH 2 , CO or a triple bond; and
  • the amount of a compound of formula (I) required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient .
  • the daily dose ranges from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, eg, 3-10 mg / kg / day.
  • an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • vials for injections, and orally administrable unit dose formulations, such as tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the abovementioned weights are based on the weight of the free compound on which the salt is based.
  • the compounds according to formula (I) may themselves be used as compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition.
  • the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may also be present, including further compounds according to formula (I).
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
  • APD62429PC APD62429PC
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used according to formula (I) is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention.
  • Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Pressed tablets may be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
  • Molded tablets can be made by molding the powdery, with a APD62429PC
  • inert liquid diluent moistened compound can be prepared in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula (I) having a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • APD62429PC APD62429PC
  • Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • the compounds of the formula I are distinguished by favorable effects on lipid metabolism, in particular they are suitable for weight loss and after weight reduction for obtaining a reduced weight in mammals and as anorectic agents.
  • the compounds are characterized by their low toxicity and their low side effects.
  • the compounds can be used alone or in combination with other weight-reducing or anorectic agents.
  • Such other anorectic agents are mentioned, for example in the Red List, Chapter 01 under weight loss agent / Appetitzügier and may also contain such agents that increase the energy expenditure of the organism and thus lead to a weight loss or even those that affect the general metabolism of the organism, That an increased calorie intake does not lead to an increase in fat deposits and a normal calorie intake to a reduction in fat deposits of the organism.
  • the compounds are suitable for the prophylaxis and in particular for the treatment of overweight or obesity.
  • the compounds are furthermore suitable for the prophylaxis and in particular for the treatment of type II diabetes, atherosclerosis and for the normalization of lipid metabolism and for the treatment of hypertension.
  • the compounds act as MCH antagonists and are also useful in the treatment of sensory and other disorders APD62429PC
  • psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia, as well as the treatment of disorders associated with the circadian rhythm and for the treatment of substance abuse.
  • the compounds of the formula I can be administered in combination with one or more further pharmacologically active substances, for example selected from antidiabetics, antiadipositas, antihypertensive agents, lipid lowering agents and agents for the treatment and / or prevention of complications caused by diabetes or associated with diabetes.
  • one or more further pharmacologically active substances for example selected from antidiabetics, antiadipositas, antihypertensive agents, lipid lowering agents and agents for the treatment and / or prevention of complications caused by diabetes or associated with diabetes.
  • Suitable antidiabetic agents include insulin and insulin derivatives, e.g. Lantus® or HMR 1964, fast-acting insulins (see US 6,221,633), amylin, GLP-1 and GLP-2 derivatives such as e.g. those disclosed in WO 98/08871 by Novo Nordisk A / S and orally active hypoglycemic agents.
  • the orally active hypoglycemic agents preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, APD62429PC
  • Potassium channel opener e.g. those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, insulin receptor kinase activators, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, e.g. Inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, lipid metabolism altering compounds such as antihyperlipidemic agents and antilipidemic agents, e.g.
  • HMGCoA reductase inhibitors cholesterol transport / cholesterol uptake inhibitors, bile acid reabsorption inhibitors or microsomal triglyceride transfer protein (MTP) inhibitors, food intake reducing compounds, PPAR and RXR agonists, and ATP-dependent drugs Potassium channel of beta cells act.
  • MTP microsomal triglyceride transfer protein
  • the present compounds are administered in combination with insulin.
  • the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside.
  • a cholesterol resorption inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside.
  • the compounds of formula I in combination with a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.
  • PPAR alpha agonist such as, for example, GW 9578, GW 7647.
  • the compounds of formula I in combination with a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847 or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.
  • a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847 or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.
  • the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
  • a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
  • the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
  • an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757.
  • the compounds of formula I are used in combination with bile acid resorption inhibitor (see, e.g., U.S. 6,245,744 or U.S. 6,221,897), e.g. HMR 1741 administered.
  • the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
  • a CETP inhibitor e.g. JTT-705.
  • the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
  • a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
  • the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
  • the compounds of the formula I are administered in combination with an ACAT inhibitor, such as avasimibe.
  • ACAT inhibitor such as avasimibe.
  • the compounds of formula I are used in combination with an antioxidant, e.g. OPC-14117 administered.
  • the compounds of formula I are used in combination with a lipoprotein lipase inhibitor, e.g. NO-1886, administered.
  • a lipoprotein lipase inhibitor e.g. NO-1886
  • the compounds of formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
  • the compounds of formula I are administered in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
  • a squalene synthetase inhibitor e.g. BMS-188494.
  • the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
  • a lipoprotein (a) antagonist e.g. CI-1027 or nicotinic acid.
  • the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
  • a lipase inhibitor e.g. Orlistat
  • the compounds of the formula I are administered in combination with insulin.
  • the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
  • a sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
  • a biguanide e.g. Metformin
  • the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.
  • a meglitinide such as repaglinide.
  • the compounds of formula I are used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, especially 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
  • the compounds of formula I are used in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
  • an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose
  • the compounds of formula I are administered in combination with an agent which acts on the ATP-dependent potassium channel of the beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an agent which acts on the ATP-dependent potassium channel of the beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compounds according to the invention can be administered in combination with one or more antiadipositas or appetite regulating active ingredients.
  • the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide; hydrochloride (CGP 71683A)), MC4 agonists (eg, 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3 , 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlor
  • DA agonists bromocriptine, doprexin
  • lipase / amylase inhibitors e.g., WO 00/40569
  • PPAR modulators e.g., WO 00/78312
  • RXR modulators or TR- ⁇ agonists.
  • the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
  • the further active ingredient is dexamphatamine or amphetamine.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the other active ingredient is sibutramine or the mono- and bis-demethylated active metabolites of sibutramine.
  • the other active ingredient is orlistat.
  • the other active ingredient is mazindol or phentermine.
  • the compounds of formula I in combination with bulking agents preferably insoluble bulking agents
  • bulking agents preferably insoluble bulking agents
  • Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
  • Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
  • Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are beta blockers such as alprenolol, atenol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as e.g.
  • the anorectic effect was tested on female NMRI mice. After 17 hours of feed withdrawal, the test preparation was administered via a gavage. In individual housing and with free access to drinking water, the animals were offered condensed milk 30 minutes after preparation. The condensed milk consumption was determined every half hour 'for 7 hours and the general condition of the animals observed. The measured milk consumption was compared with the vehicle-treated control animals.
  • APD62429PC APD62429PC
  • Table 1 Anorectic effect, measured as a reduction of cumulated milk consumption treated compared to control animals.
  • the compounds of the formula I according to the invention can be prepared by means of reactions known in principle.
  • the compounds were obtained according to the following general reaction schemes.
  • R1 H alkylX, NaH
  • enantiomerically enriched compounds are characterized by an excellent hydrogen atom at the stereogenic center. Unless otherwise stated, the enantiomerically enriched examples shown are (R) -configured at the 3-amino-pyrrolidine stereocenter.
  • the compounds according to the invention are bases and can form salts with correspondingly strong acids.
  • the compounds can be present as hydrotrifluoroacetates after HPLC chromatographic purification using a mobile phase containing trifluoroacetic acid. These can be achieved by simply treating a solution of the salts z. B. be transferred with sodium carbonate solution in the free bases shown.
  • the unit of the indicated molecular weights is "g / mol.” Observed peaks in the mass spectrum are given as an integer quotient of the molecular molar mass and the charge of the molecular ion (m / z).
  • the product may be extracted with ethyl acetate and purified after concentration by chromatography. This gave the product with the molecular weight 444.54 (C26H28N4O3); MS (ESI): 445 (M + H +).
  • Example 6 The sequence described in Example 4 was applied to (S) -N-pyrrolidin-3-yl-acetamide. This gave the product with the molecular weight 444.54 (C26H28N4O3); MS (ESI): 445 (M + H +).
  • Example 6 (f?) - 1- [4- (3-Methylamino-pyrrolidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea
  • N-methyl-acetamide obtained from (S) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide.
  • N-pyrrolidin-3-yl-acetamide was reacted with 4-fluoro-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally APD62429PC
  • N-ethyl-N-pyrrolidin-3-yl-acetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline , This gave the product of molecular weight 450.59 (C26H34N4O3); MS (ESI): 451 (M + H +).
  • N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 1-fluoro-2-methyl-4-nitro-benzene, the resulting nitro compound is reduced with hydrogen and finally the aniline with CDI and 4- (4-chloro-phenyl) -piperidine reacted. This gave the product of molecular weight 469.03 (C26H33CIN4O2); MS (ESI): 469 (M + H +).
  • N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 1,2-difluoro-4-nitro-benzene, the resulting nitro compound was reduced with hydrogen and finally the aniline with CDI and 4- (4-chloro-phenyl) -piperidine reacted. This gave the product with the molecular weight 472.99 (C25H30CIFN4O2); MS (ESI): 473 (M + H +).
  • N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 4-fluoro-2-methyl-1 -nitro-benzene, the resulting nitro compound is reduced with hydrogen and finally the aniline with CDI and 4- (4-chloro-phenyl) -piperidine reacted. This gave the product of molecular weight 469.03 (C26H33CIN4O2); MS (ESI): 469 (M + H +).
  • N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 2,4-difluoro-1-nitro-benzene, the resulting nitro compound was reduced with hydrogen and finally the aniline with CDI and 4- (4-chloro-phenyl) -piperidine reacted. This gave the product with the molecular weight 472.99 (C25H30CIFN4O2); MS (ESI): 473 (M + H +).
  • N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 2-chloro-5-nitropyridine, the resulting nitro compound was reduced with hydrogen and finally the aniline with CDI and 4- (4-chloro -phenyl) -piperidine reacted. This gave the product with the molecular weight 490.99 (C25H29CIF2N4O2); MS (ESI): 491 (M + H +).
  • Method B was used to hydrogenate tert-butyl methyl [1- (4-nitro-phenyl) -azetidin-3-yl] -carbamic acid. This gave the product of molecular weight 277.37 (C15H23N3O2); MS (ESI): 278 (M + H +).
  • N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with carbonyldiimidazole and then with 4- (pyridin-3-yloxy) -phenylamine. This gave the product with the molecular weight 445.53 (C25H27N5O3); MS (ESI): 446 (M + H +).
  • N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with carbonyldiimidazole and then with 4-piperidin-1-yl-phenylamine. This gave the product with the molecular weight 435.57 (C25H33N5O2); MS (ESI): 436 (M + H +).
  • N- (1- ⁇ 4- [3- (6-cyclopentyloxy-pyridin-3-yl) -ureido] -phenyl ⁇ -pyrrolidin-3-yl) -N-methyl-acetamide was treated with sodium hydroxide solution. This gave the product with the molecular weight 395.51 (C22H29N5O2); MS (ESI): 395 (M + H +).

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