WO2004072025A2 - Substituted n-arylheterocycles, method for production and use thereof as medicaments - Google Patents

Substituted n-arylheterocycles, method for production and use thereof as medicaments Download PDF

Info

Publication number
WO2004072025A2
WO2004072025A2 PCT/EP2004/001342 EP2004001342W WO2004072025A2 WO 2004072025 A2 WO2004072025 A2 WO 2004072025A2 EP 2004001342 W EP2004001342 W EP 2004001342W WO 2004072025 A2 WO2004072025 A2 WO 2004072025A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently
another
group
apd62429pc
Prior art date
Application number
PCT/EP2004/001342
Other languages
German (de)
French (fr)
Other versions
WO2004072025A3 (en
Inventor
Lothar Schwink
Siegfried Stengelin
Matthias Gossel
Thomas Böhme
Gerhard Hessler
Petra Stahl
Dirk Gretzke
Original Assignee
Aventis Pharma Deutschland Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32841665&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2004072025(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA002516118A priority Critical patent/CA2516118A1/en
Priority to YUP-2005/0666A priority patent/RS20050666A/en
Priority to JP2006501827A priority patent/JP2006517563A/en
Priority to AU2004212145A priority patent/AU2004212145B2/en
Priority to MXPA05008449A priority patent/MXPA05008449A/en
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to NZ541823A priority patent/NZ541823A/en
Priority to BRPI0407504-8A priority patent/BRPI0407504A/en
Priority to EP04710808A priority patent/EP1597228A2/en
Publication of WO2004072025A2 publication Critical patent/WO2004072025A2/en
Publication of WO2004072025A3 publication Critical patent/WO2004072025A3/en
Priority to HR20050710A priority patent/HRP20050710A2/en
Priority to TNP2005000194A priority patent/TNSN05194A1/en
Priority to NO20054220A priority patent/NO20054220L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 +).

Abstract

The invention relates to N-arylheterocycles and the physiologically-acceptable salts and physiologically-functional derivatives thereof. Compounds of formula (I), where the groups have the given meanings, the N-oxides and the physiologically-acceptable salts and methods for production thereof are disclosed. The compounds are suitable as anorectics for example.

Description

APD62429PCAPD62429PC
Substituierte N-Arylheterozyklen, Verfahren zu ihrer Herstellung und ihreSubstituted N-aryl heterocycles, processes for their preparation and their
Verwendung als ArzneimittelUse as a medicine
Die Erfindung betrifft substituierte N-Arylheterozyklen sowie deren physiologisch verträgliche Salze und physiologisch funktionelle Derivate.The invention relates to substituted N-Arylheterozyklen and their physiologically acceptable salts and physiologically functional derivatives.
Es sind bereits den hier beschriebenen N-Arylheterozyklen in ihrer Gesamtstruktur ähnliche Verbindungen mit pharmakologischer Wirkung im Stand der Technik beschrieben. So beschreibt z. B. WO 00/35454 Ureido substituierte Phenylpiperidine und -pyrrolidine als Mittel zur Behandlung von Entzündungs- und Autoimmunkrankheiten. Acylamido substituierte Phenylpyrrolidine werden in WO 02/042271 zur Behandlung von Diabetes, Obesitas und Lipidstoffwechselkrankheiten vorgeschlagen.Already the N-arylheterocycles described herein are described in their structure as similar compounds with pharmacological action in the prior art. So describes z. WO 00/35454 Ureido substituted phenylpiperidines and -pyrrolidines as agents for the treatment of inflammatory and autoimmune diseases. Acylamido-substituted phenylpyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and lipid metabolism diseases.
Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Verfügung zu stellen, die eine Gewichtsreduktion bei Säugetieren bewirken und die zur Prävention und Behandlung von Obesitas und Diabetes geeignet sind.It is an object of the present invention to provide compounds which bring about weight reduction in mammals and which are useful in the prevention and treatment of obesity and diabetes.
Die Erfindung betrifft daher Verbindungen der Formel I,The invention therefore relates to compounds of the formula I,
Figure imgf000003_0001
Figure imgf000003_0001
worin bedeutenin which mean
R1 , R2 unabhängig voneinander H, (d-C^-Alkyl, -(CR78R79)0-R12, (C C4)-R 1, R 2 independently of one another are H, (C 1 -C 4 -alkyl, - (C R78 R 79) O -R 12, (CC 4 ) -
Alkoxy-(CrC4)-alkyl, Aryloxy-(C C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkinyl, APD62429PCAlkoxy- (C 1 -C 4 ) -alkyl, aryloxy- (CC 4 ) -alkyl, (C 3 -C 8 ) -alkenyl, (C 3 -C 8 ) -alkynyl, APD62429PC
CO-(CrC8)-Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(CrC4)-alkyl, CO-(C2-C8)- Alkenyl, CO-(C2-C8)-Alkinyl, COCH=CH(R13), COCC(R14), CO-(C C4)- alkyl-S(O)p-(C C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 4 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, NO2, CN, (CrC^-Alkyl, O-(C C8)-Alkyl, (C C4)-Alkoxy-(Cι-C4)-alkyl, Hydroxy-(C C4)-Alkyl, (C0-C8)-Alkylen-aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(Cι-C6)-Alkyl, N(R31)(R32) oder SO2CH3;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 of oxygen and nitrogen and sulfur, where the heterocyclic ring system can additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 4 -alkyl, O- (CC 8 ) -alkyl, (CC 4 ) -alkoxy- (C -C 4 ) -alkyl, hydroxy- (CC 4 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, COO (R 29), N (R30) CO (Cι-C6) alkyl, N (R31) (R32) or SO 2 CH 3;
o 0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
P 0, 1 , 2;P 0, 1, 2;
q, r, s unabhängig voneinander 0, 1 , 2, 3, 4;q, r, s are independently 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (C C6)-Alkyl, O-(C C8)-Alkyl substituiert sein kann;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;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (CrC6)-Alkyl;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(C C6)-Alkyl, CO(R33); oder APD62429PCR18 H, (d-CeJ-alkyl, CO (CC 6) -alkyl, CO (R33); or APD62429PC
R1 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR33 is a 5-10 membered aromatic ring system containing 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (Cι-C6)-Alkyl, O-(CrC8)-Alkyl substituiert sein kann;Containing heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (-CC 6 ) alkyl, O- (CrC 8 ) alkyl;
R12 OH, O-(CrC6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(Cι-C6)-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,
COO(R80), CON(R81)(R93), N(R82)(R83), 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, J, OH, CF3, NO2, CN, OCF3) Oxo, O-(d-C6)- Alkyl, (C C4)-Alkoxy-(Cι-C4)-alkyl, S-(d-Cβ)-Alkyl, (d-C-6)-Aikyl, (C2-C6)- Alkenyl, (C3-C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O- (C3-C8)-Cycloalkenyl, (drC^-Alkinyl, O-(C0-C8)-Alkylen-aryl, (C0-C8)~ Alkylen-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t(R39), CO(d-C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40), S(O)u (R41) und COOH enthalten kann;COO (R80), CON (R81) (R93), N (R82) (R83), 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- (dC 6 ) - alkyl, (CC 4 ) alkoxy (C -C 4 ) -alkyl, S- (d-Cβ) -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 1 -C 4 -alkynyl, O- (C 0 -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 (R 37) (R 38)) t (R39), CO (dC 6) u (R41) may include alkyl, COCOO (dC 6) -alkyl, COO (R40), S (O), and COOH;
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (d-C8)-Alkyl; oder APD62429PCR34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or APD62429PC
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;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 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (d- C6)-Alkyl, O-(Cι-C8)-Alkyl substituiert sein kann;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;
R40 H, (d-C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
R41 (Cι-C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR41 (-CC 6 ) -alkyl, 5-10 membered aromatic ring system, the 0-2 more
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (d-C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;Contain heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (dC 6 ) alkyl, O- (dC 8 ) alkyl;
R78, R79 unabhängig voneinander H, (C C8)-Alkyl, Hydroxy-(d-C4)-Alkyl, OH, (d- C4)-Alkoxy-(d-C4)-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;
R80, R81 ,R80, R81,
R93 unabhängig voneinander H, (d-C8)-Alkyl, (C2-C6)-Alkenly, (C0-C8)-Alkylen-R93 independently of one another are H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 1 -C 8 ) -alkylene
Aryl;aryl;
R82, R83 unabhängig voneinander H, (d-C6)-Alkyl; oder R82 undR82, R83 independently of one another are H, (C 1 -C 6 ) -alkyl; or R82 and
R83 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 APD62429PCR83 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
weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;further heteroatoms from the group N- (C 1 -C 6 ) -alkyl, oxygen and sulfur include and may optionally be substituted by 1-2 oxo groups;
R3 H, (d-C6)-Alkyl;R 3 is H, (C 1 -C 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (d-Cβ)-Alkyl, OH, O-(d-C6)-Alkyl, O-CO(d-R4, R5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (D-)
Cβ)-Alkyl, S-(d-C6)-Alkyl;Cβ) -alkyl, S- (dC 6 ) -alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (d-C8)-Alkyl, oder R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;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 unabhängig voneinander 0, 1 , 2;n, m are independently 0, 1, 2;
A, B, D, G unabhängig voneinander N, C(R42); oder die Gruppen A und B oder die Gruppen D und G sind jeweils C(R42) und bilden gemeinsam einen 5- oder 6-gliedrigen carbocyclischen oder heterocyclischen Rest, so dass sich insgesamt ein bicyclisches System ergibt;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;
R42 H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C C6)-Alkyl, O-(C C4)-R 42 is H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (CC 6 ) -alkyl, O- (CC 4 ) -
Alkoxy-(d-C4)-alkyl, S-(d-C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C3- C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)- Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, S-Aryl, N(R43)(R44), SO2-CH3, COOH, COO-(d-C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51), - (CR84R85)x-O(R86); APD62429PCAlkoxy (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 ) -alkylene-aryl, S-aryl, N (R 43) (R 44), SO 2 -CH 3 , COOH, COO- (dC 6 ) -alkyl, CON (R 45) (R46 ), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51), - (CR84R85) x -O (R86); APD62429PC
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (d-C8)-Alkyl; oderR43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
R84, R85 unabhängig voneinander H, (C C8)-Alkyl;R84, R85 independently of one another are H, (CC 8 ) -alkyl;
R86 H, (d-C6)-Alkyl, Aryl;R 86 is H, (C 1 -C 6 ) -alkyl, aryl;
x 1 , 2, 3, 4, 5, 6;x 1, 2, 3, 4, 5, 6;
R10 H, (C C8)-Alkyl, (C3-C6)-Alkenyl, (C3-C6)-Alkinyl;R 10 is H, (CC 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)O, CO, C≡C, eine Gruppe der Formel -(CR87R88)γ-, worin eine oder mehrere Gruppen (CR87R88)- durch Y ersetzt sein können, wobei sich ein chemisch sinnvoller Rest ergibt;XN (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O, CO, C≡C, a group of the formula - (CR87R88) γ-, wherein a or several groups (CR87R88) - may be replaced by Y, resulting in a chemically meaningful residue;
Y O, S, N(R89);Y O, S, N (R89);
R52, R53, R54, R55, R56 unabhängig voneinander H, (Cι-C8)-Alkyl APD62429PCR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl APD62429PC
R87, R88 unabhängig voneinander H, (d-C4)-Alkyl, wobei R87 und R88 in den y Gruppen jeweils die gleichen oder verschiedene Bedeutungen aufweisen können;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;
y 2, 3, 4, 5, 6;y 2, 3, 4, 5, 6;
R89 H, (C Cβ)-Alkyl;R89 is H, (C Cβ) -alkyl;
E 3-14 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4E 3-14 membered bivalent carbocyclic or heterocyclic ring structure with 0-4
Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, Oxo, O-(C C6)- Alkyl, O-(d-C4)-Alkoxy-(Cι-C4)-alkyl, S-(d-C6)-Alkyl, (C C6)-Alkyl, (C2- C6)-Alkenyl, (C3-C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-aryl, O-(C0-C8),- Alkylen-aryl, S-Aryl, N(R57)(R58), SO2-CH3, COOH, COO-(d-C6)-Alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;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- (Cι-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-aryl, S-aryl, N (R 57) (R 58), SO 2 -CH 3 , COOH, COO- (dC 6 ) -alkyl, CON (R59) (R60), N (R61) CO (R62), N (R63) SO 2 (R64), CO (R65) bear and can be mono- or bicyclic;
R57, R58, R59, R60, R61 , R63 unabhängig voneinander H, (CrC8)-Alkyl; oderR 57, R 58, R 59, R 60, R 61, R 63 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 unabhängig voneinander H, (d-C8)-Alkyl, Aryl; APD62429PCR62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; APD62429PC
K eine Bindung, O, OCH2, CH2O, S, SO, SO2> N(R66), N(R67)CO,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, eine Gruppe der Formel - (CR90R91)Z-, worin eine oder mehrere Gruppen -(CR90R91)- durch Z ersetzt sein können, wobei sich ein chemisch sinnvoller Rest ergibt;CON (R68), (C (R69) (R70)) V , CO, C≡C, C = C, a group of the formula - (CR90R91) Z -, wherein one or more groups - (CR90R91) - is replaced by Z. may be, resulting in a chemically meaningful rest;
v 1 , 2, 3, 4;v 1, 2, 3, 4;
R66, R67, R68, R69, R70 unabhängig voneinander H, (CrC8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
Z O, S, N(R92), CO, SO, SO2;Z is O, S, N (R92), CO, SO, SO 2;
R90, R91 unabhängig voneinander H, (CrC8)-Alkyl, Hydroxy-(Cι-C4)-Alkyl, Hydroxy, (CrC4)-Alkoxy-(Cι-C4)-Alkyl, wobei R90 und R91 in den z Gruppen jeweils die gleichen oder verschiedene Bedeutungen aufweisen können;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;
z 2, 3, 4, 5, 6;z 2, 3, 4, 5, 6;
R92 H, (Cι-C8)-Alkyl;R 92 is H, (C 1 -C 8 ) -alkyl;
R11 H, (C C8)-Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-R11 H, (CC 8) -alkyl, (dC 4) alkoxy- (Cι-C4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
Alkinyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, NO2, CN, (C C6)-Alkyl, O-(d-C8)- Alkyl, (Cι-C4)-Alkoxy-(CrC-4)-alkyl, (C0-C8)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, Hydroxy-(C C4)-alkyl, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oder SO2CH3, SCF3 ;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, (Cι-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 unabhängig voneinander H, (d-C8)-Alkyl; APD62429PCR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
oderor
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; oderR72 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 und R11 zusammen einen Tricyclus bilden, wobei die Ringe unabhängig voneinander gesättigt, teilgesättigt oder ungesättigt und jeweils 3 - 8 Ringatome enthalten können;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;
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
In einer weiteren Ausführungsform betrifft die Erfindung daher Verbindungen der Formel I,In a further embodiment, the invention therefore relates to compounds of the formula I
Figure imgf000011_0001
Figure imgf000011_0001
worin bedeutenin which mean
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CH2)0 -R12, (C C4)-Alkoxy-R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CH 2 ) 0 -R 12, (CC 4 ) -alkoxy
(d-C4)-alkyl, Aryloxy-(d-C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkinyl, CO- (d-C8)-Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(d-C4)-alkyl, CO-(C2-C8)- Alkenyl, CO-(C2-C8)-Alkinyl, COCH=CH(R13), COCC(R14), CO-(d-C4)- alkyl-S(O)p-(CrC4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden APD62429PC(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 together with the nitrogen atom to which they are attached APD62429PC
sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 4 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, NO2, CN, (d-C6)-Alkyl, O-(C C8)-Alkyl, (d- C4)-Alkoxy-(d-C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(d-C6)-Alkyl, N(R31)(R32) oder SO2CH3;are 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 of oxygen, nitrogen and sulfur, wherein the 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 ;
o 0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
p 0, 1 , 2;p 0, 1, 2;
q, r, s unabhängig voneinander 0, 1 , 2, 3, 4;q, r, s are independently 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (C C6)-Alkyl, O-(d- C8)-Alkyl substituiert sein kann;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;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (Cι-C6)-Alkyl;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-C6)-Alkyl, CO(C C6)-Alkyl, CO(R33);R 18 is H, (C 1 -C 6 ) alkyl, CO (CC 6 ) alkyl, CO (R 33);
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C-6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; APD62429PCR17 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 ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR33 is a 5-10 membered aromatic ring system containing 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2( CN, (d-C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann;Containing heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 ( CN, (dC 6 ) alkyl, 0- (CC 8 ) alkyl;
R12 OH, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, Oxo, O-(d-C6)-Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, S-(d-C6)- Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, O-(C3-C8)- Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, O-(C0-C8)-Alkylen-Aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40), S(O)u (R41) und COOH enthalten kann;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 -C 6 ) -alkynyl, O- (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35), COCH = CH (R 36), (C (R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (CC 6) -alkyl, COCOO (dC 6) -alkyl, COO (R40), S ( O) u may contain (R41) and COOH;
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (d-C8)-Alkyl;R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl;
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;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 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, APD62429PCR36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system containing 0-2 further heteroatoms from the group nitrogen, APD62429PC
Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (d- C6)-Alkyl, O-(CrC8)-Alkyl substituiert sein kann;Containing oxygen and sulfur and may be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl;
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R40 H, (CC 8) -alkyl, (C 2 -C 6) alkenyl, (C 0 -C 8) -alkylene-aryl;
R41 (C C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR41 (CC 6 ) alkyl, 5-10 membered aromatic ring system, the 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, NO2, CN, (Cι-C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;Contain heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , NO 2 , CN, (-CC 6 ) alkyl, O- (dC 8 ) alkyl may be substituted;
R3 H, (C C6)-Alkyl;R 3 is H, (CC 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (d-C6)-Alkyl, OH, O-(d-C6)-Alkyl, θ-CO(d-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-)
C6)-Alkyl, S-(d-C6)-Aikyl;C 6 ) -alkyl, S- (dC 6 ) -alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (d-C8)-Alkyl;R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl;
R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;R6 and R7, R8 and R9 independently of one another optionally oxo;
n, m unabhängig voneinander 0, 1 , 2;n, m are independently 0, 1, 2;
A, B, D, G unabhängig voneinander N, C(R42);A, B, D, G are independently N, C (R42);
R42 H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C C6)-Alkyl, O-(C C4)-R 42 is H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (CC 6 ) -alkyl, O- (CC 4 ) -
Alkoxy-(Cι-C4)-alkyl, S-(C C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, (C3- C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8) -Cycloalkenyl, O-(C3-C8)- Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, S-Aryl, N(R43)(R44), SO2-CH3, COOH, COO-(d-C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) APD62429PCAlkoxy- (C 1 -C 4 ) -alkyl, S- (CC 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-aryl, S-aryl, N (R 43) (R 44), SO 2 -CH 3 , COOH, COO- (dC 6 ) -alkyl, CON (R 45) (R46), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51) APD62429PC
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (d-C8)-Alkyl;R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl;
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
R10 H, (d-C8)-Alkyl, (C3-C6)-Alkenyl, (C3-C6)-Alkinyl;R 10 is H, (C 1 -C 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)O;X N (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O;
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4E 3-8 membered bivalent carbocyclic or heterocyclic ring structure with 0-4
Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(d-C6)-Alkyl, O- (d-C4)-Alkoxy-(d-C4)-alkyl, S-(d-C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)- Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, S-Aryl, N(R57)(R58), SO2-CH3, COOH, COO-(d-C6)-Alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;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 ) -alkylene-aryl, S-aryl, N (R 57) (R 58), SO 2 -CH 3 , COOH, COO- (dC 6 ) -alkyl, CON (R59) (R60), N (R61) CO (R62), N (R63) SO 2 (R64), CO (R65) bear and can be mono- or bicyclic;
R57, R58, R59, R60, R61 , R63 APD62429PCR57, R58, R59, R60, R61, R63 APD62429PC
unabhängig voneinander H, (d-C8)-Alkyl;independently of one another H, (C 1 -C 8 ) -alkyl;
R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 unabhängig voneinander H, (Cι-C8)-Alkyl, Aryl;R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
K eine Bindung, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO,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;CON (R68), (C (R69) (R70)) V , CO, C≡C;
v 1 , 2, 3, 4v 1, 2, 3, 4
R66, R67, R68, R69, R70 unabhängig voneinander H, (CrC8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (C C8)-Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-R11 H, (CC 8) alkyl, (Cι-C4) alkoxy (dC 4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
Alkinyl, ein 3 bis 10-gliedriger mono-, bi- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, NO2, CN, (Cι-C6)-Alkyl, O-(d-C8)- Alkyl, (C1-C4)-Alkoxy-(Cι-C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oder SO2CH3;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 unabhängig voneinander H, (C C8)-Alkyl; APD62429PCR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (CC 8 ) -alkyl; APD62429PC
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; oderR72 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 und R11 zusammen einen Tricyclus bilden, wobei die Ringe unabhängig voneinander gesättigt, teilgesättigt oder ungesättigt und jeweils 3 - 8 Ringatome enthalten können;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;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
Die Erfindung bezieht sich auf Verbindungen der Formel I, in Form ihrer Racemate, enantiomerenangereicherten Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.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.
Die Alkyl-, Alkenyl- und Alkinylreste in den Substituenten R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R34, R35, R36, R37, R38, R39, R40, R41 , R42, R43, R44, R45, R46, R46, R47, R48, R49, R50, R51 , R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71 , R72, R73, R74, R75, R76, R77, R78, R79, R80, R81 , R82, R83, R84, R85, R86, R87, R88, R89, R90, R91 , R92 und R93 können sowohl geradkettig, verzweigt oder optional halogeniert sein.The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45 , R46, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69 , R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92 and R93 can both straight-chain, branched or optionally halogenated.
Unter dem Begriff "Aryl" wird insbesondere eine Phenyl oder Naphthylgruppe verstanden.The term "aryl" is understood to mean in particular a phenyl or naphthyl group.
Unter einem „Tricyclus" werden Strukturen mit 3 Ringen verstanden, die durch mehr als eine Bindung miteinander verbunden sind. Beispiele solcher Systeme sind kondensierte Systeme mit 3 Ringen und Spirocyclen mit ankondensiertem Ringsystem. APD62429PCBy "tricycle" is meant three-membered structures joined by more than one bond, examples of which are fused-ring condensed systems and fused-ring spirocycles. APD62429PC
In dem Fall, dass R1 und R2 zusammen mit dem Stickstoffatom an das sie gebunden sind, einen Ring bilden, kann dieser Ring mit einem oder mehreren der genannten Substituenten substituiert sein.In the event that R1 and R2 together with the nitrogen atom to which they are attached form a ring, this ring may be substituted with one or more of the said substituents.
Unter die bivalente carbo- oder heterocyclische Ringstruktur E fallen auch Strukturen, die über ein und dasselbe Atom mit den beiden benachbarten Gruppen K und X verknüpft sind.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.
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter-, Sulfon- und Schwefelsäure sowie organischer Säuren, wie z.B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isethion-, Milch-, Lactobion-, Malein-, Äpfel-, Methansulfon-, Bernstein-, p-Toluolsulfon-, Wein- und Tri- fluoressigsäure. Für medizinische Zwecke wird in besonders bevorzugter Weise das Chlorsalz verwendet. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze) und Erdalkalisalze (wie Magnesium- und Calciumsalze).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. Acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, wine and trifluoroacetic acid. For medical purposes, 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).
Salze mit einem nicht pharmazeutisch verträglichen Anion gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nichttherapeutischen, zum Beispiel in-vitro-Anwendungen.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.
Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiologisch verträgliche Derivat einer erfindungsgemäßen Verbindung der Formel I, z.B. einen Ester, der bei Verabreichung an einen Säuger, wie z.B. den Menschen, in der APD62429PCAs used herein, the term "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
Lage ist, (direkt oder indirekt) eine Verbindung der Formel I oder einen aktiven Metaboliten hiervon zu bilden.It is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
Zu den physiologisch funktionellen Derivaten zählen auch Prodrugs der erfindungsgemäßen Verbindungen. Solche Prodrugs können in vivo zu einer erfindungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z. B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.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.
Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel (I)" auf Verbindung (en) der Formel (I) wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktionellen Derivate wie hierin beschrieben.Hereinafter, all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.
Können Reste oder Substituenten mehrfach in den Verbindungen der Formel I auftreten, so können sie alle unabhängig voneinander die angegebenen Bedeutungen haben und gleich oder verschieden sein.If 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.
In einer besonders bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel I,In a particularly preferred embodiment, the present invention relates to compounds of the formula I,
worin bedeuten:in which mean:
R1 , R2 unabhängig voneinander H, (CrC8)-Alkyl, -(CH2)0 -R12, (C C4)-Alkoxy-R 1, R 2 independently of one another are H, (C 1 -C 8 ) -alkyl, - (C 2 ) 0 -R 12, (CC 4 ) -alkoxy
(d-C4)-alkyl, CO-(d-C8)-Alkyl, -CO-(CH2)0 -R12, COCH=CH(R13), COCC(R14), CO-(d-C4)-alkyl-S(O)p-(CrC4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem APD62429PC(C 1 -C 4 ) -alkyl, CO- (C 1 -C 8 ) -alkyl, -CO- (CH 2 ) 0 -R 12, COCH = CH (R 13), COCC (R 14), CO- (C 1 -C 4 ) -alkyl-S ( O) p- (CrC 4 ) alkyl, CO (C (R 15) (R 16)) q N (R 17) (R 18), CO (C (R 19) (R 20)) r CON ( R 21) ( R 22), CO (C (R23) (R24)) s O (R25); or R1 and R2 form together with the APD62429PC
Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterozyklische Ringsystem zusätzlich substituiert sein kann mit F, (d-C6)-Alkyl, O-(Cι-C8)-Alkyl, (C0- C8)-Alkylen-Aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(d-C6)-Alkyl, N(R31)(R32) oder SO2CH3, wobei bevorzugt R1 und R2 nicht gleichzeitig H bedeuten und R1 und R2 gemeinsam mit dem Stickstoffatom bevorzugt keinen Morpholino-Rest darstellen;Nitrogen atom to which they are attached, a 4 to 10-membered mono-, bi- or spiro-cyclic ring which may contain, in addition to the nitrogen atom 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system additionally substituted may be substituted by F, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), Hydroxy, COO (R29), N (R30) CO (dC 6 ) alkyl, N (R31) (R32) or SO 2 CH 3 , wherein preferably R1 and R2 are not simultaneously H and R1 and R2 together with the nitrogen atom is preferred do not represent a morpholino residue;
0, 1 , 2, 3, 40, 1, 2, 3, 4
0, 1 , 20, 1, 2
q, r, s unabhängig voneinander 0, 1 , 2, 3, bevorzugt sind q, s unabhängig voneinander 1 , 2, 3 und r 0, 1 , 2, 3;q, r, s are independently 0, 1, 2, 3, preferably q, s are independently 1, 2, 3 and r is 0, 1, 2, 3;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;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 ;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28,R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28,
R29, R30, R31 , R32 unabhängig voneinander H, (d-C6)-Alkyl;R29, R30, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18 H, (C C6)-Alkyl, CO(C C6)-Alkyl, CO(R33);R18 H, (CC 6) -alkyl, CO (CC 6) -alkyl, CO (R33);
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem APD62429PCR17 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 except the APD62429PC
Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;Nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) - alkyl, oxygen and sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, O-(C C8)-Alkyl substituiert sein kann;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;
R12 OH, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, CF3, CN, Oxo, O-(d- C6)-Alkyl, (C C6)-Alkyl, O-(C0-C8)-Alkylen-Aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40) und S(O)u (R41) enthalten kann, wobei in einer bevorzugten Ausführungsform der Substituent O-(Cr CβJ-Alkyl ausgenommen ist, wenn der 3-12 gliedrige Ring Phenyl bedeutet;R 12 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, CF 3 , CN, Oxo, O- (C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35), COCH = CH (R 36), ( C (R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (CC 6) -alkyl, COCOO (dC 6) -alkyl, COO (R40) and S (O) u (R41), wherein in a preferred embodiment the substituent O- (Cr CβJ-alkyl is excluded when the 3-12 membered ring is phenyl;
t 0, 1 , 2, 3, 4;t 0, 1, 2, 3, 4;
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (C C8)-Alkyl;R34, R35, R37, R38 independently of one another are H, (CC 8 ) -alkyl;
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;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 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatom aus der Gruppe Stickstoff, APD62429PCR36, R39 are independently (C 3 -C 8) -cycloalkyl, 5-10 membered aromatic ring system containing a further heteroatom from the group nitrogen, APD62429PC
Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, O-(d-C8)- Alkyl substituiert sein kann;Containing oxygen and sulfur and may be substituted with F, Cl, (dC 6 ) alkyl, O- (dC 8 ) alkyl;
R40 H, (d-C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
R41 (d-C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR41 (dC 6 ) alkyl, 5-10 membered aromatic ring system, the 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (C C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;Containing heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, (CC 6 ) alkyl, O- (dC 8 ) alkyl;
R3 H, (d-C6)-Alkyl;R 3 is H, (C 1 -C 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (C C6)-Alkyl, OH, O-(d-C6)-Alkyl, O-CO(CR4, R5 independently of one another are H, (CC 6 ) -alkyl, OH, O- (C 1 -C 6 ) -alkyl, O-CO (C
C6)-Alkyl;C 6 ) alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (d-C8)-Alkyl;R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl;
R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;R6 and R7, R8 and R9 independently of one another optionally oxo;
n, m unabhängig voneinander 0, 1 , 2, bevorzugt ist m 0, 1 , 2 und n 1;n, m are independently 0, 1, 2, preferably m is 0, 1, 2 and n is 1;
A, B, D, G unabhängig voneinander N, C(R42);A, B, D, G are independently N, C (R42);
R42 H, F, Cl, Br, CF3, CN, O-(d-C6)-Al yl, (C C6)-Alkyl, (C3-C8)-Cycloalkyl,R 42 is H, F, Cl, Br, CF 3 , CN, O- (C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl,
(C0-C2)-Alkylen-Aryl, O-(C0-C2)-Alkylen-Aryl, N(R43)(R44), SO2-CH3, COO- (d-C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)(C 0 -C 2 ) -alkylene-aryl, O- (C 0 -C 2 ) -alkylene-aryl, N (R 43) (R 44), SO 2 -CH 3 , COO- (dC 6 ) -alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51)
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (d-C8)-Alkyl; APD62429PCR43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann;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 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
R10 H, (C C8)-Alkyl;R 10 is H, (CC 8 ) -alkyl;
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)O;X N (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O;
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4E 3-8 membered bivalent carbocyclic or heterocyclic ring structure with 0-4
Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, CF3, NO2, OH, CN, O-(d-C6)-Alkyl, (d-C6)-Alkyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, N(R57)(R58), SO2-CH3, COO- (d-C6)-Alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) tragen und mono- oder bicyclisch sein kann, bevorzugt weist die Gruppe E in ortho-Position zum Anknüpfungspunkt von X keinen Substituenten aus der Gruppe (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl und N(R57)(R58), worin R57 und R58 gemeinsam mit dem Stickstoffatom einen 5 - 6 gliedrigen Ring bilden, auf; besonders bevorzugt ist E monocyclisch;Heteroatoms from the group N, O and S, optionally substituents from the group H, F, Cl, CF 3 , NO 2 , OH, CN, O- (dC 6 ) alkyl, (dC 6 ) alkyl, (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl, N (R 57) (R 58), SO 2 -CH 3 , COO- (dC 6 ) -alkyl, CON (R59 ) (R60), N (R61) CO (R62), N (R63) SO 2 (R64), CO (R65) bear and can be mono- or bicyclic, preferably, the group e in the ortho position to the point of attachment of X no substituent from the group (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl and N (R57) (R 58) in which R 57 and R 58 together with the nitrogen atom have a 6-membered ring form, on; E is particularly preferably monocyclic;
R57, R58, R59, R60, R61 , R63 APD62429PCR57, R58, R59, R60, R61, R63 APD62429PC
unabhängig voneinander H, (d-C8)-Alkyl;independently of one another H, (C 1 -C 8 ) -alkyl;
R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann, wobei R59 und R60 bevorzugt nicht gleichzeitig H sind;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 unabhängig voneinander H, (C C8)-Alkyl, Aryl;R62, R64, R65 independently of one another are H, (CC 8 ) -alkyl, aryl;
K eine Bindung, O, CH2O, N(R66), (C(R69)(R70))V, C≡C, OCH2, CON(R68), bevorzugt eine Bindung, O, CH2O, ((CR69)(R70))V, C≡C, N(R66);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);
1 , 2;1, 2;
R66, R68, R69, R70 unabhängig voneinander H, (d-C8)-Alkyl;R66, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (d-C8)-Alkyl, (C C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl, ein 3 bis 10- gliedriger mono-, bi- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, NO2, CN, (d-C6)-Alkyl, O-(C C8)-Alkyl, (C C4)- Alkoxy-(d-C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oder SO2CH3, bevorzugt ist R11 nicht COO(R74);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, N (R76) (R77) or SO 2 CH 3, preferably R11 is not COO (R74);
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (d-C8)-Alkyl; APD62429PCR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(CrC6)- Alkyl, Sauerstoff und Schwefel beinhalten kann.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.
Besonders bevorzugt sind Verbindungen der Formel I, worinParticular preference is given to compounds of the formula I in which
A, B, D, G unabhängig voneinander N oder C(R42) bedeuten und die Gesamtzahl der Stickstoffatome in diesem Ring 0-2, bevorzugt 0 oder 1 beträgt.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.
Ganz besonders bevorzugt sind die Verbindungen der Formel I, worinVery particular preference is given to the compounds of the formula I in which
n 1 und m 1 oder 2 bedeuten.n is 1 and m is 1 or 2.
Insbesondere bevorzugt sind Verbindungen der Formel I, worinParticular preference is given to compounds of the formula I in which
A, B, D, G unabhängig voneinander N oder C(R42) bedeuten und die Gesamtzahl der , Stickstoffatome in diesem Ring 0-2, bevorzugt 0 oder 1 beträgt;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;
1 und1 and
m 1 oder 2 bedeuten.m is 1 or 2.
In einer weiteren bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel I,In a further preferred embodiment, the present invention relates to compounds of the formula I,
worin bedeuten: APD62429PCin which mean: APD62429PC
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CR78R79)0 -R12, (d-C4)-R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR 78 R 79) 0 -R 12, (dC 4 ) -
Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl, CO-(d-C8)-Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(C 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); oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (d-C6)-Alkyl, O-(Cι-C4)- Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, Hydroxy-(C C4)-alkyl, (C0-C2)-Alkylen- aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(d- C6)-Alkyl, N(R31)(R32) oder SO2CH3; bevorzugt unabhängig voneinander H, (d-C8)-Alkyl, -(CR78R79)0 -R12, (d-C4)-Alkoxy-(d-C4)-alkyl, CO-(C C8)-Alkyl, -CO- (CH2)0 -R12, COCH=CH(R13), COCC(R14),Alkoxy- (Cι-C4) alkyl, (C 3 -C 8) -alkenyl, CO- (dC 8) -alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (CC 4) - alkyl, COCH = CH (R13), COCC (R14), 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, together with the nitrogen atom to which they are attached, form a 4 to 10 membered mono-, bi- or spiro-cyclic ring which, in addition to the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3, (dC 6) -alkyl, O- (Cι-C4) - alkyl, (dC 4) alkoxy- (Cι-C4) - alkyl, hydroxy- (CC 4 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, COO (R 29), N (R 30) CO (C 1 -C 6 ) alkyl, N (R31) (R 32) or SO 2 CH 3 ; 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, COCH = CH (R13), COCC (R14),
CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono- oder bicyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (d-C6)-Alkyl, O-(d-C4)-Alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C0-C2)- Alkylen-Aryl, Oxo, CO(R26), Hydroxy, N(R31)(R32) oder SO2CH3; besonders bevorzugt unabhängig voneinander H, (Cι-C8)-Alkyl, - (CR78R79)0 -R12, (C1-C4)-Alkoxy-(C1-C4)-alkyl, CO-(C C8)-Alkyl, -CO- (CH2)0 -R12, CO(C(R15)(R16))qN(R17)(R18), oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono- oder bicyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, APD62429PCCO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) s O (R25); or 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, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, CO- (CC 8 ) - Alkyl, -CO- (CH 2 ) 0 -R 12, CO (C (R 15) (R 16)) q N (R 17) (R 18), or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4 to a 10-membered mono- or bicyclic ring which may contain, in addition to the nitrogen atom, 0 to 2 additional heteroatoms, APD62429PC
ausgewählt aus der Gruppe Sauerstoff und Stickstoff, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, (d- C6)-Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, Oxo, CO(R26), Hydroxy, N(R31)(R32);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) (R32);
o 0, 1 , 2, 3, 4, 5, 6; bevorzugt 0, 1 , 2, 3, 4; besonders bevorzugt 0, 1 , 2, 3;0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;
q, r unabhängig voneinander 1 , 2, 3; bevorzugt ist q 1 oder 2;q, r are independently 1, 2, 3; preferably q is 1 or 2;
s 0, 1 , 2, 3, 4; bevorzugt 0, 1, 2, 3; besonders bevorzugt 0, 1 , 2;s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
R13, R14 unabhängig voneinander einen Phenylring, der 0-1 Stickstoffatome enthalten kann;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 unabhängig voneinander H, (d-C6)-Alkyl;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, (d-C6)-Alkyl, CO(d-C6)-Alkyl, CO(R33); bevorzugt H, (Ci-Cej-Alkyl,R18 H, (dC 6) -alkyl, CO (dC 6) -alkyl, CO (R33); preferably H, (C 1 -C 12 -alkyl,
CO(d-C6)-Alkyl; besonders bevorzugt H, (d-C6)-Alkyl; oderCO (dC 6 ) alkyl; particularly preferably H, (C 1 -C 6 ) -alkyl; or
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; bevorzugt ist der Ring Pyrrolidin, Piperidin, N-Methylpiperazin, Morpholin;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 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten kann und mit F, Cl, (d-C6)-Alkyl, O-(C C8)-Alkyl substituiert sein kann; APD62429PCR33 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
R12 OH, O-(Cι-C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(C C6)-Alkyl,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 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3, CN, Oxo, O-(C C6)-Alkyl, (d-C4)- Alkoxy-(d-C4)-alkyl, (d-C6)-Alkyl- O-(C0-C8)-Alkylen-Aryl, (C0-C8)-Alkylen- aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t(R39), CO(C C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40), S(O)u (R41) enthalten kann; bevorzugt OH, O-(d-C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, 3-10 gliedriger mono-, oder bicyclischer Ring, der 1-3 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3, CN, Oxo, O-(d-C6)-Alkyl, (C1-C4)-Alkoxy-(C1-C4)- alkyl, (C C6)-Alkyl, (C0-C2)-Alkylen-aryl, N(R34)(R35), CO(d-C6)-Alkyl enthalten kann; besonders bevorzugt OH, O-(d-C6)-Alkyl, 3-10 gliedriger mono-, oder bicyclischer Ring, der 1-2 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-10 gliedrige Ring weitere Substituenten wie F, OH, Oxo, (Cι-C6)-Alkyl, CO(d-C6)-Alkyl enthalten kann;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), S (O) u; preferably OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring containing 1-3 heteroatoms from the group N, O and may contain S and the 3-10 membered ring further substituents such as F, Cl, Br, OH, CF 3, CN, oxo, O- (dC 6) alkyl, (C 1 -C 4) alkoxy- (C 1 -C 4 ) -alkyl, (CC 6 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, N (R 34) (R 35), CO (dC 6 ) -alkyl; particularly preferably OH, O- (C 1 -C 6 ) -alkyl, 3-10 membered mono- or bicyclic ring which may contain 1-2 heteroatoms from the group N, O and S and the 3-10 membered ring further substituents such as F , OH, oxo, (C 1 -C 6 ) -alkyl, CO (C 1 -C 6 ) -alkyl may contain;
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2; bevorzugt 0 oder 2; besonders bevorzugt 2;u 0, 1, 2; preferably 0 or 2; more preferably 2;
R34, R35, R37, R38 unabhängig voneinander H, (d-C8)-Alkyl; oderR34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R34 und R35 optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 APD62429PCR34 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
weitere Heteroatome aus der Gruppe N-(CrC6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;include further 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 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (C C6)-Alkyl, O-(d-C8)- Alkyl substituiert sein kann;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;
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-aryl;R 40 is H, (CC 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
R41 (C C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR41 (CC 6 ) alkyl, 5-10 membered aromatic ring system, the 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (C C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;Containing heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, (CC 6 ) alkyl, O- (dC 8 ) alkyl;
R78, R79 unabhängig voneinander H, (C C8)-Alkyl, Hydroxy-(d-C4)-Alkyl, OH, (C C4)-Alkoxy-(d-C4)-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 unabhängig voneinander H, (d-C8)-Alkyl;R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl;
R3 H, (C C6)-Alkyl; bevorzugt H;R 3 is H, (CC 6 ) -alkyl; preferably H;
R4, R5 unabhängig voneinander H, (d-C6)-Alkyl, OH, O-(d-C6)-Alkyl, O-CO(d-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-)
C6)-Alkyl, S-(d-C6)-Alkyl; bevorzugt unabhängig voneinander H, (C C6)- Alkyl, OH, O-(d-C6)-Alkyl, O-CO(d-C6)-Alkyl; besonders bevorzugt unabhängig voneinander H, OH, O-(CrC6)-Alkyl;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, R9R6, R7, R8, R9
H; oder R6 und R7, R8 und R9 unabhängig voneinander optional Oxo; APD62429PCH; or R6 and R7, R8 and R9 independently of one another optionally oxo; APD62429PC
bevorzugt sind R6, R7, R8, R9 H; n 1preferably R6, R7, R8, R9 are H; n 1
m 1 oder 2; bevorzugt 1 ;m is 1 or 2; preferably 1;
A, B, D, G unabhängig voneinander N, C(R42); oder die Gruppen A und B oder D und G sind jeweils C(R42) und bilden gemeinsam eine ortho-Phenyleneinheit, so dass sich insgesamt ein 1 ,4- bisubstituiertes Naphthalinsystem ergibt; bevorzugt sindA, 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
B N, C(R42); und A, D, G C(R42); besonders bevorzugt sindB N, C (R42); and A, D, G C (R42); are particularly preferred
A, B, D, G C(R42);A, B, D, G C (R42);
R42 H, F, Cl, Br, CF3, CN, O-(d-C6)-Alkyl, O-(Cι-C4)-Alkoxy-(d-C4)-alkyl, S-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--
(Cι-C6)-Alkyl, (C C6)-Alkyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl,(C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl,
N(R43)(R44), SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -N (R43) (R44), SO 2 -CH 3, CON (R45) (R46), N (R47) CO (R48), CO (R51), -
(CR84R85)x-O(R86); bevorzugt H, F, Cl, Br, CF3, CN, O-(C C6)-Alkyl, (d-C6)-Alkyl, SO2-CH3,(CR84R85) x -O (R86); preferably H, F, Cl, Br, CF 3 , CN, O- (CC 6 ) -alkyl, (C 1 -C 6 ) -alkyl, SO 2 -CH 3 ,
CON(R45)(R46), N(R47)CO(R48), CO(R51),CON (R45) (R46), N (R47) CO (R48), CO (R51),
-(CR84R85)x-O(R86); besonders bevorzugt H, F, Cl, CF3, CN, (d-C6)-Alkyl,- (CR84R85) x -O (R86); particularly preferably H, F, Cl, CF 3 , CN, (C 1 -C 6 ) -alkyl,
-(CR84R85)x-O(R86); R43, R44, R45, R46, R47 unabhängig voneinander H, (Cι-C8)-Alkyl; oder R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem- (CR84R85) x -O (R86); 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
Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Nitrogen atom still 0-1 further heteroatoms from the group N- (dC 6 ) -
Alkyl, Sauerstoff und Schwefel beinhalten kann; APD62429PCMay include alkyl, oxygen and sulfur; APD62429PC
R48, R50, R51 unabhängig voneinander H, (d-C8)-Alkyl, Aryl; bevorzugt unabhängig voneinander H, (d-C8)-Alkyl; R84, R85 H;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;
R86 H, (d-C6)-Alkyl;R86 H, (dC 6) alkyl;
x 0, 1 , 2; bevorzugt 0, 1 ; besonders bevorzugt 1 ;x 0, 1, 2; preferably 0, 1; more preferably 1;
R10 H, (Cι-C8)-Alkyl;R 10 is H, (C 1 -C 8 ) -alkyl;
X N(R52), eine Bindung, C=C, C(R53)(R54), C(R55)(R56)O, C≡C, CH2-CH2,XN (R52), a bond, C = C, C (R53) (R54), C (R55) (R56) O, C≡C, CH 2 -CH 2,
YCH2; bevorzugt N(R52), eine Bindung, C=C, C(R53)(R54), CH2-CH2; besonders bevorzugt eine Bindung, C=C, C(R53)(R54), CH2-CH2;YCH 2 ; preferably N (R52), a bond, C = C, C (R53) (R54), CH 2 -CH 2; particularly preferably a bond, C = C, C (R53) (R54), CH 2 -CH 2;
Y O, S, N(R89);Y O, S, N (R89);
R89 H, (C1 -C8)-Alkyl;R89 is H, (C1-C8) -alkyl;
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4E 3-8 membered bivalent carbocyclic or heterocyclic ring structure with 0-4
Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(d-C6)-Alkyl, O-(d- C4)-Alkoxy-(d-C4)-alkyl, S-(d-C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, O- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen- aryl, O-(C0-C8)-Alkylen-aryl, S-Aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64), CO(R65) tragen und mono- oder bicyclisch sein kann; bevorzugt 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-3 Heteroatomen aus der Gruppe N, O und S, die optional APD62429PCHeteroatoms 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 (R65) bear and can be mono- or bicyclic; preferably 5-7 membered bivalent carbo- or heterocyclic ring structure having 0-3 heteroatoms from the group N, O and S, which is optional APD62429PC
Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-Substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O-
(d-C6)-Alkyl, S-(d-C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, O-(C0-C8)-(dC 6) -alkyl, S- (dC 6) alkyl, (CC 6) alkyl, (C 2 -C 6) -alkenyl, O- (C 0 -C 8) -
Alkylen-Aryl, S-Aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), CO(R65) tragen und mono- oder bicyclisch sein kann; besonders bevorzugt 5-7 gliedrige bivalente carbo- oder heterocyclischeAlkylene-aryl, S-aryl, N (R57) (R58), SO 2 -CH 3, N (R61) CO (R62), CO (R65) bear and can be mono- or bicyclic; more preferably 5-7 membered bivalent carbocyclic or heterocyclic
Ringstruktur mit 0-2 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3,Ring structure with 0-2 heteroatoms from the group N, O and S, which optionally have substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 ,
O-(d-C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3,O- (dC 6 ) -alkyl, (CC 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, N (R 57) (R 58), SO 2 -CH 3 ,
CO(R65) tragen kann z.B. ist E ausgewählt aus der Gruppe bestehend ausCO (R65) may carry e.g. E is selected from the group consisting of
Figure imgf000032_0001
die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(C C6)- Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3, CO(R65) tragen können;
Figure imgf000032_0001
the optional substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O- (CC 6 ) alkyl, (CC 6 ) alkyl, (C 2 -C 6 ) alkenyl , N (R57) (R58), SO 2 -CH 3, CO (R65) can carry;
bevorzugt APD62429PCprefers APD62429PC
Figure imgf000033_0001
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0002
die o die. vorstehend gena.nnxten Sxubstituen-ten trag xen kxönnen;the o the. above-mentioned substitution levels;
R57, R58, R61 , R63 unabhängig voneinander H, (d-C8)-Alkyl;R57, R58, R61, R63 independently of one another are H, (C 1 -C 8 ) -alkyl;
R62, R64, R65 unabhängig voneinander H, (d-C8)-Alkyl, Aryl; bevorzugt unabhängig voneinander H, (Cι-C8)-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 eine Bindung, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO,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, SCH2, SO2CH2; bevorzugt eine Bindung, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))V, CO, CsC, SCH2; besonders bevorzugt eine Bindung, O, OCH2, CH2O, CON(R68), (C(R69)(R70))V, CO, C^C;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; bevorzugt 1 , 2, 3; besonders bevorzugt 1 ,2;v 1, 2, 3, 4; preferably 1, 2, 3; more preferably 1, 2;
R66, R67, R68, R69, R70 unabhängig voneinander H, (d-C8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (C C8)-Alkyl, (Cι-C4)-Alkoxy-(C C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-R 11 H, (CC 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (CC 4 ) -alkyl, (C 3 -C 8 ) -alkenyl, (C 3 -C 8 ) -
Alkinyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich APD62429PCAlkynyl, 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
substituiert sein kann mit F, Cl, Br, CF3, CN, (d-C6)-Alkyl, O-(d-C8)-Alkyl, (d-C4)-Alkoxy-(CrC4)-alkyl, Hydroxy-(d-C4)-alkyl, (C0-C8)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)- Alkyl, N(R76)(R77) oder SO2CH3; bevorzugt (Cι-C8)-Alkyl, (Cι-C4)-Alkoxy-(Cι-C4)-alkyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 3 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (C C6)-Alkyl, O-(d-C8)-Alkyl, (C0-C2)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, N(R75)CO(C C6)-Alkyl, N(R76)(R77) oder SO2CH3; besonders bevorzugt (Cι-C8)-Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, ein 3 bis 10-gliedriger mono-oder bicyclischer Ring, welcher 0 bis 2 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (d-C6)-Alkyl, O-(d-C8)-Alkyl, Oxo, CO(R71), CON(R72)(R73), N(R75)CO(C C6)-Alkyl, oder SO2CH3;may be substituted with F, Cl, Br, CF 3 , CN, (dC 6 ) alkyl, O- (dC 8 ) alkyl, (dC 4 ) alkoxy (CrC 4 ) alkyl, hydroxy (dC 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; preferably (C 1 -C 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 has 0 to 3 Heteroatoms selected from the group of oxygen, nitrogen and sulfur, which ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (CC 6 ) -alkyl, O- (dC 8 ) -alkyl, ( C 0 -C aryl alkylene-2), oxo, CO (R71), CON (R72) (R73), hydroxy, N (R75) CO (CC 6) -alkyl, N (R76) (R77) or SO 2 CH 3 ; (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 among Group oxygen, nitrogen and sulfur, wherein the ring system may additionally be substituted with F, Cl, Br, CF 3 , CN, (dC 6 ) alkyl, O- (dC 8 ) alkyl, oxo, CO (R71), CON (R72) (R73), N (R75) CO (CC 6) alkyl, or SO 2 CH 3;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (d-C8)-Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(C C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; oderR72 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
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
In einer weiteren bevorzugten Ausführungsform bedeuten A, B, G und D in Formel I CH oder: APD62429PCIn a further preferred embodiment, A, B, G and D in formula I mean CH or: APD62429PC
Wenn E 1 ,4-Phenylen bedeutet, haben A, B, G und D des Weiteren bevorzugt die in der nachfolgenden Tabelle I aufgeführten Bedeutungen:If E is 1,4-phenylene, A, B, G and D furthermore preferably have the meanings given in Table I below:
Tabelle I:Table I:
A B G DA B G D
N CH CH CHN CH CH CH
CH N CH CHCH N CH CH
C-Cl N CH CHC-ClN CH CH
C-F CH C-F CHC-F CH C-F CH
CH CH C-F CHCH CH C-F CH
CH C-F CH CHCH C-F CH CH
CH CH CH CFCH CH CH CF
CH C-Br CH CHCH C-Br CH CH
CH CH C-Br CHCH CH C-Br CH
CH C-Cl CH CHCH C-Cl CH CH
CH CH C-Cl CHCH CH C-Cl CH
CH CH C-CN CH APD62429PCCH CH C-CN CH APD62429PC
CH CH CH C-CNCH CH CH C-CN
CH CH C-CH3 CHCH CH C -CH 3 CH
CH CH CH C-CH3 CH CH CH C-CH 3
CH CH C-CF3 CHCH CH C-CF 3 CH
CH CH CH C-CF3 CH CH CH C-CF 3
CH CH CH CH2OHCH CH CH CH 2 OH
CH C-F CH C-FCH C-F CH C-F
CH C-F C-F CHCH C-F C-F CH
CH CH C-F C-FCH CH C-F C-F
CH CH C-F C-ClCH CH C-F C-Cl
CH CH C-Cl C-CNCH CH C-Cl C-CN
CH C-CH3 C-Cl CHCH C-CH 3 C-Cl CH
CH N CH C-CH3 CH N CH C-CH 3
CH C-CH3 CH NCH C-CH 3 CH N
CH N C-CH3 CH APD62429PCCH N -C -CH 3 CH APD62429PC
CH CHCH CH
\_J\ _J
Wenn E
Figure imgf000037_0001
bedeutet, haben A, B, G und D des Weiteren bevorzugt die in der nachfolgenden Tabelle II aufgeführten Bedeutungen:If E
Figure imgf000037_0001
A, B, G and D furthermore preferably have the meanings listed in the following Table II:
Tabelle II:Table II:
A B G DA B G D
CH C --CCHH33 CH CHCH C - CHCH 33 CH CH
CH C C--FF CH CHCH C C - FF CH CH
CH C CHH C-CH3 CHCH C CHH C-CH 3 CH
CH C CHH C-F CHCH C CHH C-F CH
CH N CH CHCH N CH CH
CH CH CH NCH CH CH N
C-F CH C-F CHC-F CH C-F CH
Wenn E
Figure imgf000037_0002
haben A, B, G und D des Weiteren bevorzugt die in der nachfolgenden Tabelle III aufgeführten Bedeutungen: APD62429PCIf E
Figure imgf000037_0002
A, B, G and D furthermore preferably have the meanings listed in Table III below: APD62429PC
Tabelletable
A B G DA B G D
CH CH C-F CHCH CH C-F CH
CH N CH CHCH N CH CH
CH CH CH NCH CH CH N
In Tabelle IV sind weitere bevorzugte Kombinationen für E und A, B, G und D aufgeführt.Table IV lists further preferred combinations for E and A, B, G and D.
Tabelle IV:Table IV:
E A B G DE A B G D
CH C-F CH CHCH C-F CH CH
-Q-- CH CH C-F CH-Q-- CH CH C-F CH
r CH C-F CH CHr CH C-F CH CH
Figure imgf000038_0001
Figure imgf000038_0001
Figure imgf000038_0002
APD62429PC
Figure imgf000038_0002
APD62429PC
Figure imgf000039_0001
APD62429PC
Figure imgf000039_0001
APD62429PC
L CH C-F CH CHL CH C-F CH CH
Die Reste R11 , K, X und E in Formel I haben in einer besonders bevorzugten Ausführungsform eine der folgenden Bedeutungen:The radicals R11, K, X and E in formula I have, in a particularly preferred embodiment, one of the following meanings:
R11 ist bevorzugt ausgewählt aus der Gruppe bestehend aus: n-Propyl, n-Butyl, iso-Butyl, iso-Pentyl, 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-methyiphenyl,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,
Figure imgf000040_0001
Figure imgf000040_0001
K ist bevorzugt ausgewählt aus der Gruppe bestehend aus:K is preferably selected from the group consisting of:
-O-, Bindung, C≡C, CH2, CH2O, CONH, OCH2, CO, SCH2 und (CH2)2O.-O-, bond, C≡C, CH 2 , CH 2 O, CONH, OCH 2 , CO, SCH 2 and (CH 2 ) 2 O.
X ist bevorzugt ausgewählt aus der Gruppe bestehend aus Bindung, NH und CH2.X is preferably selected from the group consisting of bond, NH and CH 2 .
E ist bevorzugt ausgewählt aus der Gruppe bestehend aus: APD62429PCE is preferably selected from the group consisting of: APD62429PC
Figure imgf000041_0001
Figure imgf000041_0001
Bevorzugte Kombinationen von R11 , K, X und E sind im Folgenden aufgeführt:Preferred combinations of R11, K, X and E are listed below:
Wenn K und X jeweils eine Bindung bedeuten, haben E und R11 besonders bevorzugt die folgenden Bedeutungen:When K and X are each a bond, E and R11 particularly preferably have the following meanings:
■ Wenn E 1 ,4-Phenylen ist, ist R11 ausgewählt aus der Gruppe bestehend aus: Cyclohexyl, p-Tolyl, p-Fluorophenyl, o-Fluorophenyl, p-Methoxyphenyl, p- Chlorophenyl, o-Chlorophenyl, 2,4-Difluorophenyl, 3-Fluoro-4-methylphenyl, o- Cyanophenyl,■ When E is 1, 4-phenylene, 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,
Figure imgf000041_0002
Figure imgf000041_0002
Wenn E
Figure imgf000041_0003
ist, R11 ausgewählt aus der Gruppe bestehend aus: p-Chlorophenyl, p-Tolyl, p-Fluorophenyl, p-Methoxyphenyl, p- Trifluoromethylphenyl, o-Fluorophenyl, Phenyl und APD62429PCIf E
Figure imgf000041_0003
R11 is selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl, o-fluorophenyl, phenyl and APD62429PC
Figure imgf000042_0001
Figure imgf000042_0001
In Tabelle V sind weitere Kombinationen von E und R11 aufgeführt, für den Fall, dass K und X jeweils eine Bindung bedeuten:Table V lists other combinations of E and R11 in the case where K and X are each a bond:
Tabelle V:Table V:
R11 ER11 E
p-Chlorophenyl 1 ,4-Cyclohexylenp-Chlorophenyl 1, 4-cyclohexylene
2-Nitro-4-methylphenyl tr~Λ2-nitro-4-methylphenyl tr ~ Λ
p-Chlorophenyl Λ \p-Chlorophenyl Λ \
p-Bromophenylp-bromophenyl
— N N-- N N
p-Fluorophenyl
Figure imgf000042_0002
p-fluorophenyl
Figure imgf000042_0002
p-Chlorophenylp-chlorophenyl
-N N--N N-
Figure imgf000042_0003
APD62429PC
Figure imgf000042_0003
APD62429PC
p-Tolylp-tolyl
Figure imgf000043_0001
Figure imgf000043_0001
n-Butyl
Figure imgf000043_0002
n-butyl
Figure imgf000043_0002
p-Chlorophenylp-chlorophenyl
Figure imgf000043_0003
Figure imgf000043_0003
Figure imgf000043_0004
Figure imgf000043_0004
Figure imgf000043_0005
Figure imgf000043_0005
p-Methylthiophenyl kp-methylthiophenyl k
2-Amino-4-methylphenyl λ2-amino-4-methylphenyl
Wenn K -O- ist und X eine Bindung, NH oder CH2 bedeutet, haben E und R11 besonders bevorzugt die folgenden Bedeutungen:When K is -O- and X is a bond, NH or CH 2 , E and R 11 particularly preferably have the following meanings:
■ Wenn E 1 ,4-Phenylen ist, ist R11 ausgewählt aus der Gruppe bestehend aus: Phenyl, Cyclopentyl, n-Butyl, iso-Butyl, iso-Pentyl, 2,4-Difluorophenyl und p- Fluorophenyl. APD62429PC■ When E is 1, 4-phenylene, R11 is selected from the group consisting of phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyl and p-fluorophenyl. APD62429PC
In Tabelle VI sind weitere Kombinationen von E und R11 aufgeführt, für den Fall, dass K -O- ist und X eine Bindung, NH oder CH2 bedeutet:In Table VI, further combinations of E and R11 are listed, in the case where K is -O- and X is a bond, NH or CH 2 :
Tabelle VI:Table VI:
R11R11
Phenyl
Figure imgf000044_0001
phenyl
Figure imgf000044_0001
Cyclopentyl
Figure imgf000044_0002
cyclopentyl
Figure imgf000044_0002
Phenyl
Figure imgf000044_0003
phenyl
Figure imgf000044_0003
n-Butyln-butyl
Figure imgf000044_0004
Figure imgf000044_0004
n-Butyl
Figure imgf000044_0005
n-butyl
Figure imgf000044_0005
Wenn K C=C ist und X eine Bindung ist, haben E und R11 besonders bevorzugt die folgenden Bedeutungen:When K is C = C and X is a bond, E and R11 more preferably have the following meanings:
■ Wenn E
Figure imgf000044_0006
ist, ist R11 ausgewählt aus der Gruppe bestehend aus: Phenyl, p-Fluorophenyl und p-Chlorophenyl. APD62429PC■ If E
Figure imgf000044_0006
R11 is selected from the group consisting of: phenyl, p-fluorophenyl and p-chlorophenyl. APD62429PC
Wenn K CH2 ist und X eine Bindung ist, haben E und R11 besonders bevorzugt die folgenden in Tabelle VII angegebenen Bedeutungen:When K is CH 2 and X is a bond, E and R 11 particularly preferably have the following meanings given in Table VII:
Tabelle VII:Table VII:
R11R11
Phenyl 1 ,4-PhenylenPhenyl 1, 4-phenylene
1 ,4-Phenylen
Figure imgf000045_0001
1, 4-phenylene
Figure imgf000045_0001
p-Chlorophenyl
Figure imgf000045_0002
p-chlorophenyl
Figure imgf000045_0002
Wenn K CH2O ist und X eine Bindung ist, haben E und R11 besonders bevorzugt die folgenden Bedeutungen:When K is CH 2 O and X is a bond, E and R 11 particularly preferably have the following meanings:
■ Wenn E 1 ,4-Phenylen ist, ist R11 ausgewählt aus der Gruppe bestehend aus: Phenyl, Cyclopropyl und Cyclohexyl. ■ When E is 1, 4-phenylene, R11 is selected from the group consisting of: phenyl, cyclopropyl and cyclohexyl.
Wenn K CONH ist und X eine Bindung ist, haben E und R11 besonders bevorzugt die folgenden in Tabelle VIII angegebenen Bedeutungen:When K is CONH and X is a bond, E and R11 particularly preferably have the following meanings given in Table VIII:
Tabelle VIII: APD62429PCTable VIII: APD62429PC
R11R11
Cyclopentyl 1 ,4-PhenylenCyclopentyl 1,4-phenylene
Cyclohex-(1)-enyl 1 ,4-PhenylenCyclohex- (1) -enyl 1, 4-phenylene
Cyclopentylcyclopentyl
Figure imgf000046_0001
Figure imgf000046_0001
Wenn K OCH2 ist und X eine Bindung ist, haben E und R11 besonders bevorzugt die folgenden in Tabelle IX angegebenen Bedeutungen:When K is OCH 2 and X is a bond, E and R 11 particularly preferably have the following meanings given in Table IX:
Tabelle IX:Table IX:
R11R11
o-Chlorophenyl
Figure imgf000046_0002
o-chlorophenyl
Figure imgf000046_0002
p-Tolyl 1 ,4-Phenylenp-tolyl 1,4-phenylene
n-Propyl 1 ,4-Phenylenn-propyl 1, 4-phenylene
Cyclobutyl 1 ,4-Phenylen APD62429PCCyclobutyl 1, 4-phenylene APD62429PC
Des Weiteren sind zusätzlich zu den vorstehend genannten Kombinationen die folgenden in Tabelle X aufgeführten Kombinationen von R11 , K und E besonders bevorzugt, wobei X ganz besonders bevorzugt eine Bindung ist:Furthermore, in addition to the abovementioned combinations, the following combinations of R11, K and E listed in Table X are particularly preferred, wherein X is very particularly preferably a bond:
Tabelle X:Table X:
R11 K ER11 K E
o-Fluorophenyl CO rx^o-fluorophenyl CO rx ^
Phenyl SCH2 1 ,4-PhenylenPhenyl SCH 2 1, 4-phenylene
Cyclopropyl (CH2)2OCyclopropyl (CH 2 ) 2 O
Figure imgf000047_0001
Figure imgf000047_0001
Die Verbindungen der Formel I sind in einer ganz besonders bevorzugten Ausführungsform Verbindungen der Formel laIn a very particularly preferred embodiment, the compounds of the formula I are compounds of the formula Ia
Figure imgf000047_0002
Figure imgf000047_0002
worin die Reste R1 , R2, R10, R11 , R42, und Gruppen X, E, K die vorstehend genannten Bedeutungen aufweisen und R42' wie R42 definiert ist, wobei R42 und R42' in den Verbindungen der Formel la gleich oder verschieden sein können, oder deren N-Oxide sowie deren physiologisch verträgliche Salze. APD62429PCin 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. APD62429PC
In einer bevorzugten Ausführungsform der Erfindung weisen die Reste R1, R2, R10, R11 , R42, R42' und Gruppen X, E, K die folgenden Bedeutungen auf:In a preferred embodiment of the invention, the radicals R1, R2, R10, R11, R42, R42 'and groups X, E, K have the following meanings:
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CR78R79)0 -R12, (C1-C4)-R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR 78 R 79) 0 -R 12, (C 1 -C 4) -
Alkoxy-(d-C4)-alkyl, oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, (d-C6)-Alkyl, O-(C C4)-Alkyl, (d- C4)-Alkoxy-(d-C4)-alkyl, Hydroxy-(C C4)-alkyl, (C0-C2)-Alkylen-aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, N(R31)(R32) oder SO2CH3; wobei R1 und R2 nicht beide gleichzeitig CO(R26) sind,Alkoxy- (C 1 -C 4 ) -alkyl, or R 1 and R 2, together with the nitrogen atom to which they are attached, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, in addition to the nitrogen atom, contains 0 to 2 additional heteroatoms may be selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may additionally be substituted with F, (dC 6 ) alkyl, O- (CC 4 ) alkyl, (d- C 4 ) alkoxy (dC 4 ) -alkyl, hydroxy- (CC 4 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, N (R 31) (R 32) or SO 2 CH 3 ; where R 1 and R 2 are not both simultaneously CO (R26),
bevorzugt H, (Cι-C8)-Alkyl, -(CR78R79)0-R12, (CrC4)-Alkoxy-(d-C4)-alkyl, oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono- oder bicyclischen Ring, welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff und Stickstoff, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, (d-C6)-Alkyl, (C1-C4)-Alkoxy-(C1-C4)-alkyl, Oxo, CO(R26), Hydroxy, N(R31)(R32);preferably H, (-CC 8 ) -alkyl, - (CR78R79) O -R12, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, or 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);
o 0, 1 , 2, 3, 4, bevorzugto 0, 1, 2, 3, 4, preferably
0, 1 , 2, 3;0, 1, 2, 3;
q 1 , 2, 3, bevorzugtq 1, 2, 3, preferred
1 oder 2;1 or 2;
0, 1 , 2; APD62429PC0, 1, 2; APD62429PC
R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31 , R32 unabhängig voneinander H, (d-C6)-Alkyl; oderR15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of one another are H, (C 1 -C 6 ) -alkyl; or
R17 und R18, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann, bevorzugt ist der Ring ein Pyrrolidin-, Piperidin-, N-Methylpiperazin-, Morpholinring;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;
R12 OH, O-(d-C6)-Alkyl, O-(C0-C2)-Alkylen-aryl, CN, S-(C C6)-Alkyl, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der 1 bis 3 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, OH, CF3, CN, Oxo, (d-C6)-Alkyl, (C0-C2)- Alkylen-aryl, N(R34)(R35), COO(R40), CO(C C6)-Alkyl enthalten kann, bevorzugt OH, O-(d-C6) -Alkyl, 3-10 gliedriger mono- oder bicyclischer Ring, der 1-2 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-10 gliedrige Ring weitere Substituenten wie F, OH, Oxo, (d-C6)- Alkyl, CO(d-C6)-Alkyl enthalten kann;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, OH, oxo, (dC 6) - alkyl may include alkyl, CO (6 dC);
R34, R35 unabhängig voneinander H, (Cι-C4)-Alkyl;R34, R35 independently of one another are H, (C 1 -C 4 ) -alkyl;
R40 H, (C C6)-Alkyl, (C0-C2)-Alkylen-aryl;R 40 is H, (CC 6 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl;
R78, R79 unabhängig voneinander H, (C C8)-Alkyl, Hydroxy-(d-C4)-Alkyl, OH, (d- C4)-Alkoxy-(d-C4)-alkyl;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;
R42, R42' unabhängig voneinander H, F, Cl, Br, CF3, CN, (C C6)-Alkyl; APD62429PCR 42, R 42 'independently of one another are H, F, Cl, Br, CF 3 , CN, (CC 6 ) -alkyl; APD62429PC
R10 H, (C C8)-Alkyl;R 10 is H, (CC 8 ) -alkyl;
X N(R52), eine Bindung, C=C, C(R53)(R54), CH2CH2;XN (R52), a bond, C = C, C (R53) (R54), CH 2 CH 2;
R52, R53, R54 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54 independently of one another are H, (C 1 -C 8 ) -alkyl
E 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-3E 5-7 membered bivalent carbocyclic or heterocyclic ring structure with 0-3
Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, CF3, OH, CN, OCF3, NO2, O-(d-C6)-Alkyl, (C C6)-Alkyl, SO2-CH3, CO(R65) tragen kann;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);
bevorzugt 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-2 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe, H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(C C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3, CO(R65) tragen kann z.B. ist E ausgewählt aus der Gruppe bestehend aus preferably 5-7 membered bivalent carbo- or heterocyclic ring structure having 0-2 heteroatoms from the group N, O and S, optionally substituents from the group, H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 For example, 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
APD62429PCAPD62429PC
Figure imgf000051_0001
Figure imgf000051_0001
die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(C C6)- Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3, CO(R65) tragen können;the optional substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O- (CC 6 ) - alkyl, (dC 6 ) alkyl, (C 2 -C 6 ) alkenyl , N (R57) (R58), SO 2 -CH 3, CO (R65) can carry;
bevorzugtprefers
Figure imgf000051_0002
Figure imgf000051_0002
Figure imgf000051_0003
die optional die vorstehend genannten Substituenten tragen können;
Figure imgf000051_0003
which may optionally carry the abovementioned substituents;
R65 H, (d-C8)-Alkyl; APD62429PCR65 is H, (C 1 -C 8 ) -alkyl; APD62429PC
K eine Bindung, O, OCH2, CH2O, S, SO2, N(R66), N(R67)CO, CON(R68),K is a bond, O, OCH 2 , CH 2 O, S, SO 2, N (R66), N (R67) CO, CON (R68),
(C(R69)(R70))V, CO, C≡C, SCH2, SO2CH2; bevorzugt eine Bindung, O, OCH2, CH2O, CON(R68), (C(R69)(R70))V, besonders bevorzugt CH2l CO, C≡C;(C (R69) (R70)) v, CO, C≡C, SCH 2, SO 2 CH 2; preferably a bond, O, OCH 2 , CH 2 O, CON (R68), (C (R69) (R70)) V , more preferably CH 2l CO, C≡C;
v 1 , 2, 3, bevorzugtv 1, 2, 3, preferred
1 , 2;1, 2;
R66, R67, R68, R69, R70 unabhängig voneinander H, (d-C8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 (C C8)-Alkyl, (Cι-C4)-Alkoxy-(Cι-C4)-alkyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (C C6)-Alkyl, O-(d-C8) -Alkyl, Oxo, CO(R71), Hydroxy, N(R75)CO(Cι- C6)-Alkyl, oder SO2CH3; bevorzugt (d-C8) -Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, ein 3 bis 10- gliedriger mono- oder bicyclischer Ring, welcher 0 bis 2 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (d-C6)-Alkyl, O-(d-C8) -Alkyl, Oxo, CO(R71), CON(R72)(R73), N(R75)CO(C C6) -Alkyl, oder SO2CH3;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 (Cι- 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, Nitrogen and sulfur, where the ring system can additionally be substituted by F, Cl, Br, CF 3 , CN, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl, oxo, CO (R 71), CON (R 72) (R73), N (R75) CO (CC 6) alkyl, or SO 2 CH 3;
R71, R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (Ci-Cs) -Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8) -alkyl; or
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem APD62429PCR72 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
Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann.Nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) - alkyl, oxygen and sulfur.
In einer bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel la,In a preferred embodiment, the present invention relates to compounds of the formula Ia,
worinwherein
X CH2CH2, N(R52), CH2, OCH2, SCH2, CH=CH, bevorzugt CH2CH2, CH=CH bedeutet;X is CH 2 CH 2 , N (R 52), CH 2 , OCH 2 , SCH 2 , CH = CH, preferably CH 2 CH 2 , CH = CH;
Figure imgf000053_0001
Figure imgf000053_0001
bevorzugt
Figure imgf000053_0002
prefers
Figure imgf000053_0002
bedeutet
Figure imgf000053_0003
means
Figure imgf000053_0003
K eine Bindung, O oder C(R69)(R70) bedeutet;K is a bond, O or C (R69) (R70);
und die übrigen Symbole R1, R2, R10, R11 , R42, R42', R52, R69 und R70 die vorstehend bezüglich der Definition der Reste der Verbindung der Formel la angegebenen Bedeutungen aufweisen. APD62429PCand the remaining symbols R1, R2, R10, R11, R42, R42 ', R52, R69 and R70 have the meanings given above with regard to the definition of the radicals of the compound of the formula Ia. APD62429PC
In einer weiteren bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel laIn a further preferred embodiment, the present invention relates to compounds of the formula Ia
worinwherein
X N(R52), bevorzugt NH, oder C(R53)(R54) bedeutet;X is N (R52), preferably NH, or C (R53) (R54);
Figure imgf000054_0001
Figure imgf000054_0001
bevorzugt oder bedeutet;
Figure imgf000054_0003
Figure imgf000054_0002
Figure imgf000054_0004
preferred or meaning;
Figure imgf000054_0003
Figure imgf000054_0002
Figure imgf000054_0004
K eine Bindung, O oder C(R69)(R70), bevorzugt 0 bedeutet; bevorzugt OK is a bond, O or C (R69) (R70), preferably 0; preferably O
und die übrigen Symbole R1 , R2, R10, R11 , R42, R42',R52, R53, R54, R69 und R70 die vorstehend bezüglich der Definition der Reste der Verbindung der Formel la angegebenen Bedeutungen aufweisen.and the remaining symbols 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.
In einer weiteren besonders bevorzugten Ausführungsform sind die Verbindungen der Formel I Verbindungen der Formel IbIn a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula Ib
Figure imgf000054_0005
APD62429PC
Figure imgf000054_0005
APD62429PC
worin die Reste R1 , R2, R10 und R11 und die Gruppen E und D die vorstehend genannten Bedeutungen aufweisen oder deren N-Oxide sowie deren physiologisch verträgliche Salze.wherein the 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.
In einer bevorzugten Ausführungsform weisen die Reste R1 , R2, R10 und R11 die Gruppen E und D die folgenden Bedeutungen auf:In a preferred embodiment, the radicals R1, R2, R10 and R11 the groups E and D have the following meanings:
R1 , R2 unabhängig voneinander H, (d-C8)-Alkyl, -(CR78R79)0 -R12, (Cι-C4)-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 ) -
Alkoxy-(d-C4)-alkyl, (C3-C8)-Alkenyl, CO-(d-C8)-Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(C 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); oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (d-C6)-Alkyl, O-(d-C4)- Alkyl, (C1-C4)-Alkoxy-(C1-C4)-alkyl, Hydroxy-(d-C4)-alkyl, (C0-C2)-Alkylen- aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(C C6)-Alkyl, N(R31)(R32) oder SO2CH3, wobei R1 und R2 nicht beide gleichzeitig CO(R26) sind; bevorzugt unabhängig voneinander H, (d-C8)-Alkyl, -(CR78R79)0 -R12, (C C4)-Alkoxy-(Cι-C4)-alkyl, CO-(Cι-C8)-Alkyl, -CO- (CH2)0 -R12, COCH=CH(R13), COCC(R14),Alkoxy (dC 4) alkyl, (C 3 -C 8) -alkenyl, CO- (dC 8) -alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (CC 4) alkyl, COCH = CH (R13), COCC (R14), 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, together with the nitrogen atom to which they are attached, form a 4 to 10 membered mono-, bi- or spiro-cyclic ring which, in addition to 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 be additionally substituted with F, Cl, CF 3 , (dC 6 ) alkyl, O- (dC 4 ) alkyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) -alkyl, hydroxy- (C 1 -C 4 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, COO (R 29), N (R 30 ) CO (CC 6 ) alkyl, N (R 31) (R 32) or SO 2 CH 3 , wherein R 1 and R 2 are not both simultaneously CO (R 26); preferably independently of one another are H, (C 1 -C 8 ) -alkyl, - (C-R 7 R 7) 0 -R 12, (CC 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, CO- (C 1 -C 8 ) -alkyl, -CO- (CH 2) 0 -R12, COCH = CH (R13), COCC (R14),
CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono- oder bicyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (d-C6)-Alkyl, O-(C C4)-Alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C0-C2)- APD62429PCCO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) s O (R25); or 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
Alkylen-Aryl, Oxo, Hydroxy, N(R31)(R32) oder SO2CH3, wobei R1 und R2 nicht gleichzeitig CO-(CrC8) -Alkyl sind; besonders bevorzugt unabhängig voneinander H, (d-C8)-Alkyl, - (CR78R79)0 -R12, (d-C )-Alkoxy-(CrC4)-al yl, CO-(C C8)-Alkyl, -CO- (CH2)0 -R12, CO(C(R15)(R16))qN(R17)(R18), oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono- oder bicyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff und Stickstoff, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, (d- C6)-Alkyl, (C C4)-Alkoxy-(Cι-C4)-alkyl, Oxo, CO(C C8)-Alkyl, Hydroxy, N(R31)(R32), wobei R1 und R2 nicht beide gleichzeitig CO(d-C8) -Alkyl sind;Alkylene-aryl, oxo, hydroxy, N (R31) (R32) or SO 2 CH 3, where 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, (C 1 -C 6 ) -alkyl, (CC 4 ) -alkoxy- C 1 -C 4 ) alkyl, oxo, CO (CC 8 ) alkyl, hydroxy, N (R31) (R 32), wherein R 1 and R 2 are not both simultaneously CO (C 1 -C 8 ) alkyl;
o 0, 1 , 2, 3, 4, 5, 6; bevorzugt 0, 1 , 2, 3, 4; besonders bevorzugt 0, 1 , 2, 3;0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly preferably 0, 1, 2, 3;
q, r unabhängig voneinander 1 , 2, 3; bevorzugt ist q 1 oder 2;q, r are independently 1, 2, 3; preferably q is 1 or 2;
s 0, 1 , 2, 3, 4; bevorzugt 0, 1 , 2, 3; besonders bevorzugt 0, 1 , 2;s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 2;
R13, R14 unabhängig voneinander einen Phenylring, der 0-1 Stickstoffatome enthalten kann;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 unabhängig voneinander H, (d-C6)-Alkyl;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, (Cι-C6)-Alkyl, CO(C C6)-Alkyl, CO(R33); bevorzugt H, (Cι-C6) -Alkyl,R18 is H, (-CC 6 ) -alkyl, CO (CC 6 ) -alkyl, CO (R33); preferably H, (C 1 -C 6 ) -alkyl,
CO(d-C6)-Alkyl; besonders bevorzugt H, (d-C6)-Alkyl; oder R17 und R18, R21 und R22, R27 und R28, R31 und R32 APD62429PCCO (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
unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(C C6)- Alkyl, Sauerstoff und Schwefel beinhalten kann; bevorzugt ist der Ring Pyrrolidin, Piperidin, N-Methylpiperazin, Morpholin;independently of one another optionally together with the nitrogen atom to which they are attached, 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 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten kann und mit F, Cl, (d-C6)-Alkyl, O-(d-C8)-Alkyl substituiert sein kann;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;
R12 OH, O-(C C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(C C6)-Alkyl,R 12 is OH, O- (CC 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, S- (CC 6 ) -alkyl,
COO(R80), CON(R81)(R82), 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3, CN, Oxo, O-(d-C6) -Alkyl, (C1-C4)- Alkoxy-(d-C4)-alkyl, (d-C6) -Alkyl, O-(C0-C8)-Alkylen-Aryl, (C0-C8)-Alkylen- aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C C6)-Alkyl, COCOO(d-C6) -Alkyl, COO(R40), S(O)u (R41) enthalten kann; bevorzugt OH, O-(d-C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, 3-10 gliedriger mono-, oder bicyclischer Ring, der 1-3 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3, CN, Oxo, O-(d-C6)-Alkyl, (C1-C4)-Alkoxy-(C1-C4)- alkyl, (C C6)-Alkyl, (C0-C2)-Alkylen-aryl, N(R34)(R35), CO(C C6)-Alkyl enthalten kann; besonders bevorzugt OH, O-(d-C6)-Alkyl, 3-10 gliedriger mono-, oder bicyclischer Ring, der 1-2 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-10 gliedrige Ring weitere Substituenten wie F, OH, Oxo, (C C6)-Alkyl, CO(d-C6) -Alkyl enthalten kann;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- (C 1 -C 6 ) -alkyl, (C 1 -C 4 ) -alkoxy (C 1 -C 4 ) -alkyl, (C 1 -C 6 ) -alkyl, O- ( C 0 -C 8 ) -alkylene-aryl, (C 0 -C 8 ) -alkylene-aryl, N (R34) (R35), COCH = CH (R36), (C (R37) (R38)) t (R39 ), CO (C (R37) (R38)) t (R39) u (R41 may) contain CO (CC 6) -alkyl, COCOO (dC 6) -alkyl, COO (R40), S (O); preferably OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring containing 1-3 heteroatoms from the group N, O and S may contain and the 3-10 membered ring further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, O- (dC 6 ) alkyl, (C 1 -C 4) alkoxy (C 1 -C 4 ) -alkyl, (CC 6 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, N (R34) (R35), CO (CC 6 ) -alkyl; particularly preferably OH, O- (C 1 -C 6 ) -alkyl, 3-10 membered mono- or bicyclic ring which may contain 1-2 heteroatoms from the group N, O and S and the 3-10 membered ring further substituents such as F , OH, oxo, (CC 6 ) -alkyl, CO (dC 6 ) -alkyl may contain;
t 0, 1, 2, 3, 4, 5, 6; APD62429PCt 0, 1, 2, 3, 4, 5, 6; APD62429PC
u 0, 1 , 2; bevorzugt 0 oder 2; besonders bevorzugt 2;u 0, 1, 2; preferably 0 or 2; more preferably 2;
R34, R35, R37, R38 unabhängig voneinander H, (d-C8) -Alkyl; oderR34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(C C6)-Alkyl, Sauerstoff undR34 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
Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;Include sulfur and may optionally be substituted with 1-2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, O-(C C8)- Alkyl substituiert sein kann;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;
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-aryl;R 40 is H, (CC 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
R41 (d-C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR41 (dC 6 ) alkyl, 5-10 membered aromatic ring system, the 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, O-(d-C8) -Alkyl substituiert sein kann;Contain heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, (dC 6 ) alkyl, O- (dC 8 ) alkyl;
R78, R79 unabhängig voneinander H, (C C8)-Alkyl, Hydroxy-(d-C4)-Alkyl, OH, (d- C4)-Alkoxy-(Cι-C4)-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;
R80, R81 unabhängig voneinander H, (d-C8)-Alkyl;R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl;
R10 H, (C C8)-Alkyl; APD62429PCR 10 is H, (CC 8 ) -alkyl; APD62429PC
3-8 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(d-C6)-Alkyl, O-(d- C4)-Alkoxy-(d-C4)-alkyl, S-(C C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, O- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen- aryl, O-(C0-C8)-Alkylen-aryl, S-Aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64), CO(R65) tragen und mono- oder bicyclisch sein kann; bevorzugt 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-3 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O- (d-C6)-Alkyl, S-(d-C6)-Alkyl, (C C6)-Alkyl, (C2-Ce)-Alkenyl, O-(C0-C8)- Alkylen-Aryl, S-Aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), CO(R65) tragen und mono- oder bicyclisch sein kann; besonders bevorzugt 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-2 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(C C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3, CO(R65) tragen kann z.B. ist E ausgewählt aus der Gruppe bestehend aus 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group N, O and S, which optionally substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (dC 6) -alkyl, O- (dC 4) alkoxy- (dC 4) alkyl, S- (CC 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, (C 0 -C 8 ) -alkylene-aryl, S-aryl, N (R 57) (R 58), SO 2 -CH 3 , N (R 61) CO (R 62), N (R 63) SO 2 (R 64), CO (R65) and may be mono- or bicyclic; preferably 5-7 membered bivalent carbo- or heterocyclic ring structure having 0-3 heteroatoms from the group N, O and S, which optionally substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (dC 6 ) alkyl, S- (dC 6 ) alkyl, (CC 6 ) alkyl, (C 2 -C e ) alkenyl, O- (C 0 -C 8 ) alkylene aryl , S-aryl, N (R57) (R58), SO 2 -CH 3, N (R61) CO (R62), CO (R65) bear and can be mono- or bicyclic; particularly preferred 5-7 membered bivalent carbo- or heterocyclic ring structure having 0-2 heteroatoms from the group N, O and S, optionally substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 For example, 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
APD62429PCAPD62429PC
Figure imgf000060_0001
Figure imgf000060_0001
die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(d-C6)- Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2-CH3, CO(R65) tragen können;the optional substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O- (dC 6 ) - alkyl, (CC 6 ) alkyl, (C 2 -C 6 ) alkenyl , N (R57) (R58), SO 2 -CH 3, CO (R65) can carry;
bevorzugtprefers
Figure imgf000060_0002
Figure imgf000060_0002
Figure imgf000060_0003
die optional die vorstehend genannten Substituenten tragen können; APD62429PC
Figure imgf000060_0003
which may optionally carry the abovementioned substituents; APD62429PC
R57, R58, R61 , R63 unabhängig voneinander H, (d-C8)-Alkyl;R57, R58, R61, R63 independently of one another are H, (C 1 -C 8 ) -alkyl;
R62, R64, R65 unabhängig voneinander H, (d-C8) -Alkyl, Aryl; bevorzugt unabhängig voneinander H, (d-C8)-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 eine Bindung, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO,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, SCH2, SO2CH2; bevorzugt eine Bindung, O, OCH2, CH2O, N(R66), CON(R68), (C(R69)(R70))V, CO, C≡C, SCH2; besonders bevorzugt eine Bindung, O, OCH2, CH2O, CON(R68), (C(R69)(R70))V, CO, CsC;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; bevorzugt 1 , 2, 3; besonders bevorzugt 1 ,2;v 1, 2, 3, 4; preferably 1, 2, 3; more preferably 1, 2;
R66, R67, R68, R69, R70 unabhängig voneinander H, (C C8)-Alkyl;R66, R67, R68, R69, R70 are independently H, (CC 8) alkyl;
R11 H, (Cι-C8) -Alkyl, (d-C4)-Alkoxy-(C C4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-R11 H, (Cι-C8) alkyl, (dC 4) alkoxy- (CC 4) alkyl, (C 3 -C 8) -alkenyl, (C 3 -C 8) -
Alkinyl, ein 3 bis 10-gliedriger mono-, bi-; tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (d-C6)-Alkyl, O-(Cι-C8)-Alkyl, (Cι-C4)-Alkoxy-(Cι-C4)-alkyl, Hydroxy-(Cι-C4)-alkyl, (C0-C8)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)- Alkyl, N(R76)(R77) oder SO2CH3SCF3; bevorzugt (C C8) -Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 3 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und APD62429PCAlkynyl, 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- (Cι-C8) alkyl, (Cι-C4) alkoxy- (Cι-C4) alkyl, hydroxy (Cι-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 -C 4 ) -alkyl, a 3 to 10-membered mono-, bi-, tri- or spiro-cyclic ring which may contain 0 to 3 heteroatoms, selected from the group oxygen, nitrogen and APD62429PC
Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (Cι-C6)-Alkyl, O-(d-C8)-Alkyl, (C0-C2)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, N(R75)CO(C C6)-Alkyl, N(R76)(R77) oder SO2CH3; besonders bevorzugt (Cι-C8)-Alkyl, (CrC4)-Alkoxy-(CrC4)-alkyl, ein 3 bis 10-gliedriger mono-oder bicyclischer Ring, welcher 0 bis 2 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (d-C6)-Alkyl, O-(C C8)-Alkyl, Oxo, CO(R71), CON(R72)(R73), N(R75)CO(d-C6)-Alkyl, oder SO2CH3;Sulfur, where the 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, oxo, CO (R71), CON (R72 ) (R73), N (R75) CO (dC 6) alkyl, or SO 2 CH 3;
R71, R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (Cι-C8)-Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann.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.
In einer bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel IbIn a preferred embodiment, the present invention relates to compounds of formula Ib
worinwherein
X eine Bindung bedeutet, APD62429PCX means a bond APD62429PC
Figure imgf000063_0001
Figure imgf000063_0001
oder bedeutet, wobei
Figure imgf000063_0002
Figure imgf000063_0003
or means, where
Figure imgf000063_0002
Figure imgf000063_0003
die vorstehend genannten Gruppen optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(Cι-C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2- CH3, CO(R65) tragen können; bevorzugt bedeutet E 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
APD62429PCAPD62429PC
Figure imgf000064_0001
Figure imgf000064_0001
Figure imgf000064_0002
worin die Gruppen die vorstehend genannten Substituenten tragen können;
Figure imgf000064_0002
wherein the groups may carry the abovementioned substituents;
K eine Bindung bedeutet; undK means a bond; and
die übrigen Reste R1 , R2, R10 und R11 und die Gruppe D die vorstehend bezüglich der Definition der Reste der Verbindung der Formel Ib angegebenen Bedeutungen aufweisen.the remaining radicals R1, R2, R10 and R11 and the group D have the meanings given above with regard to the definition of the radicals of the compound of the formula Ib.
Besonders bevorzugt ist R11 in den vorstehend genannten Verbindungen der Formel Ib ein substituiertes mono- oder bicyclisches Ringsystem mit 5-10 Gliedern, das 0-3 Heteroatome, insbesondere N, O und/oder S, aufweisen kann, besonders bevorzugt Phenyl mit 0-1 N-Atom, Cyclohexyl oder ein bicyclisches System mit 8-10 Gliedern und 1-2 Heteroatomen, insbesondere N, O und/oder S.Particularly preferably 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.
In einer weiteren bevorzugten Ausführungsform betrifft die vorliegende Erfindung Verbindungen der Formel IbIn a further preferred embodiment, the present invention relates to compounds of the formula Ib
worinwherein
X eine Bindung bedeutet; APD62429PCX represents a bond; APD62429PC
Figure imgf000065_0001
Figure imgf000065_0001
Figure imgf000065_0002
Xr bedeutet,
Figure imgf000065_0002
Xr means
wobei die vorstehend genannten Gruppen optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(d-C6) -Alkyl, (C C6) -Alkyl, (C2-C6)-Alkenyl, N(R57)(R58), SO2CH3 und CO(R65) tragen können;wherein the abovementioned groups optionally contain substituents from the group H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O- (dC 6 ) -alkyl, (CC 6 ) -alkyl, (C 2 -C , N (R57) (R58), SO 2 CH 3, and CO (R65 can wear) 6) alkenyl;
bevorzugtprefers
Figure imgf000065_0003
Figure imgf000065_0003
worin die Gruppen die vorstehend genannten Substituenten tragen können;wherein the groups may carry the abovementioned substituents;
K CH2, CH2CH2, O, CH2O, OCH2, CON(R68), N(R67)CO, S, SO2, SCH2, SO2, SO2CH2, CO oder eine Dreifachbindung; bevorzugt CH2, O, CH2O, OCH2, CON(R68), SCH2, CO oder eine Dreifachbindung; undK 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
die übrigen Reste R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R67 und R68 und die Gruppe D die vorstehend bezüglich der Definition der Reste der Verbindung der Formel Ib angegebenen Bedeutungen aufweisen. APD62429PCthe remaining radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 and R68 and the group D have the meanings given above with regard to the definition of the radicals of the compound of formula Ib. APD62429PC
Die Menge einer Verbindung gemäß Formel (I), die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z.B. der gewählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg bis 50 mg) pro Tag pro Kilogramm Körpergewicht, z.B. 3-10 mg/kg/Tag. Eine intravenöse Dosis kann z.B. im Bereich von 0,3 mg bis 1 ,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. Geeignete Infusionslösungen für diese Zwecke können z.B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z.B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Ampullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisformulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1 ,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Im Falle pharmazeutisch verträglicher Salze beziehen sich die vorgenannten Gewichtsangaben auf das Gewicht der dem Salz zugrunde liegenden freien Verbindung. Zur Prophylaxe oder Therapie der oben genannten Zustände können die Verbindungen gemäß Formel (I) selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muss natürlich verträglich sein, in dem Sinne, dass er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel (I). Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesentlichen darin bestehen, dass die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen gemischt werden. APD62429PCThe 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 , Generally, 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. For example, 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. Thus, for example, from 1 mg to 100 mg, 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. In the case of pharmaceutically acceptable salts, the abovementioned weights are based on the weight of the free compound on which the salt is based. For the prophylaxis or therapy of the abovementioned conditions, 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
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z.B. sublinguale) und parenterale (z.B. subkutane, intramuskuläre, intradermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel (I) abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Polyvinylacetatphthalat, Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Pharmaceutical 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. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung gemäß Formel (I) enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wässrigen oder nicht-wässrigen Flüssigkeit; oder als eine Öl-in-Wasser- oder Wasser-in Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfasst, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allgemeinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpresst oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepresste Tabletten können durch Tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem APD62429PCSuitable 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. As already mentioned, 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). In general, 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. For example, 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
inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.inert liquid diluent moistened compound can be prepared in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel (I) mit einem Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.Pharmaceutical 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.
Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wässrige Zubereitungen einer Verbindung gemäß Formel (I), die vorzugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. Diese Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich die Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann. Diese Zubereitungen können vorzugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die erhaltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungsgemäße Zusammensetzungen enthalten im allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.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.
Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vorzugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel (I) mit einem oder mehreren herkömmlichen festen Trägern, beispielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt.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.
Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglycole, Alkohole und Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der Wirkstoff ist im allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%. APD62429PCSuitable 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
Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammensetzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wässrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine geeignete Wirkstoff-Konzentration beträgt ca. 1% bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondere Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder lontophorese freigesetzt werden.Transdermal administration is also possible. 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%. As a particular possibility, the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
Die Verbindungen der Formel I zeichnen sich durch günstige Wirkungen auf den Fettstoffwechsel aus, insbesondere sind sie zur Gewichtsreduktion und nach erfolgter Gewichtsreduktion zum Erhalt eines reduzierten Gewichtes bei Säugetieren und als Anorektika geeignet. Die Verbindungen zeichnen sich durch ihre geringe Toxizität und ihre geringen Nebenwirkungen aus.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.
Die Verbindungen können allein oder in Kombination mit weiteren gewichtsreduzierenden oder anorektischen Wirkstoffen eingesetzt werden. Solche weiteren anorektischen Wirkstoffe werden z.B. in der Roten Liste, Kapitel 01 unter Abmagerungsmittel/Appetitzügier genannt und können auch solche Wirkstoffe beinhalten, die den Energieumsatz des Organismus erhöhen und damit zu einer Gewichtsreduktion führen oder auch solche, welche den allgemeinen Metabolismus des Organismus so beeinflussen, dass eine erhöhte Kalorienzufuhr nicht zu einer Vergrößerung der Fettdepots und eine normale Kalorienzufuhr zu einer Verringerung der Fettdepots des Organismus führt. Die Verbindungen eignen sich zur Prophylaxe sowie insbesondere zur Behandlung von Übergewicht oder Obesitas. Die Verbindungen eignen sich weiterhin zur Prophylaxe sowie insbesondere zur Behandlung von Typ II Diabetes, der Arteriosklerose sowie zur Normalisierung des Lipidstoffwechsels und zur Behandlung des Bluthochdrucks. Die Verbindungen wirken als MCH Antagonisten und eignen sich auch zur Behandlung von Störungen des Empfindens und anderer APD62429PCThe 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
psychiatrischen Indikationen, wie zum Beispiel Depressionen, Angstzuständen, Angstneurosen, Schizophrenie sowie zur Behandlung von Störungen assoziiert mit dem zirkadianen Rhythmus und zur Behandlung von Drogenmissbrauch.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.
Bei einem weiteren Aspekt der Erfindung können die Verbindungen der Formel I in Kombination mit einer oder mehreren weiteren pharmakologisch wirksamen Substanzen verabreicht werden, die beispielsweise ausgewählt sind aus Antidiabetika, Antiadiposita, blutdrucksenkenden Wirkstoffen, Lipidsenkern und Wirkstoffen zur Behandlung und/oder Prävention von Komplikationen, die von Diabetes verursacht werden oder mit Diabetes assoziiert sind.In a further aspect of the invention, 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.
Als weitere pharmakologisch wirksame Substanzen sind insbesondere geeignet:As further pharmacologically active substances are particularly suitable:
Alle Antidiabetika, die in der Roten Liste 2001 , Kapitel 12 genannt sind. Sie können mit den erfindungsgemäßen Verbindungen der Formel I insbesondere zur synergistischen Wirkungsverbesserung kombiniert werden. Die Verabreichung der Wirkstoffkombination kann entweder durch getrennte Gabe der Wirkstoffe an den Patienten oder in Form von Kombinationspräparaten, worin mehrere Wirkstoffe in einer pharmazeutischen Zubereitung vorliegen, erfolgen. Die meisten der nachfolgend aufgeführten Wirkstoffe sind in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001 , offenbart.All antidiabetic medicines mentioned in the Red List 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention in particular for the synergistic effect improvement. The administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
Geeignete Antidiabetika umfassen Insulin und Insulinderivate, wie z.B. Lantus® oder HMR 1964, schnell wirkende Insuline (siehe US 6,221 ,633), Amylin, GLP-1- und GLP-2- Derivate wie z.B. diejenigen die in WO 98/08871 von Novo Nordisk A/S offenbart wurden, sowie oral wirksame hypoglykämische Wirkstoffe.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.
Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweise Sulphonylhamstoffe, Biguanidine, Meglitinide, Oxadiazolidindione, Thiazolidindione, Glukosidase-Inhibitoren, Glukagon-Rezeptor-Antagonisten, GLP-1 -Agonisten, APD62429PCThe orally active hypoglycemic agents preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, APD62429PC
Kaliumkanalöffner wie z.B. diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden, Insulin-Sensitizer, Aktivatoren der Insulin Rezeptor Kinase, Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind, z.B. Inhibitoren der Glycogenphosphorylase, Modulatoren der Glukoseaufnahme und Glukoseausscheidung, den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe, z.B. HMGCoA-Reduktase-lnhibitoren, Inhibitoren des Cholesteroltransports/der Cholesterolaufnahme, Inhibitoren der Gallensäurerückresorption oder Inhibitoren des mikrosomalen Triglycerid-Transfer Proteins (MTP), Verbindungen, die die Nahrungsmitteleinnahme verringern, PPAR- und RXR-Agonisten und Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal der Betazellen wirken.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.
Bei einer Ausführungsform der Erfindung werden die vorliegenden Verbindungen in Kombination mit Insulin verabreicht.In one embodiment of the invention, the present compounds are administered in combination with insulin.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem HMGCoA-Reduktase Inhibitor wie Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Cerivastatin, Rosuvastatin verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Cholesterinresorptionsinhibitor, wie z.B. Ezetimibe, Tiqueside, Pamaqueside, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel l in Kombination mit einem PPAR gamma Agonist, wie z.B. Rosiglitazon, Pioglitazon, JTT- 501 , Gl 262570, verabreicht.In one embodiment of the invention, the compounds of formula I in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit PPAR alpha Agonist, wie z.B. GW 9578, GW 7647, verabreicht. APD62429PCIn one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647. APD62429PC
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem gemischten PPAR alpha/gamma Agonisten, wie z.B. GW 1536, AVE 8042, AVE 8134, AVE 0847, oder wie in PCT/US 11833, PCT/US 11490, DE10142734.4 beschrieben verabreicht.In one embodiment of the invention, 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.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Fibrat, wie z.B. Fenofibrat, Clofibrat, Bezafibrat, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem MTP-Inhibitor, wie z.B. Implitapide , BMS-201038, R-103757, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit Gallensäureresorptionsinhibitor (siehe z.B. US 6,245,744 oder US 6,221 ,897), wie z.B. HMR 1741 , verabreicht.In one embodiment of the invention, 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.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem CETP-Inhibitor, wie z.B. JTT-705 , verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem polymeren Gallensäureadsorber, wie z.B. Cholestyramin, Colesevelam, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem LDL-Rezeptorinducer (siehe US 6,342,512), wie z.B. HMR1171 , HMR1586, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ACAT-Inhibitor, wie z.B. Avasimibe, verabreicht. APD62429PCIn one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as avasimibe. APD62429PC
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Antioxidans, wie z.B. OPC-14117, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with an antioxidant, e.g. OPC-14117 administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein-Lipase Inhibitor, wie z.B. NO-1886, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a lipoprotein lipase inhibitor, e.g. NO-1886, administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ATP-Citrat-Lyase Inhibitor, wie z.B. SB-204990, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Squalen Synthetase Inhibitor, wie z.B. BMS-188494, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein(a) antagonist, wie z.B. CI-1027 oder Nicotinsäure, verabreicht.In one embodiment of the invention, the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipase Inhibitor, wie z.B. Orlistat, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit Insulin verabreicht.In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Sulphonylharnstoff, wie z.B. Tolbutamid, Glibenclamid, Glipizid oder Glimepirid verabreicht.In one embodiment, the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Biguanid, wie z.B. Metformin, verabreicht.In one embodiment, the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
Bei wieder einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Meglitinid, wie z.B. Repaglinid, verabreicht. APD62429PCIn yet another embodiment, the compounds of formula I are administered in combination with a meglitinide, such as repaglinide. APD62429PC
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Thiazolidindion, wie z.B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[[4-[(3,4-Dihydro-3-methyl-4-oxo-2-chinazolinylmethoxy]phenyl]methyl]- 2,4-thiazolidindion, verabreicht.In one embodiment, 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.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem α-Glukosidase-lnhibitor, wie z.B. Miglitol oder Acarbose, verabreicht.In one embodiment, the compounds of formula I are used in combination with an α-glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Wirkstoff verabreicht, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, wie z.B. Tolbutamid, Glibenclamid, Glipizid, Glimepirid oder Repaglinid.In one embodiment, 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.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z.B. in Kombination mit einem Sulphonylharnstoff und Metformin, einem Sulphonylharnstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulphonylharnstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht.In one embodiment, 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.
Weiterhin können die erfindungsgemäßen Verbindungen in Kombination mit einem oder mehreren Antiadiposita oder appetitregulierenden Wirkstoffen verabreicht werden.Furthermore, the compounds according to the invention can be administered in combination with one or more antiadipositas or appetite regulating active ingredients.
Bei einer weiteren Ausführungsform werden die Verbindungen der Formel I in Kombination mit CART-Modulatoren (siehe "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolie Research (2001), 33(9), 554-558), NPY-Antagonisten z.B. Naphthalin-1-sulfonsäure {4-[(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}- amid; hydrochlorid (CGP 71683A)), MC4-Agonisten (z.B. 1-Amino-1 ,2,3,4-tetrahydro- naphthalin-2-carbonsäure [2-(3a-benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro- pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chloro-phenyl)-2-oxo-ethyl]- amid; (WO 01/91752)) , Orexin-Antagonisten (z.B. 1-(2-Methyl-benzoxazol-6-yl)-3-[1 ,5]naphthyridin-4-yl- hamstoff; hydrochloride (SB-334867-A)), H3-Agonisten (3-Cyclohexyl-1-(4,4-dimethyl- APD62429PCIn a further embodiment, 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-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752 )), Orexin antagonists (eg, 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-yl-urea; hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1- (4,4-dimethyl- APD62429PC
1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-1- on Oxalsäuresalz (WO 00 / 63208)); TNF-Agonisten, CRF-Antagonisten (z.B. [2-Methyl-9-(2,4,6-trimethyl-phenyl)- 9H-1 ,3,9-triaza-fluoren-4-yl]-dipropyl-amin (WO 00/66585)), CRF BP-Antagonisten (z.B. Urocortin), Urocortin-Agonisten, ß3-Agonisten (z.B. 1-(4-Chloro-3- methanesulfonylmethyl-phenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)- ethylamino]- ethanol; hydrochloride (WO 01/83451)), MSH (Melanocyt-stimulierendes Hormon)- Agonisten, CCK-A Agonisten (z.B. {2-[4-(4-Chloro-2,5-dimethoxy-phenyl)-5-(2- cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl]-5,7- dimethyl-indol-1 -yl}-acetic acid Trifluoressigsäuresalz (WO 99/15525)); Serotonin-Wiederaufnahme-Inhibitoren (z.B. Dexfenfluramine), gemischte Sertonin- und noradrenerge Verbindungen (z.B. WO 00/71549), 5HT-Agonisten z.B. 1-(3-Ethyl-benzofuran-7-yl)-piperazin Oxalsäuresalz (WO 01/09111), Bombesin-Agonisten, Galanin-Antagonisten, Wachstumshormon (z.B. humanes Wachstumshormon), Wachstumshormon freisetzende Verbindungen (6- Benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester (WO 01/85695)), TRH-Agonisten (siehe z.B. EP 0462 884) entkoppelnde Protein 2- oder 3-Modulatoren, Leptinagonisten (siehe z.B. Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881),1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propane-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (eg, [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, β3 agonists (eg 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl- 1H-indol-6-yloxy) -ethylamino] -ethanol; hydrochloride (WO 01/83451)), MSH (melanocyte stimulating hormone) agonists, CCK-A agonists (eg, {2- [4- (4-chloro) 2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indole-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)); Serotonin reuptake inhibitors (e.g., dexfenfluramines), mixed sertonine and noradrenergic compounds (e.g., WO 00/71549), 5HT agonists, e.g. 1- (3-ethylbenzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2 -diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see eg EP 0462 884) decoupling protein 2- or 3-modulators Leptin agonists (see eg Lee, Daniel W., Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity.) Drugs of the Future (2001), 26 (9) , 873-881),
DA-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase- Inhibitoren (z.B. WO 00/40569), PPAR-Modulatoren (z.B. WO 00/78312), RXR-Modulatoren oder TR-ß- Agonisten verabreicht.DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (e.g., WO 00/40569), PPAR modulators (e.g., WO 00/78312), RXR modulators, or TR-β agonists.
Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff Leptin; siehe z.B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez- Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.In one embodiment of the invention, 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.
Bei einer Ausführungsform ist der weitere Wirkstoff Dexamphatamin oder Amphetamin.In one embodiment, the further active ingredient is dexamphatamine or amphetamine.
Bei einer Ausführungsform ist der weitere Wirkstoff Fenfluramin oder Dexfenfluramin. APD62429PCIn one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. APD62429PC
Bei noch einer Ausführungsform ist der weitere Wirkstoff Sibutramin oder die mono- und bisdemethylierten Wirkmetabolite von Sibutramin.In yet another embodiment, the other active ingredient is sibutramine or the mono- and bis-demethylated active metabolites of sibutramine.
Bei einer Ausführungsform ist der weitere Wirkstoff Orlistat.In one embodiment, the other active ingredient is orlistat.
Bei einer Ausführungsform ist der weitere Wirkstoff Mazindol oder Phentermin.In one embodiment, the other active ingredient is mazindol or phentermine.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit Ballaststoffen, vorzugsweise unlöslichen Ballaststoffen (siehe z.B. Carob/ Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax ist ein Carob enthaltendes Produkt der Fa. Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) verabreicht. Die Kombination mit Caromax® kann in einer Zubereitung erfolgen, oder durch getrennte Gabe von Verbindungen der Formel I und Caromax®. Caromax® kann dabei auch in Form von Lebensmitteln, wie z.B. in Backwaren oder Müsliriegeln, verabreicht werden. In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6.) Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 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.
APD62429PCAPD62429PC
Figure imgf000077_0001
Figure imgf000077_0001
JTT-501 APD62429PCJTT-501 APD62429PC
Weiterhin können die vorliegenden Verbindungen in Kombination mit einem oder mehreren antihypertensiven Wirkstoffen verabreicht werden. Beispiele für antihypertensive Wirkstoffe sind Betabiocker wie Alprenolol, Atenol, Timolol, Pindolol, Propanolol und Metoprolol, ACE (Angiotensin Converting Enzym)-Hemmer wie z.B. Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Quinapril und Rampril, Calciumkanal-Blocker wie Nifedipin, Felodipin, Nicardipin, Isradipin, Nimodipin, Diltiazem und Verapamil, sowie Alphablocker wie Doxazosin, Urapidil, Prazosin und Terazosin. Weiterhin kann verwiesen werden auf Remington: The Science and Practice of Pharmacy, 19. Auflage, Gennaro, Hrsg., Mack Publishing Co., Easton, PA, 1995.Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are beta blockers such as alprenolol, atenol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as e.g. Benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, as well as alpha-blockers such as doxazosin, urapidil, prazosin and terazosin. Further, reference may be made to Remington: The Science and Practice of Pharmacy, 19th Ed., Gennaro, eds., Mack Publishing Co., Easton, PA, 1995.
Es versteht sich, dass jede geeignete Kombination der erfindungsgemäßen Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird.It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.
BeispieleExamples
Die Wirksamkeit der Verbindungen wurde wie folgt getestet:The effectiveness of the compounds was tested as follows:
Biologisches Prüfmodell:Biological test model:
Die Prüfung der anorektischen Wirkung erfolgte an weiblichen NMRI Mäusen. Nach 17stündigem Futterentzug wurde über eine Schlundsonde das Testpräparat verabreicht. In Einzelhaltung und bei freiem Zugang zu Trinkwasser wurde den Tieren 30 Minuten nach Präparatgabe Kondensmilch angeboten. Der Kondensmilchverbrauch wurde halbstündlich' 7 Stunden lang bestimmt und das Allgemeinbefinden der Tiere beobachtet. Der gemessene Milchverbrauch wurde mit den Vehikel-behandelten Kontrolltieren verglichen. APD62429PCThe 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
Tabelle 1 : Anorektische Wirkung, gemessen als Reduktion des kumulierten Milchkonsums behandelter im Vergleich zu Kontrolltieren.Table 1: Anorectic effect, measured as a reduction of cumulated milk consumption treated compared to control animals.
Figure imgf000079_0001
Figure imgf000079_0001
VERSUCHSBESCHREIBUNGEXPERIMENTAL DESCRIPTION
Funktionelle Messungen zur Ermittlung von IC50-WertenFunctional measurements to determine IC50 values
Die Klonierung der cDNA für den humanen MCH-Rezeptor, Herstellung einer rekombinanten HEK293-Zellinie, welche den humanen MCH-Rezeptor exprimiert, sowie funktioneile Messungen mit der rekombinanten Zellinie erfolgten sinngemäß wie von Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001) beschrieben. Im Unterschied zur Literaturstelle wurde jedoch für die Konstruktion des Expressionsvektors das Plasmid pEAK8 der Fa. EDGE Biosystems (USA) verwendet. Als Wirt für die Transfektion diente APD62429PCThe cloning of the cDNA for the human MCH receptor, production of a recombinant HEK293 cell line expressing the human MCH receptor and functional measurements with the recombinant cell line were carried out analogously as described by Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). In contrast to the reference, however, the plasmid pEAK8 from EDGE Biosystems (USA) was used for the construction of the expression vector. Served as host for the transfection APD62429PC
eine transformierte HEK-Zellinie namens „PEAK Stable Cells" (ebenfalls von EDGE Biosystems). Die funktionellen Messungen des zellulären Calciumflusses nach Agonistenzugabe (MCH) in Gegenwart von erfindungsgemäßem Ligand erfolgten mit Hilfe des FLIPR-Gerätes der Fa. Molecular Devices (USA), unter Verwendung von Vorschriften des Geräteherstellers.a transformed HEK cell line named "PEAK stable cells" (likewise from EDGE Biosystems) The functional measurements of the cellular calcium flux after agonist addition (MCH) in the presence of ligand according to the invention were carried out with the aid of the FLIPR device from Molecular Devices (USA), using regulations of the equipment manufacturer.
Die nachfolgend aufgeführten Beispiele und Herstellungsmethoden dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken.The following examples and preparation methods serve to illustrate the invention, but without limiting it.
Die erfindungsgemäßen Verbindungen der Formel I können mit Hilfe von im Prinzip bekannten Reaktionen hergestellt werden. Beispielsweise wurden die Verbindungen nach folgenden allgemeinen Reaktionsschemata erhalten. The compounds of the formula I according to the invention can be prepared by means of reactions known in principle. For example, the compounds were obtained according to the following general reaction schemes.
APD62429PCAPD62429PC
NR-,^
Figure imgf000081_0001
NR -, ^
Figure imgf000081_0001
R1 = H Alkyl-X, NaHR1 = H alkylX, NaH
Methode F R1 = Alkyl
Figure imgf000081_0002
(für R2 = Ac, Boc)Method F R1 = alkyl
Figure imgf000081_0002
(for R2 = Ac, Boc)
DD
GG
Figure imgf000081_0003
Figure imgf000081_0003
Andere erfindungsgemäße Verbindungen können auf weiteren Wegen erhalten werden, die im folgenden Schema beispielhaft skizziert sind. APD62429PCOther compounds of the invention can be obtained in other ways, which are outlined by way of example in the following scheme. APD62429PC
(L = Linker)(L = linker)
Figure imgf000082_0001
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000082_0002
Figure imgf000082_0003
Figure imgf000082_0003
APD62429PC APD62429PC
Wieder andere Beispiele wurden erhalten wie im folgenden Schema angedeutet.Still other examples were obtained as indicated in the following scheme.
Figure imgf000083_0001
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0002
(M = Metall(M = metal
Nu- = Nukleophil)Nu- = nucleophile)
Figure imgf000083_0003
Figure imgf000083_0003
Beschreibungen der verwendeten allgemeinen Methoden finden sich exemplarisch an folgenden Stellen beschrieben:Descriptions of the general methods used are described by way of example in the following places:
Methode A, B und C im Beispiel 1 ;Method A, B and C in Example 1;
Methode D im Beispiel 2; APD62429PCMethod D in Example 2; APD62429PC
Methode E im Beispiel 3;Method E in Example 3;
Methode E-a im Beispiel 275;Method E-a in Example 275;
Methode E-b im Beispiel 286;Method E-b in Example 286;
Methode F im Beispiel 4;Method F in Example 4;
Methode F-a im Beispiel 264;Method F-a in Example 264;
Methode G im Beispiel 15;Method G in Example 15;
Methode H im Beispiel 237;Method H in Example 237;
Methode H-a im Beispiel 298;Method H-a in Example 298;
Methode I im Beispiel 238;Method I in Example 238;
Methode J im Beispiel 245;Method J in Example 245;
Methode J-a im Beispiel 297;Method J-a in Example 297;
Methode K im Beispiel 250;Method K in Example 250;
Methode L im Beispiel 254;Method L in Example 254;
Methode M im Beispiel 274;Method M in Example 274;
Methode N im Beispiel 277;Method N in Example 277;
Methode O im Beispiel 279;Method O in Example 279;
Methode O-a im Beispiel 292;Method O-a in Example 292;
Methode O-b im Beispiel 280;Method O-b in Example 280;
Methode P im Beispiel 285; APD62429PCMethod P in Example 285; APD62429PC
Methode Q im Beispiel 290;Method Q in Example 290;
Methode R im Beispiel 309.Method R in Example 309.
Allgemeine ErläuterungenGeneral explanations
a) Zeichenweise der Strukturformelna) Signs of the structural formulas
In den Strukturformeln der gegebenen Beispiele sind zur Übersichtlichkeit nur Nicht- Wasserstoffatome dargestellt.In the structural formulas of the examples given, only non-hydrogen atoms are shown for clarity.
In den Tabellen 6-13 sind enantiomerenangereicherte Verbindungen durch ein ausgezeichnetes Wasserstoffatom am stereogenen Zentrum gekennzeichnet. Falls nicht ausdrücklich anders vermerkt, sind die gezeigten enantiomerenangereicherten Beispiele am 3-Amino-pyrrolidin-Stereozentrum (R)-konfiguriert.In Tables 6-13, 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.
b) Salzformenb) salt forms
Viele der erfindungsgemäßen Verbindungen sind Basen und können mit entsprechend starken Säuren Salze bilden. Insbesondere können die Verbindungen nach HPLC- chromatograpischer Reinigung unter Verwendung eines Trifluoressigsaure enthaltenden Laufmittels als Hydrotrifluoraceatate vorliegen. Diese können durch einfaches Behandeln einer Lösung der Salze z. B. mit Natriumcarbonatlösung in die gezeigten freien Basen überführt werden.Many of the compounds according to the invention are bases and can form salts with correspondingly strong acids. In particular, 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.
c) Einheiten der Charakterisierungsdatenc) units of characterization data
Die Einheit der angegebenen Molekulargewichte ist „g/mol". Beobachtete Peaks im Massenspektrum sind angegeben als ganzzahliger Quotient der molaren Molekülionmasse und der Ladung des Molekülions (m/z).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).
Beispiel 1 APD62429PCexample 1 APD62429PC
N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamidN-methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide
Figure imgf000086_0001
Figure imgf000086_0001
Methode AMethod A
Zu einer auf 0 °C gekühlten Lösung von Carbonyldiimidazol (2,92 g) in DMF (12 mL) wurde eine Lösung von 4-Phenoxy-anilin (3,33 g) in DMF (10 mL) getropft. Nach 30 Minuten wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid (3,80 g) in DMF (10 mL) zugetropft. Die Reaktionslösung wurde zunächst für 2 Stunden bei Raumtemperatur und dann für 30 Minuten bei 80°C gehalten. Die Mischung wurde in Wasser (600 mL) eingetropft und der entstandene Niederschlag abgesaugt und mit Wasser gewaschen. Alternativ kann das Produkt auch mit Ethylacetat extrahiert und nach dem Einengen durch Chromatographie gereinigt werden. Man erhielt so das Produkt mit dem Molekulargewicht 444,54 (C26H28N4O3); MS (ESI): 445 (M+H+).To a cooled solution of carbonyldiimidazole (2.92 g) in DMF (12 mL) was added dropwise a solution of 4-phenoxy-aniline (3.33 g) in DMF (10 mL). After 30 minutes, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide (3.80 g) in DMF (10 mL) was added dropwise. The reaction solution was first kept at room temperature for 2 hours and then at 80 ° C for 30 minutes. The mixture was dripped into water (600 ml) and the resulting precipitate was filtered off with suction and washed with water. Alternatively, 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 +).
N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid Methode BN- [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide Method B
Eine Suspension von N-Methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid (3,5 g) und Palladium(ll)hydroxid (20%ig auf Kohle; 0,9 g) in Ethanol (150 mL) und Ethylacetat (300 mL) wurde unter Wasserstoffatmosphäre (Normaldruck) für 3 Stunden heftig gerührt. Dann wurde der Katalysator durch Filtration entfernt und das Filtrat eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 233,32 (C13H19N3O); MS (ESI): 234 (M+H+).A suspension of N-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide (3.5 g) and palladium (II) hydroxide (20% on charcoal, 0.9 g) in ethanol (150 mL) and ethyl acetate (300 mL) was stirred vigorously under hydrogen atmosphere (atmospheric pressure) for 3 hours. Then the catalyst was removed by filtration and the filtrate was concentrated. This gave the product with the molecular weight 233.32 (C13H19N3O); MS (ESI): 234 (M + H +).
N-Methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid Methode C APD62429PCN-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide Method C APD62429PC
Eine Suspension von N-Methyl-N-pyrrolidin-3-yl-acetamid (25,2 g) und Caesiumcarbonat (57,6 g) in DMF (300 mL) wurde langsam mit 4-Fluor-nitrobenzol (25,0 g) versetzt. Nach 2 Stunden wurde die Reaktionsmischung auf Wasser gegossen und der entstandene Niederschlag abgesaugt. Alternativ kann das Produkt auch mit Ethylacetat extrahiert und nach dem Einengen durch Chromatographie gereinigt werden. Man erhielt so das Produkt mit dem Molekulargewicht 263,30 (C13H17N3O3); MS (ESI): 264 (M+H+).A suspension of N-methyl-N-pyrrolidin-3-yl-acetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 mL) was added slowly with 4-fluoro-nitrobenzene (25.0 g). added. After 2 hours, the reaction mixture was poured into water and the resulting precipitate was filtered off with suction. Alternatively, the product may be extracted with ethyl acetate and purified after concentration by chromatography. This gave the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M + H +).
Beispiel 2 1-[4-(3-Methylamino-pyrrolidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)-harnstoffExample 2 1- [4- (3-Methylamino-pyrrolidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea
Figure imgf000087_0001
Figure imgf000087_0001
Methode DMethod D
Eine Mischung aus N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}-pyrrolidin-3- yl)-acetamid (6,0 g), Ethanol (250 mL), Wasser (60 mL) und Natronlauge (10 M; 80 mL) wurde für 12 Stunden zum Rückfluss erhitzt. Der Alkohol wurde abdestilliert und der entstandene Niederschlag abgesaugt und mit Dichlormethan gewaschen. Zusätzliches Produkt wurde durch Einengen der organischen Phase und Chromatographie (Kieselgel, Dichlormethan/Methanol 9:1 mit 1% Triethylamin) gewonnen. Man erhielt so das Produkt mit dem Molekulargewicht 402,50 (C24H26N4O2); MS (ESI): 403 (M+H+).A mixture of N-methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide (6.0 g), ethanol (250 mL), water (60 mL) and caustic soda (10 M, 80 mL) were heated to reflux for 12 h. The alcohol was distilled off and the resulting precipitate was filtered off with suction and washed with dichloromethane. Additional product was recovered by concentration of the organic phase and chromatography (silica gel, dichloromethane / methanol 9: 1 with 1% triethylamine). This gave the product with a molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M + H +).
Beispiel 3Example 3
N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-2-phenyl- acetamid APD62429PCN-methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -2-phenyl-acetamide APD62429PC
Figure imgf000088_0001
Figure imgf000088_0001
Methode EMethod E
Eine Lösung von 1-[4-(3-Methylamino-pyrrolidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)- hamstoff (402 mg) in DMF (3 mL) wurde bei 0°C mitTOTU (327 mg) versetzt. Nach 10 Minuten wurde Hünig-Base (130 mg) und dann eine Lösung von Phenylessigsaure (136 mg) in DMF (1 mL) zugesetzt. Nach 12 Stunden Reaktionszeit bei Raumtemperatur wurde die Mischung mit Wasser versetzt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 520,64 (C32H32N4O3); MS (ESI): 521 (M+H+) als Hydrotrifluoracetat.A solution of 1- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea (402 mg) in DMF (3 mL) was treated at 0 ° C with TOTU (327 mg). After 10 minutes, Hünig's base (130 mg) was added followed by a solution of phenylacetic acid (136 mg) in DMF (1 mL). After 12 hours reaction time at room temperature, water was added to the mixture and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 520.64 (C32H32N4O3); MS (ESI): 521 (M + H +) as hydrotrifluoroacetate.
Beispiel 4 (R)-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamidExample 4 (R) -N-Methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide
Figure imgf000088_0002
Figure imgf000088_0002
Nach Methode A wurde (fi)-N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4-Phenoxy-anilin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 444,54 (C26H28N4O3); MS (ESI): 445 (M+H+).By Method A, (fi) - N - [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4-phenoxy-aniline. This gave the product with the molecular weight 444.54 (C26H28N4O3); MS (ESI): 445 (M + H +).
(f?)-N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid APD62429PC(F?) - N- [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide APD62429PC
Nach Methode B wurde (fl)-N-Methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 233,32 (C13H19N3O); MS (ESI): 234 (M+H+).According to Method B, (fl) -N-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide was hydrogenated. This gave the product with the molecular weight 233.32 (C13H19N3O); MS (ESI): 234 (M + H +).
(R)-N-Methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid(R) -N-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide
Methode FMethod F
Eine Suspension von Natriumhydrid (50%ig in Öl; 0,25 g) in DMF (50 mL) wurde portionsweise mit (fl)-N-[1-(4-Nitro~phenyl)-pyrrolidin-3-yl]-acetamid (1 ,3 g) versetzt. Nach beendeter Gasentwicklung wurde lodmethan (0,82 g) zugesetzt. Nach einer Stunde wurde die Reaktionsmischung vorsichtig mit Wasser hydrolysiert und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 263,30 (C13H17N3O3); MS (ESI): 264 (M+H+).A suspension of sodium hydride (50% in oil, 0.25 g) in DMF (50 mL) was added portionwise with (fl) -N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide (1, 3 g). When gas evolution ceased, iodomethane (0.82 g) was added. After 1 hour, the reaction mixture was carefully hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This gave the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M + H +).
(R)-N-[1-(4-Nitro-phenyl)-pyrrolidin-3-yl]-acetamid(R) -N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide
Nach Methode C wurde (f?)-N-Pyrrolidin-3-yl-acetamid mit 4-Fluor-nitrobenzol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 249,27 (C12H15N3O3); MS (ESI): 250 (M+H+).According to method C, (f?) - N-pyrrolidin-3-yl-acetamide was reacted with 4-fluoro-nitrobenzene. This gave the product with the molecular weight 249.27 (C12H15N3O3); MS (ESI): 250 (M + H +).
Beispiel 5 (S)-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamidExample 5 (S) -N-Methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide
Figure imgf000089_0001
APD62429PC
Figure imgf000089_0001
APD62429PC
Die im Beispiel 4 beschriebene Sequenz wurde auf (S)-N-Pyrrolidin-3-yl-acetamid angewendet. Man erhielt so das Produkt mit dem Molekulargewicht 444,54 (C26H28N4O3); MS (ESI): 445 (M+H+). Beispiel 6 (f?)-1-[4-(3-Methylamino-pyrrolidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)-harnstoffThe 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
Figure imgf000090_0001
Figure imgf000090_0001
Nach Methode D wurde (R)-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-acetamid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 402,50 (C24H26N4O2); MS (ESI): 403 (M+H+).By method D, (R) -N-methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide was reacted. This gave the product with a molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M + H +).
Beispiel 7 (S)-1-[4-(3-Methylamino-pyrrolidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)-harnstoffExample 7 (S) -1- [4- (3-Methylamino-pyrrolidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea
Figure imgf000090_0002
Figure imgf000090_0002
Nach Methode D wurde (S)-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-acetamid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 402,50 (C24H26N4O2); MS (ESI): 403 (M+H+).By method D, (S) -N-methyl-N- (1- {4- [3- (4-phenoxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide was reacted. This gave the product with a molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M + H +).
Beispiel 8 APD62429PCExample 8 APD62429PC
(fl)-N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl- acetamid(fl) -N- (1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-methyl-acetamide
Figure imgf000091_0001
Figure imgf000091_0001
Nach Methode A wurde (R)-N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4-Cyclopentyloxy-anilin umgesetzt. Man erhielt so das Produkt mit demBy method A, (R) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4-cyclopentyloxy-aniline. One received thus the product with the
Molekulargewicht 436,56 (C25H32N4O3); MS (ESI): 437 (M+H+).Molecular weight 436.56 (C25H32N4O3); MS (ESI): 437 (M + H +).
Analog wurde (S)-N-(1 -{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-Analogously, (S) -N- (1 - {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -
N-methyl-acetamid aus (S)-N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid erhalten.N-methyl-acetamide obtained from (S) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide.
4-Cyclopentyloxy-anilin4-Cyclopentyloxy-aniline
Eine Mischung von 4-Nitrophenol (63,7 g), Bromcyclopentan (68,2 g), Kaliumcarbonat (63,3 g) und DMF (300 mL) wurde für 24 Stunden auf 80 °C erwärmt. Nach dem Abkühlen wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 177,25 (C11H15NO); MS (ESI): 178 (M+H+).A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 mL) was heated to 80 ° C for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by Method B. This gave the product with the molecular weight 177.25 (C11H15NO); MS (ESI): 178 (M + H +).
Beispiel 9 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1-yl)-phenyl]-hamstoffExample 9 1- (4-Cyclopentyloxy-phenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea
APD62429PC APD62429PC
Nach Methode D wurde N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin- 3-yl)-N-methyl-acetamid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 394,52 (C23H30N4O2); MS (ESI): 395 (M+H+).By method D, N- (1- {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-methyl-acetamide was reacted. This gave the product with the molecular weight 394.52 (C23H30N4O2); MS (ESI): 395 (M + H +).
Analog wurden (R)- und (S)-1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin- 1 -yl)-phenyl]-hamstoff aus (R)- und (S)-N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]- phenyl}-pyrrolidin-3-yl)-N-methyl-acetamid erhalten.Analogously, (R) - and (S) -1- (4-cyclopentyloxyphenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea were prepared from (R) - and (S ) -N- (1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-methyl-acetamide.
Beispiel 10Example 10
(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-methyl- carbaminsäureethylester(1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -methyl-carbamic acid ethyl ester
Figure imgf000092_0001
Figure imgf000092_0001
Zu einer Lösung von 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1-yl)- phenylj-harnstoff (20 mg) und Hünig-Base (10 mg) in Dichlormethan (3 mL) wurde Chlorameisensäureethylester (8μL) getropft. Nach 12 Stunden wurde die Reaktionsmischung eingeengt und der Rückstand durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 466,59 (C26H34N4O4); MS (ESI): 467 (M+H+) als Hydrotrifluoracetat.To a solution of 1- (4-cyclopentyloxyphenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 mL), ethyl chloroformate (8 μL) was added dropwise. After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This gave the product with the molecular weight 466.59 (C26H34N4O4); MS (ESI): 467 (M + H +) as hydrotrifluoroacetate.
Beispiel 11Example 11
1 -(1 -{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-3-ethyl-1 -methyl- harnstoff APD62429PC1 - (1 - {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -3-ethyl-1-methyl-urea APD62429PC
Figure imgf000093_0001
Figure imgf000093_0001
Zu einer Lösung von 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1-yl)- phenylj-harnstoff (20 mg) und Hünig-Base (10 mg) in Dichlormethan (3 mL) wurde Ethylisocyanat (7μL) getropft. Nach 12 Stunden wurde die Reaktionsmischung eingeengt und der Rückstand durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 465,60 (C26H35N5O3); MS (ESI): 466 (M+H+) als Hydrotrifluoracetat.To a solution of 1- (4-cyclopentyloxyphenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 mL), ethyl isocyanate (7 μL) was added dropwise. After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This gave the product with the molecular weight 465.60 (C26H35N5O3); MS (ESI): 466 (M + H +) as hydrotrifluoroacetate.
Beispiel 12Example 12
1-(4-Cyclopentyloxy-phenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2-ylmethyl)-amino]- pyrrolidin-1-yl}-phenyl)-hamstoff1- (4-Cyclopentyloxyphenyl) -3- (4- {3- [methyl- ((R) -5-oxopyrrolidin-2-ylmethyl) -amino] -pyrrolidin-1-yl} -phenyl) - urea
Figure imgf000093_0002
Figure imgf000093_0002
Zu einer Suspension von 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1- yl)-phenyl]-hamstoff (30 mg) und Kaliumcarbonat (20 mg) in DMF (3 mL) wurde (R)-5- Brommethyl-pyrrolidin-2-on (15 mg) gegeben. Nach 2 Stunden wurde die Reaktionsmischung filtriert, eingeengt und der Rückstand durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 491 ,64 (C28H37N5O3); MS (ESI): 492 (M+H+) als Hydrotrifluoracetat.To a suspension of 1- (4-cyclopentyloxyphenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea (30 mg) and potassium carbonate (20 mg) in DMF (3 mL ) was added (R) -5-bromomethylpyrrolidin-2-one (15 mg). After 2 hours, the reaction mixture was filtered, concentrated and the residue purified by preparative HPLC. This gave the product with the molecular weight 491, 64 (C28H37N5O3); MS (ESI): 492 (M + H +) as hydrotrifluoroacetate.
Beispiel 13 APD62429PCExample 13 APD62429PC
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]- phenyl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000094_0001
Figure imgf000094_0001
Nach Methode A wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mitBy method A was N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide with
Carbonyldiimidazol und dann mit 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 455,00 (C25H31CIN4O2); MS (ESI): 455Carbonyldiimidazole and then reacted with 4- (4-chloro-phenyl) -piperidine. This gave the product with a molecular weight of 455.00 (C25H31CIN4O2); MS (ESI): 455
(M+H+).(M + H +).
Analog wurden (R)- und (S)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl- methyl-amino)-pyrrolidin-1-yl]-phenyl}-amid aus (R)- und (S)-N-[1-(4-Amino-phenyl)- pyrrolidin-3-yl]-N-methyl-acetamid erhalten.Analogously, (R) - and (S) -4- (4-chlorophenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} - amide from (R) - and (S) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide.
Beispiel 14Example 14
(/:?)-[1-(4-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}-phenyl)-pyrrolidin-3-yl]- methyl-carbaminsäure tert-butylester (/?) - [1- (4 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -phenyl) -pyrrolidin-3-yl] - methyl-carbamic acid tert-butyl ester
Figure imgf000094_0002
Figure imgf000094_0002
Nach Methode A wurde (f?)-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester mit Carbonyldiimidazol und dann mit 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 513,09 (C28H37CIN4O3); MS (ESI): 513 (M+H+). APD62429PCAccording to method A, tert-butyl (f?) - [1- (4-amino-phenyl) -pyrrolidin-3-yl] -methyl-carbamate was reacted with carbonyldiimidazole and then with 4- (4-chloro-phenyl) -piperidine , This gave the product of molecular weight 513.09 (C28H37CIN4O3); MS (ESI): 513 (M + H +). APD62429PC
(R)-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester(R) - [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode B wurde (fl)-Methyl-[1-(4-nitro-phenyl)-pyrrolidin-3~yl]-carbaminsäure tert-butylester hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 291 ,40 (C16H25N3O2); MS (ESI): 292 (M+H+).According to method B, tert-butyl (fl) -methyl- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid was hydrogenated. This gave the product of molecular weight 291, 40 (C16H25N3O2); MS (ESI): 292 (M + H +).
(R)-Methyl-[1 -(4-nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert-butylester(R) -methyl- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester
Nach Methode F wurde (f?)-[1-(4-Nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert- butylester mit lodmethan alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 321 ,38 (C16H23N3O4); MS (ESI): 322 (M+H+).According to method F, tert-butyl ester of (f?) - [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid was alkylated with iodomethane. This gave the product with the molecular weight 321, 38 (C16H23N3O4); MS (ESI): 322 (M + H +).
(ft)-[1-(4-Nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert-butylester(ft) - [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert -butyl ester
Nach Methode C wurde (R)-Pyrrolidin-3-yl-carbaminsäure tert-butylester mit 4-Fluor- nitrobenzol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 307,35 (C15H21 N3O4); MS (ESI): 308 (M+H+).According to method C, (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester was reacted with 4-fluoronitrobenzene. This gave the product with the molecular weight 307.35 (C15H21 N3O4); MS (ESI): 308 (M + H +).
Beispiel 15Example 15
(f?)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3-methylamino-pyrrolidin-1 -yl)- phenyl]-amid(f?) - 4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid [4- (3-methyl-aminopyrrolidin-1-yl) -phenyl] -amide
Figure imgf000095_0001
Figure imgf000095_0001
Methode G APD62429PCMethod G APD62429PC
Eine Lösung von (R)-[1-(4-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}-phenyl)- pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester (1 ,5 g) in Dichlormethan (50 mL) wurde mit Trifluoressigsaure (6,67 g) versetzt. Nach 3 Stunden wurden flüchtige Anteile entfernt und der Rückstand in Dichlormethan aufgenommen. Nach dem Waschen mit Natriumcarbonatlösung wurde die organische Phase über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 412,97 (C23H29CIN4O); MS (ESI): 413 (M+H+).A solution of (R) - [1- (4 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert. butyl ester (1.5 g) in dichloromethane (50 mL) was added trifluoroacetic acid (6.67 g). After 3 hours, volatiles were removed and the residue taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product with the molecular weight 412.97 (C23H29CIN4O); MS (ESI): 413 (M + H +).
Beispiel 16Example 16
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure (4-{(ft)-3-[methyl-(1 -methyl-piperidin-3-yl- carbonyl)-amino]-pyrrolidin-1-yl}-phenyl)-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid (4 - {(ft) -3- [methyl- (1-methyl-piperidin-3-yl-carbonyl) -amino] -pyrrolidin-1-yl } -phenyl) -amide
Figure imgf000096_0001
Figure imgf000096_0001
Nach Methode E wurde (fl)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3- methylamino-pyrrolidin-1 -yl)-phenyl]-amid mit 1 -Methyl-piperidin-3-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 538,14 (C30H40CIN5O2); MS (ESI): 538 (M+H+).According to method E, (fl) -4- (4-chlorophenyl) -piperidine-1-carboxylic acid [4- (3-methylaminopyrrolidin-1-yl) -phenyl] -amide with 1-methyl-piperidine-3 -carboxylic acid reacted. This gave the product of molecular weight 538.14 (C30H40CIN5O2); MS (ESI): 538 (M + H +).
Beispiel 17Example 17
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure (4-(fl)-{3-[methyl-(2-piperidin-1 -yl-acetyl)- amino]-pyrrolidin-1-yl}-phenyl)-amid APD62429PC4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid (4- (fl) - {3- [methyl- (2-piperidin-1-yl-acetyl) -amino] -pyrrolidin-1-yl} - phenyl) -amide APD62429PC
Figure imgf000097_0001
Figure imgf000097_0001
Nach Methode E wurde ( ?)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3- methylamino-pyrrolidin-1-yl)-phenyl]-amid mit Piperidin-1-yl-essigsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 538,14 (C30H40CIN5O2); MS (ESI): 538 (M+H+).According to method E, (?) - 4- (4-chlorophenyl) -piperidine-1-carboxylic acid [4- (3-methylaminopyrrolidin-1-yl) -phenyl] -amide with piperidin-1-yl-acetic acid implemented. This gave the product of molecular weight 538.14 (C30H40CIN5O2); MS (ESI): 538 (M + H +).
Beispiel 18Example 18
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure (4-(f?)-{3-[methyl-(2-oxo-thiazolidin-4- carbonyl)-amino]-pyrrolidin-1 -yl}-phenyl)-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid (4- (f) - {3- [methyl- (2-oxo-thiazolidine-4-carbonyl) -amino] -pyrrolidin-1-yl} phenyl) amide
Figure imgf000097_0002
Figure imgf000097_0002
Nach Methode E wurde (/?)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3- methylamino-pyrrolidin-1 -yl)-phenyl]-amid mit 2-Oxo-thiazolidin-4-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 542,10 (C27H32CIN5O3S); MS (ESI): 542 (M+H+).According to method E, (/?) - 4- (4-chloro-phenyl) -piperidine-1-carboxylic acid [4- (3-methylaminopyrrolidin-1-yl) -phenyl] -amide with 2-oxothiazolidine 4-carboxylic acid reacted. This gave the product of molecular weight 542.10 (C27H32CIN5O3S); MS (ESI): 542 (M + H +).
Beispiel 19Example 19
(R)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure (4-{3-[methyl-(2,2,2-trifluor-acetyl)- amino]-pyrrolidin-1 -yl}-phenyl)-amid APD62429PC(R) -4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid (4- {3- [methyl- (2,2,2-trifluoro-acetyl) -amino] -pyrrolidin-1-yl} - phenyl) -amide APD62429PC
Figure imgf000098_0001
Figure imgf000098_0001
Nach Methode A wurde (R)-[ N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-2,2,2-trifluor-N- methyl-acetamid mit Carbonyldiimidazol und dann mit 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 508,98 (C25H28CIF3N4O2); MS (ESI): 509 (M+H+).According to method A, (R) - [N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -2,2,2-trifluoro-N-methyl-acetamide with carbonyldiimidazole and then with 4- ( 4-chloro-phenyl) -piperidine reacted. This gave the product of molecular weight 508.98 (C25H28CIF3N4O2); MS (ESI): 509 (M + H +).
(R)-[ N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-2,2,2-trifluor-N-methyl-acetamid(R) - [N- [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -2,2,2-trifluoro-N-methyl-acetamide
Nach Methode B wurde (R)-2,2,2-Trifluor-N-methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]- acetamid hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 287,29 (C13H16F3N3O); MS (ESI): 288 (M+H+).According to Method B, (R) -2,2,2-trifluoro-N-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide was hydrogenated. This gave the product with the molecular weight 287.29 (C13H16F3N3O); MS (ESI): 288 (M + H +).
(/:?)-2,2,2-Trifluor-N-methyl-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid (/?) - 2,2,2-trifluoro-N-methyl-N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide
Zu einer Lösung von (f?)-Methyl-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-amin (0,48 g) in Pyridin (2 mL) wurde Trifluoressigsäureanhydrid (0,5 mL) getropft. Nach 3 Stunden wurde die Reaktionsmischung mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde mit Zitronensäurelösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 317,27 (C13H14F3N3O3); MS (ESI): 318 (M+H+).To a solution of (f) -methyl- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -amine (0.48 g) in pyridine (2 mL) was added trifluoroacetic anhydride (0.5 mL). dripped. After 3 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with citric acid solution, dried over magnesium sulfate and concentrated. This gave the product with the molecular weight 317.27 (C13H14F3N3O3); MS (ESI): 318 (M + H +).
(fi)-Methyl-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-amin APD62429PC(Fi) -methyl- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -amine APD62429PC
Eine Lösung von (fi)-Methyl-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert- butylester (0,7 g) in Dichlormethan (5 mL) wurde für 1 Stunde mit Trifluoressigsaure (3 mL) behandelt. Die Reaktionslösung wurde eingeengt und der Rückstand in Dichlormethan aufgenommen. Nach dem Waschen mit Natriumcarbonatlösung wurde die organische Phase über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 221 ,26 (C11H15N3O2); MS (ESI): 222 (M+H+).A solution of (fi) -methyl- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (0.7 g) in dichloromethane (5 mL) was treated with trifluoroacetic acid (1 mL) for 1 h. 3 mL). The reaction solution was concentrated and the residue taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product with the molecular weight 221, 26 (C11H15N3O2); MS (ESI): 222 (M + H +).
Beispiel 20Example 20
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]~ phenyl}-methyl-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -methyl-amide
Figure imgf000099_0001
Figure imgf000099_0001
Nach Methode F wurde 4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyi- amino)-pyrrolidin-1-yl]-phenyl}-amid mit lodmethan umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 469,03 (C26H33CIN4O2); MS (ESI): 469 (M+H+).According to method F, 4- (4-chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methylamino) -pyrrolidin-1-yl] -phenyl} -amide was reacted with iodomethane. This gave the product of molecular weight 469.03 (C26H33CIN4O2); MS (ESI): 469 (M + H +).
Beispiel 21Example 21
(f?)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure (4-{3-[acetyl-(2-diethylamino-ethyl)- amino]-pyrrolidin-1-yl}-phenyl)-amid APD62429PC(f?) - 4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid (4- {3- [acetyl- (2-diethylamino-ethyl) -amino] -pyrrolidin-1-yl} -phenyl) - amide APD62429PC
Figure imgf000100_0001
Figure imgf000100_0001
Nach Methode A wurde (ft)-N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-(2-diethylamino- ethyl)-acetamid mit 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 540,15 (C30H42CIN5O2); MS (ESI): 540 (M+H+).According to method A, (ft) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N- (2-diethylamino-ethyl) -acetamide with 4- (4-chlorophenyl) - reacted with piperidine. This gave the product with a molecular weight of 540.15 (C30H42CIN5O2); MS (ESI): 540 (M + H +).
(R)-N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-(2-diethylamino-ethyl)-acetamid Nach Methode B wurde (R)-N-(2-Diethylamino-ethyl)-N-[1-(4-nitro-phenyl)-pyrrolidin-3- yl]-acetamid hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 318,47 (C18H30N4O); MS (ESI): 319 (M+H+).(R) -N- [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -N- (2-diethylamino-ethyl) -acetamide According to Method B, (R) -N- (2-diethylamino) ethyl) -N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide. This gave the product with the molecular weight 318.47 (C18H30N4O); MS (ESI): 319 (M + H +).
(f?)-N-(2-Diethylamino-ethyl)-N-[1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid(F?) - N- (2-diethylamino-ethyl) -N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide
Nach Methode F wurde (f?)-N-[1-(4-Nitro-phenyl)-pyrrolidin-3-yl]-acetamid mit 2- Chlorethyl-diethylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 348,45 (C18H28N4O3); MS (ESI): 349 (M+H+).According to method F, (f?) - N- [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide was reacted with 2-chloroethyl-diethylamine. This gave the product with the molecular weight 348.45 (C18H28N4O3); MS (ESI): 349 (M + H +).
Beispiel 22 1-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)-harnstoffExample 22 1- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea
Figure imgf000100_0002
APD62429PC
Figure imgf000100_0002
APD62429PC
Nach Methode A, B und C wurde Dimethyl-pyrrolidin-3-yl-amin mit 4-Fluor-nitrobenzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-Phenoxyanilin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 416,53 (C25H28N4O2); MS (ESI): 417 (M+H+).After method A, B and C dimethyl-pyrrolidin-3-yl-amine was reacted with 4-fluoro-nitrobenzene, the resulting nitro compound is reduced with hydrogen and finally the aniline with CDI and 4-phenoxyaniline reacted. This gave the product with the molecular weight 416.53 (C25H28N4O2); MS (ESI): 417 (M + H +).
Beispiel 23Example 23
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-isobutoxy-phenyl)- propionamidN- {4- [3- (Acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-isobutoxy-phenyl) -propionamide
Figure imgf000101_0001
Figure imgf000101_0001
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 2- (4-lsobutoxy-phenyl)-propionsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 437,59 (C26H35N3O3); MS (ESI): 438 (M+H+).According to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 2- (4-isobutoxy-phenyl) -propionic acid. This gave the product with the molecular weight 437.59 (C26H35N3O3); MS (ESI): 438 (M + H +).
Beispiel 24 N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamidExample 24 N- (1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide
Figure imgf000101_0002
Figure imgf000101_0002
Nach Methode A, B und C wurde N-Pyrrolidin-3-yl-acetamid mit 4-Fluor-nitrobenzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend APD62429PCAccording to method A, B and C, N-pyrrolidin-3-yl-acetamide was reacted with 4-fluoro-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally APD62429PC
das Anilin mit CDI und 4-Cyclopentyloxy-anilin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 422,53 (C24H30N4O3); MS (ESI): 423 (M+H+).reacted the aniline with CDI and 4-cyclopentyloxy-aniline. This gave the product with the molecular weight 422.53 (C24H30N4O3); MS (ESI): 423 (M + H +).
In analoger Weise wurden ausgehend von (R)- und (S)-N-Pyrrolidin-3-yl-acetamid (R)- und (S)-N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamid erhalten.In an analogous manner, starting from (R) - and (S) -N-pyrrolidin-3-yl-acetamide (R) - and (S) -N- (1- {4- [3- (4-cyclopentyloxy-phenyl ) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide.
Beispiel 25 N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-ethyl-acetamidExample 25 N- (1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-ethyl-acetamide
Figure imgf000102_0001
Figure imgf000102_0001
Nach Methode A, B und C wurde N-Ethyl-N-pyrrolidin-3-yl-acetamid mit 4-Fluor- nitrobenzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-Cyclopentyloxy-anilin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 450,59 (C26H34N4O3); MS (ESI): 451 (M+H+).According to method A, B and C, 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 +).
Beispiel 26Example 26
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-3- methyl-phenyl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -3-methyl-phenyl} -amide
Figure imgf000102_0002
APD62429PC
Figure imgf000102_0002
APD62429PC
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 1-Fluor-2- methyl-4-nitro-benzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 469,03 (C26H33CIN4O2); MS (ESI): 469 (M+H+).According to method A, B and C 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 +).
Beispiel 27Example 27
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-3- fluor-phenyl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -3-fluoro-phenyl} -amide
Figure imgf000103_0001
Figure imgf000103_0001
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 1 ,2-Difluor-4- nitro-benzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 472,99 (C25H30CIFN4O2); MS (ESI): 473 (M+H+).According to method A, B and C, 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 +).
Beispiel 28Example 28
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -
2,6-difluor-phenyl}-amid2,6-difluoro-phenyl} -amide
Figure imgf000103_0002
APD62429PC
Figure imgf000103_0002
APD62429PC
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 1 ,3,5-Trifluor- 2-nitro-benzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 490,99 (C25H29CIF2N4O2); MS (ESI): 491 (M+H+).After method A, B and C, N-methyl-N-pyrrolidin-3-yl-acetamide was reacted with 1, 3,5-trifluoro-2-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 with the molecular weight 490.99 (C25H29CIF2N4O2); MS (ESI): 491 (M + H +).
Beispiel 29Example 29
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-2- methyl-phenyl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -2-methyl-phenyl} -amide
Figure imgf000104_0001
Figure imgf000104_0001
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 4-Fluor-2- methyl-1 -nitro-benzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 469,03 (C26H33CIN4O2); MS (ESI): 469 (M+H+).According to method A, B and C 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 +).
Beispiel 30Example 30
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-2- fluor-phenyl}-amid APD62429PC4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -2-fluoro-phenyl} -amide APD62429PC
Figure imgf000105_0001
Figure imgf000105_0001
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 2,4-Difluor-1 - nitro-benzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 472,99 (C25H30CIFN4O2); MS (ESI): 473 (M+H+).According to method A, B and C, 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 +).
Beispiel 31Example 31
(/:?)-[1-(5-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}-pyridin-2-yl)-pyrrolidin-3-yl]- methyl-carbaminsäure tert-butylester (/?) - [1- (5 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -pyridin-2-yl) -pyrrolidin-3-yl] - methyl carbamic acid tert-butyl ester
Figure imgf000105_0002
Figure imgf000105_0002
Die Synthesesequenz zur Darstellung von (fl)-[1-(4-{[4-(4-Chlor-phenyl)-piperidin-1- carbonyl]-amino}-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester ausgehend von 2-Chlor-5-nitropyridin statt 4-Fluor-nitrobenzol wurde durchlaufen. Man erhielt so das Produkt mit dem Molekulargewicht 514,07 (C27H36CIN5O3); MS (ESI): 514 (M+H+).The synthesis sequence for the preparation of (fl) - [1- (4 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester starting from 2-chloro-5-nitropyridine instead of 4-fluoro-nitrobenzene was passed through. This gave the product of molecular weight 514.07 (C27H36CIN5O3); MS (ESI): 514 (M + H +).
Beispiel 32Example 32
(R)-[ 4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [6-(3-methylamino-pyrrolidin-1 -yl)- pyridin-3-yl]-amid APD62429PC(R) - [4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid [6- (3-methyl-aminopyrrolidin-1-yl) -pyridin-3-yl] -amide APD62429PC
Figure imgf000106_0001
Figure imgf000106_0001
Nach Methode G wurde (fi)-[1-(5-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}- pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester mit Trifluoressigsaure behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 413,95 (C22H28CIN5O); MS (ESI): 414 (M+H+).According to Method G, (fi) - [1- (5 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -pyridin-2-yl) -pyrrolidin-3-yl] - Methyl-carbamic acid tert-butyl ester treated with trifluoroacetic acid. This gave the product with a molecular weight of 413.95 (C22H28CIN5O); MS (ESI): 414 (M + H +).
In analoger Weise konnte man racemisches [ 4-(4-Chlor-phenyl)-piperidin-1- carbonsäure [6-(3-methylamino-pyrrolidin-1 -yl)-pyridin-3-yl]-amid erhalten.In an analogous manner, racemic [4- (4-chlorophenyl) -piperidine-1-carboxylic acid [6- (3-methylamino-pyrrolidin-1-yl) -pyridin-3-yl] -amide was obtained.
Beispiel 33Example 33
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {6-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]- pyridin-3-yl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {6- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -pyridin-3-yl} -amide
Figure imgf000106_0002
Figure imgf000106_0002
Nach Methode A, B und C wurde N-Methyl-N-pyrrolidin-3-yl-acetamid mit 2-Chlor-5- nitropyridin umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-(4-Chlor-phenyl)-piperidin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 490,99 (C25H29CIF2N4O2); MS (ESI): 491 (M+H+).According to method A, B and C, 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 +).
Beispiel 34 1-[4-(4-Dimethylamino-piperidin-1-yl)-phenyl]-3-(4-phenoxy-phenyl)-harnstoff APD62429PCExample 34 1- [4- (4-Dimethylamino-piperidin-1-yl) -phenyl] -3- (4-phenoxy-phenyl) -urea APD62429PC
Figure imgf000107_0001
Figure imgf000107_0001
Nach Methode A, B und C wurde Dimethyl-piperidin-4-yl-amin mit 4-Fluor-nitrobenzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin ([1-(4-Amino-phenyl)-piperidin-4-yl]-dimethyl-amin) mit CDI und 4-Phenoxy- anilin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 430,55 (C26H30N4O2); MS (ESI): 431 (M+H+).By methods A, B and C dimethyl-piperidin-4-yl-amine was reacted with 4-fluoro-nitrobenzene, the resulting nitro compound is reduced with hydrogen and finally the aniline ([1- (4-amino-phenyl) -piperidin-4 -yl] -dimethyl-amine) with CDI and 4-phenoxy- aniline reacted. This gave the product with the molecular weight 430.55 (C26H30N4O2); MS (ESI): 431 (M + H +).
Beispiel 35 1-(4-Cyclopentyloxy-phenyl)-3-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-harnstoffExample 35 1- (4-Cyclopentyloxy-phenyl) -3- [4- (4-morpholin-4-yl-piperidin-1-yl) -phenyl] -urea
Figure imgf000107_0002
Figure imgf000107_0002
Nach Methode A, B und C wurde 4-Piperidin-4-yl-morpholin mit 4-Fiuor-nitrobenzol umgesetzt, die erhaltene Nitroverbindung mit Wasserstoff reduziert und abschließend das Anilin mit CDI und 4-Cyclopentyloxy-anilin zur Reaktion gebracht. Man erhielt so das Produkt mit dem Molekulargewicht 464,61 (C27H36N4O3); MS (ESI): 465 (M+H+).According to methods A, B and C, 4-piperidin-4-yl-morpholine 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 with the molecular weight 464.61 (C27H36N4O3); MS (ESI): 465 (M + H +).
Beispiel 36 4-Butoxy-N-[4-(4-dimethylamino-piperidin-1-yl)-phenyl]-benzamid APD62429PCExample 36 4-Butoxy-N- [4- (4-dimethylamino-piperidin-1-yl) -phenyl] -benzamide APD62429PC
Figure imgf000108_0001
Figure imgf000108_0001
Nach Methode E wurde ([1-(4-Amino-phenyl)-piperidin-4-yl]-dimethyl-amin) mit 4-4- Butoxy-benzoesäure umgesetzt . Man erhielt so das Produkt mit dem Molekulargewicht 395,55 (C24H33N3O2); MS (ESI): 396 (M+H+).According to method E ([1- (4-amino-phenyl) -piperidin-4-yl] -dimethyl-amine) was reacted with 4-4-butoxy-benzoic acid. This gave the product with the molecular weight 395.55 (C24H33N3O2); MS (ESI): 396 (M + H +).
Beispiel 37Example 37
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)-azetidin-1 -yl]- phenyl}-amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -azetidin-1-yl] -phenyl} -amide
Figure imgf000108_0002
Figure imgf000108_0002
Nach Methode A wurde N-[1-(4-Amino-phenyl)-azetidin-3-yl]-N-methyl-acetamid mit Carbonyldiimidazol und 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 440,98 (C24H29CIN4O2); MS (ESI): 441 (M+H+).According to Method A, N- [1- (4-amino-phenyl) -azetidin-3-yl] -N-methyl-acetamide was reacted with carbonyldiimidazole and 4- (4-chloro-phenyl) -piperidine. This gave the product with the molecular weight 440.98 (C24H29CIN4O2); MS (ESI): 441 (M + H +).
N-[1-(4-Amino-phenyl)-azetidin-3-yl]-N-methyl-acetamidN- [1- (4-Amino-phenyl) azetidin-3-yl] -N-methyl-acetamide
Nach Methode B wurde N-Methyl-N-[1 -(4-nitro-phenyl)-azetidin-3-yl]-acetamid hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 219,29 (C12H17N3O); MS (ESI): 220 (M+H+).According to Method B, N-methyl-N- [1- (4-nitro-phenyl) -azetidin-3-yl] -acetamide was hydrogenated. This gave the product with the molecular weight 219.29 (C12H17N3O); MS (ESI): 220 (M + H +).
N-Methyl-N-[1-(4-nitro-phenyl)-azetidin-3-yl]-acetamidN-methyl-N- [1- (4-nitro-phenyl) azetidin-3-yl] -acetamide
Nach Methode F wurde N-[1-(4-Nitro-phenyl)-azetidin-3-yl]-acetamid mit lodmethan alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 249,27 (C12H15N3O3); MS (ESI): 250 (M+H+). APD62429PCBy Method F, N- [1- (4-nitro-phenyl) -azetidin-3-yl] -acetamide was alkylated with iodomethane. This gave the product with the molecular weight 249.27 (C12H15N3O3); MS (ESI): 250 (M + H +). APD62429PC
N-[1-(4-Nitro-phenyl)-azetidin-3-yl]-acetamidN- [1- (4-nitro-phenyl) azetidin-3-yl] -acetamide
Eine Lösung von 1-(4-Nitro-phenyl)-azetidin-3-ylamin (0,5 g) in Pyridin (1,2 mL) wurde mit Essigsäureanhydrid (0,6 mL) versetzt. Nach einer Stunde wurden flüchtige Anteile entfernt. Man erhielt so das Produkt mit dem Molekulargewicht 235,24 (C11 H13N3O3); MS (ESI): 236 (M+H+).A solution of 1- (4-nitro-phenyl) -azetidin-3-ylamine (0.5 g) in pyridine (1.2 mL) was added with acetic anhydride (0.6 mL). After one hour, volatiles were removed. This gave the product with the molecular weight 235.24 (C11 H13N3O3); MS (ESI): 236 (M + H +).
1-(4-Nitro-phenyl)-azetidin-3-ylamin1- (4-nitro-phenyl) azetidin-3-ylamine
Nach Methode G wurde [1-(4-Nitro-phenyl)-azetidin-3-yl]-carbaminsäure tert-butylester mit Trifluoressigsaure behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 193,21 (C9H11N3O2); MS (ESI): 194 (M+H+).According to Method G, tert-butyl [1- (4-nitro-phenyl) -azetidin-3-yl] -carbamate was treated with trifluoroacetic acid. This gave the product with the molecular weight 193.21 (C9H11N3O2); MS (ESI): 194 (M + H +).
[1-(4-Nitro-phenyl)-azetidin-3-yl]-carbaminsäure tert-butylester Nach Methode C wurde Azetidin-3-yl-carbaminsäure tert-butylester mit 4-Fluor- nitrobenzol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 293,33 (C14H19N3O4); MS (ESI): 294 (M+H+).[1- (4-Nitro-phenyl) -azetidin-3-yl] -carbamic acid tert-butyl ester According to Method C, tert-butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene. This gave the product with the molecular weight 293.33 (C14H19N3O4); MS (ESI): 294 (M + H +).
Beispiel 38Example 38
[1-(4-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}-phenyl)-azetidin-3-yl]-methyl- carbaminsäure tert-butylester[1- (4 - {4- (4-Chloro-phenyl) -piperidine-1-carbonyl] -amino} -phenyl) -azetidin-3-yl] -methyl-carbamic acid tert-butyl ester
Figure imgf000109_0001
Figure imgf000109_0001
Nach Methode A wurde [1-(4-Amino-phenyl)-azetidin-3-yl]-methyl-carbaminsäure tert- butylester mit Carbonyldiimidazol und 4-(4-Chlor-phenyl)-piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 499,06 (C27H35CIN4O3); MS (ESI): 499 (M+H+).According to method A, [1- (4-amino-phenyl) -azetidin-3-yl] -methyl-carbamic acid tert-butyl ester was reacted with carbonyldiimidazole and 4- (4-chloro-phenyl) -piperidine. This gave the product with the molecular weight 499.06 (C27H35CIN4O3); MS (ESI): 499 (M + H +).
[1-(4-Amino-phenyl)-azetidin-3-yl]-methyl-carbaminsäure tert-butylester APD62429PC[1- (4-Amino-phenyl) -azetidin-3-yl] -methyl-carbamic acid tert-butyl ester APD62429PC
Nach Methode B wurde Methyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-carbaminsäure tert- butylester hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 277,37 (C15H23N3O2); MS (ESI): 278 (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 +).
Methyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-carbaminsäure tert-butylester Nach Methode F wurde [1 -(4-Nitro-phenyl)-azetidin-3-yl]-carbaminsäure tert-butylester mit lodmethan alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 307,35 (C15H21 N3O4); MS (ESI): 308 (M+H+).Tert-Butyl methyl- [1- (4-nitro-phenyl) -azetidin-3-yl] -carbamic acid According to Method F, tert-butyl [1- (4-nitro-phenyl) -azetidin-3-yl] -carbamate was obtained alkylated with iodomethane. This gave the product with the molecular weight 307.35 (C15H21 N3O4); MS (ESI): 308 (M + H +).
Beispiel 39Example 39
4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3-methylamino-azetidin-1 -yl)-phenyl]- amid4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid [4- (3-methylamino-azetidin-1-yl) -phenyl] -amide
Figure imgf000110_0001
Figure imgf000110_0001
Nach Methode G wurde [1-(4-{[4-(4-Chlor-phenyl)-piperidin-1-carbonyl]-amino}-phenyl)- azetidin-3-yl]-methyl-carbaminsäure tert-butylester mit Trifluoressigsaure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 398,94 (C22H27CIN4O); MS (ESI): 399 (M+H+).According to method G, tert-butyl [1- (4 - {[4- (4-chloro-phenyl) -piperidine-1-carbonyl] -amino} -phenyl) -azetidin-3-yl] -methylcarbamate with trifluoroacetic acid was obtained implemented. This gave the product with the molecular weight 398.94 (C22H27CIN4O); MS (ESI): 399 (M + H +).
Beispiel 40 N-Methyl-N-[1 -(4-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-phenyl)-pyrrolidin-3-yl]-acetamidExample 40 N-Methyl-N- [1- (4- {3- [4- (pyridin-3-yloxy) -phenyl] -ureido} -phenyl) -pyrrolidin-3-yl] -acetamide
Figure imgf000110_0002
APD62429PC
Figure imgf000110_0002
APD62429PC
Nach Methode A wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit Carbonyldiimidazol und dann mit 4-(Pyridin-3-yloxy)-phenylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 445,53 (C25H27N5O3); MS (ESI): 446 (M+H+).According to Method A, 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 +).
Beispiel 41Example 41
N-Methyl-N-(1-{4-[3-(4-piperidin-1-yl-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-acetamidN-methyl-N- (1- {4- [3- (4-piperidin-1-yl-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -acetamide
Figure imgf000111_0001
Figure imgf000111_0001
Nach Methode A wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit Carbonyldiimidazol und dann mit 4-Piperidin-1-yl-phenylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 435,57 (C25H33N5O2); MS (ESI): 436 (M+H+).According to Method A, 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 +).
Beispiel 42Example 42
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-4-phenoxy-benzamidN- {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -4-phenoxy-benzamide
Figure imgf000111_0002
Figure imgf000111_0002
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4- Phenoxybenzoesäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 429,52 (C26H27N3O3); MS (ESI): 430 (M+H+).According to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4-phenoxybenzoic acid. This gave the product with the molecular weight 429.52 (C26H27N3O3); MS (ESI): 430 (M + H +).
Beispiel 43 N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-4-butoxy-benzamid APD62429PCExample 43 N- {4- [3- (Acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -4-butoxy-benzamide APD62429PC
Figure imgf000112_0001
Figure imgf000112_0001
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4- Butoxybenzoesäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 409,53 (C24H31N3O3); MS (ESI): 410 (M+H+).According to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4-butoxybenzoic acid. This gave the product with the molecular weight 409.53 (C24H31N3O3); MS (ESI): 410 (M + H +).
Beispiel 44Example 44
4-(4-Chlor-phenyl)-cyclohexancarbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]- phenyl}-amid4- (4-Chloro-phenyl) -cyclohexanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000112_0002
Figure imgf000112_0002
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4- (4-Chlor-phenyl)-cyclohexancarbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 454,02 (C26H32CIN3O2); MS (ESI): 454 (M+H+).In Method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4- (4-chloro-phenyl) -cyclohexanecarboxylic acid. This gave the product of molecular weight 454.02 (C26H32CIN3O2); MS (ESI): 454 (M + H +).
Beispiel 45Example 45
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-3-(4-isopropyl-phenyl)-acrylamidN- {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] phenyl} -3- (4-isopropyl-phenyl) -acrylamide
Figure imgf000112_0003
APD62429PC
Figure imgf000112_0003
APD62429PC
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 3- (4-lsopropyl-phenyl)-acrylsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 405,54 (C25H31 N3O2); MS (ESI): 406 (M+H+).In method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 3- (4-isopropyl-phenyl) -acrylic acid. This gave the product with the molecular weight 405.54 (C25H31 N3O2); MS (ESI): 406 (M + H +).
Beispiel 46Example 46
Tetrahydro-furan-2-carbonsäure (1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-methyl-amidTetrahydrofuran-2-carboxylic acid (1- {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -methyl-amide
Figure imgf000113_0001
Figure imgf000113_0001
Nach Methode E wurde 1-(4-Cyclopentyloxy-phenyi)-3-[4-(3-methylamino-pyrrolidin-1- yl)-phenyl]-harnstoff mit Tetrahydro-furan-2-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 492,62 (C28H36N4O4); MS (ESI): 493 (M+H+).In Method E, 1- (4-cyclopentyloxy-phenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea was reacted with tetrahydrofuran-2-carboxylic acid. This gave the product with the molecular weight 492.62 (C28H36N4O4); MS (ESI): 493 (M + H +).
Beispiel 47Example 47
1 -Acetyl-pyrrolidin-2-carbonsäure (1 ~{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-methyl-amid1-Acetylpyrrolidine-2-carboxylic acid (1 - {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -methyl-amide
Figure imgf000113_0002
APD62429PC
Figure imgf000113_0002
APD62429PC
Nach Methode E wurde 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1- yl)-phenyl]-harnstoff mit 1-Acetyl-pyrrolidin-2-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 533,68 (C30H39N5O4); MS (ESI): 534 (M+H+).According to Method E, 1- (4-cyclopentyloxyphenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea was reacted with 1-acetylpyrrolidine-2-carboxylic acid. This gave the product of molecular weight 533.68 (C30H39N5O4); MS (ESI): 534 (M + H +).
Beispiel 48Example 48
5-Oxo-pyrrolidin-2-carbonsäure (1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-methyl-amid5-Oxo-pyrrolidine-2-carboxylic acid (1- {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -methyl-amide
Figure imgf000114_0001
Figure imgf000114_0001
Nach Methode E wurde 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1- yl)-phenyl]-harnstoff mit 5-Oxo-pyrrolidin-2-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 505,62 (C28H35N5O4); MS (ESI): 506 (M+H+).According to Method E, 1- (4-cyclopentyloxy-phenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea was reacted with 5-oxo-pyrrolidine-2-carboxylic acid. This gave the product with the molecular weight 505.62 (C28H35N5O4); MS (ESI): 506 (M + H +).
Beispiel 49Example 49
2-Oxo-thiazolidin-4-carbonsäure (1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}- pyrrolidin-3-yl)-methyl-amid2-oxo-thiazolidine-4-carboxylic acid (1- {4- [3- (4-cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -methyl-amide
Figure imgf000114_0002
yl)-phenyl]-harnstoff mit 2-Oxo-thiazolidin-4-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 523,66 (C27H33N5O4S); MS (ESI): 524 (M+H+). APD62429PC
Figure imgf000114_0002
yl) -phenyl] urea reacted with 2-oxo-thiazolidine-4-carboxylic acid. This gave the product of molecular weight 523.66 (C27H33N5O4S); MS (ESI): 524 (M + H +). APD62429PC
Beispiel 50Example 50
(R)-1 -Methyl-piperidin-3-carbonsäure {1 -[4-(4-cyclohexyl-benzoylamino)-phenyl]- pyrrolidin-3-yl}-methyl-amid(R) -1-Methyl-piperidine-3-carboxylic acid {1- [4- (4-cyclohexyl-benzoylamino) -phenyl] -pyrrolidin-3-yl} -methyl-amide
Figure imgf000115_0001
Figure imgf000115_0001
Nach Methode E wurde (R)-4-Cyclohexyl-N-[4-(3-methylamino-pyrrolidin-1-yl)-phenyl]- benzamid mit 1-Methyl-piperidin-3-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 502,71 (C31H42N4O2); MS (ESI): 503 (M+H+).According to method E, (R) -4-cyclohexyl-N- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -benzamide was reacted with 1-methyl-piperidine-3-carboxylic acid. This gave the product with the molecular weight 502.71 (C31H42N4O2); MS (ESI): 503 (M + H +).
Beispiel 51Example 51
N-(1-{4-[3-(6-Cyclopentyloxy-pyridin-3-yl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl- acetamidN- (1- {4- [3- (6-Cyclopentyloxy-pyridin-3-yl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-methyl-acetamide
Figure imgf000115_0002
Figure imgf000115_0002
Nach Methode A wurde N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit Carbonyldiimidazol und dann 6-Cyclopentyloxy-pyridin-3-ylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 437,55 (C24H31N5O3); MS (ESI): 438 (M+H+). APD62429PCAccording to Method A, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with carbonyldiimidazole and then 6-cyclopentyloxy-pyridin-3-ylamine. This gave the product with the molecular weight 437.55 (C24H31N5O3); MS (ESI): 438 (M + H +). APD62429PC
6-Cyclopentyloxy-pyridin-3-ylamin6-cyclopentyloxy-pyridin-3-ylamine
Eine Mischung aus 5-Nitro-pyridin-2-ol (14,0 g), Bromcyclopentan (8,0 g), Kaliumcarbonat (14 g) und DMF (200 mL) wurde für 6 Stunden auf 80 °C erwärmt. Nach dem Abkühlen wurde die Reaktionsmischung mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel gereinigt. Das erhaltene Produkt (2-Cyclopentyloxy-5-nitro-pyridin) wurde nach Methode B hydriert.A mixture of 5-nitro-pyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 mL) was heated to 80 ° C for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product obtained (2-cyclopentyloxy-5-nitro-pyridine) was hydrogenated by Method B.
Man erhielt so das Produkt mit dem Molekulargewicht 178,24 (C10H14N2O); MS (ESI): 179 (M+H+).This gave the product with the molecular weight 178.24 (C10H14N2O); MS (ESI): 179 (M + H +).
Beispiel 52 1-(6-Cyclopentyloxy-pyridin-3-yl)-3-[4-(3-methylamino-pyrrolidin-1 -yl)-phenyl]-hamstoffExample 52 1- (6-Cyclopentyloxypyridin-3-yl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea
Figure imgf000116_0001
Figure imgf000116_0001
Nach Methode D wurde N-(1-{4-[3-(6-Cyclopentyloxy-pyridin-3-yl)-ureido]-phenyl}- pyrrolidin-3-yl)-N-methyl-acetamid mit Natronlauge behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 395,51 (C22H29N5O2); MS (ESI): 395 (M+H+).According to method D, 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 +).
Beispiel 53 APD62429PCExample 53 APD62429PC
4'-Fluor-biphenyl-4-carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}- amid4'-Fluoro-biphenyl-4-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000117_0001
Figure imgf000117_0001
Nach Methode E wurde N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4'- Fluor-biphenyl-4-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 431 ,51 (C26H26FN3O2); MS (ESI): 432 (M+H+).According to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4'-fluorobiphenyl-4-carboxylic acid. This gave the product with the molecular weight 431, 51 (C26H26FN3O2); MS (ESI): 432 (M + H +).
Beispiel 54Example 54
4'-Trifluormethyl-biphenyl-4-carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]- phenyl}-amid4'-Trifluoromethyl-biphenyl-4-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000117_0002
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 4'- Trifluormethyl-biphenyl-4-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 481 ,52 (C27H26F3N3O2); MS (ESI): 482 (M+H+).
Figure imgf000117_0002
By method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic acid. This gave the product with the molecular weight 481, 52 (C27H26F3N3O2); MS (ESI): 482 (M + H +).
Beispiele 55 - 103Examples 55-103
Nach Methode E wurde 1-(4-Phenoxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1-yl)- phenylj-harnstoff mit verschiedenen Carbonsäuren umgesetzt. Die Produkte sind in der Tabelle 2 zusammengefasst. APD62429PCAccording to Method E, 1- (4-phenoxy-phenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea was reacted with various carboxylic acids. The products are summarized in Table 2. APD62429PC
Beispiele 104 - 144Examples 104-144
Nach Methode E wurde 1-(4-Cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1- yl)-phenyl]-harnstoff mit verschiedenen Carbonsäuren umgesetzt. Die Produkte sind in der Tabelle 3 zusammengefasst.According to method E, 1- (4-cyclopentyloxy-phenyl) -3- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -urea was reacted with various carboxylic acids. The products are summarized in Table 3.
Beispiele 145-185Examples 145-185
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit verschiedenen Carbonsäuren umgesetzt. Die Produkte sind in der Tabelle 4 zusammengefasst.By method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with various carboxylic acids. The products are summarized in Table 4.
Beispiele 186-234Examples 186-234
Nach Methode A wurde N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit Carbonyldiimidazol und dann mit verschiedenen Aminen umgesetzt. Die Produkte sind in der Tabelle 5 zusammengefasst. According to Method A, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with carbonyldiimidazole and then with various amines. The products are summarized in Table 5.
Figure imgf000119_0001
Figure imgf000119_0001
APD62429PCAPD62429PC
Figure imgf000120_0001
Figure imgf000120_0001
APD62429PCAPD62429PC
Figure imgf000121_0001
Figure imgf000121_0001
APD62429PCAPD62429PC
Figure imgf000122_0001
Figure imgf000122_0001
APD62429PCAPD62429PC
Figure imgf000123_0001
Figure imgf000123_0001
APD62429PCAPD62429PC
Figure imgf000124_0001
Figure imgf000124_0001
APD62429PCAPD62429PC
Figure imgf000125_0001
Figure imgf000125_0001
APD62429PCAPD62429PC
Figure imgf000126_0001
Figure imgf000126_0001
APD62429PCAPD62429PC
Figure imgf000127_0001
Figure imgf000127_0001
Figure imgf000128_0001
APD62429PC
Figure imgf000128_0001
APD62429PC
Figure imgf000129_0001
Figure imgf000129_0001
APD62429PCAPD62429PC
Figure imgf000130_0001
Figure imgf000130_0001
APD62429PCAPD62429PC
Figure imgf000131_0001
Figure imgf000131_0001
APD62429PCAPD62429PC
Figure imgf000132_0001
Figure imgf000132_0001
Tabelle 4Table 4
Figure imgf000132_0002
Figure imgf000132_0002
APD62429PCAPD62429PC
Figure imgf000133_0001
Figure imgf000133_0001
APD62429PCAPD62429PC
Figure imgf000134_0001
Figure imgf000134_0001
APD62429PCAPD62429PC
Figure imgf000135_0001
Figure imgf000135_0001
APD62429PCAPD62429PC
Figure imgf000136_0001
Figure imgf000136_0001
APD62429PCAPD62429PC
Figure imgf000137_0001
Figure imgf000137_0001
APD62429PCAPD62429PC
Figure imgf000138_0001
Figure imgf000138_0001
APD62429PCAPD62429PC
Figure imgf000139_0001
Figure imgf000139_0001
APD62429PCAPD62429PC
Figure imgf000140_0001
Figure imgf000140_0001
APD62429PCAPD62429PC
Figure imgf000141_0001
Figure imgf000141_0001
APD62429PCAPD62429PC
Figure imgf000142_0001
Figure imgf000142_0001
APD62429PCAPD62429PC
Figure imgf000143_0001
Figure imgf000143_0001
APD62429PCAPD62429PC
Figure imgf000144_0001
Figure imgf000144_0001
APD62429PCAPD62429PC
Figure imgf000145_0001
Figure imgf000145_0001
APD62429PCAPD62429PC
Figure imgf000146_0001
Figure imgf000146_0001
APD62429PCAPD62429PC
Figure imgf000147_0001
Figure imgf000147_0001
Beispiel 235Example 235
N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-2- piperidin-1 -yl-acetamidN- (1- {4- [3- (4-Cyclopentyloxy-phenyl) -ureido] -phenyl} -pyrrolidin-3-yl) -N-methyl-2-piperidine-1-yl-acetamide
Figure imgf000148_0001
Figure imgf000148_0001
Nach Methode E wurde 1-(4-Cyclopentyloxy-phenyl)~3-[4-(3-methylamino- pyrrolidin-1-yl)-phenyl]-harnstoff mit Piperidin-1-yl-essigsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 519,69 (C30H41 N5O3); MS (ESI): 520 (M+H+).According to Method E, 1- (4-cyclopentyloxy-phenyl) -3- [4- (3-methylaminopyrrolidin-1-yl) -phenyl] -urea was reacted with piperidin-1-yl-acetic acid. This gave the product with the molecular weight 519.69 (C30H41 N5O3); MS (ESI): 520 (M + H +).
Beispiel 236Example 236
1 -Methyl-piperidin-3-carbonsäure {(/ϊ.)-1 -[5-(4-cyclohexyl-benzoylamino)-pyridin-2- yl]-pyrrolidin-3-yl}-methyl-amid1-Methyl-piperidine-3-carboxylic acid {(/ϊ.)-1 - [5- (4-cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-amide
Figure imgf000148_0002
Figure imgf000148_0002
Nach Methode E wurde (ft)-4-Cyclohexyl-N-[6-(3-methylamino-pyrrolidin-1-yl)- pyridin-3-yl]-benzamid mit 1-Methyl-piperidin-3-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 503,69 (C30H41 N502); MS (ESI): 504 (M+H+).According to Method E, (ft) -4-cyclohexyl-N- [6- (3-methylamino-pyrrolidin-1-yl) -pyridin-3-yl] -benzamide was reacted with 1-methyl-piperidine-3-carboxylic acid. This gave the product with the molecular weight 503.69 (C30H41 N502); MS (ESI): 504 (M + H +).
Beispiel 237Example 237
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-butoxy-phenyl)- propionamid APD62429PCN- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-butoxy-phenyl) -propionamide APD62429PC
Figure imgf000149_0001
Figure imgf000149_0001
Methode HMethod H
Zu einer Lösung von N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1 -yl]-phenyl}-2-(4- hydroxy-phenyl)-propionamid (27 mg) in DMF (1 mL) wurden Cäsiumcarbonat (36 mg) und n-Butylbromid (15 mg) zugegeben. Nach 2 Stunden Reaktionszeit bei Raumtemperatur wurde der Ansatz mit Wasser versetzt und mit Ethylacetat extrahiert. Die organische Phase wurde über Natriumsulfat getrocknet, eingeengt und der Rückstand aus Diethylether/Methanol kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 437,59 (C26H35N303); MS(ESI): 438 (M+H+).To a solution of N- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxy-phenyl) -propionamide (27 mg) in DMF (1 mL Cesium carbonate (36 mg) and n-butylbromide (15 mg) were added. After a reaction time of 2 hours at room temperature, water was added to the reaction and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the residue crystallized from diethyl ether / methanol. This gave the product with the molecular weight 437.59 (C26H35N303); MS (ESI): 438 (M + H +).
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-hydroxy-phenyl)- propionamidN- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxyphenyl) -propionamide
Nach Methode I wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 2-(4-Hydroxyphenyl)-propionsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 381 ,48 (C22H27N303); MS(ESI): 382 (M+H+).According to method I, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 2- (4-hydroxyphenyl) -propionic acid. This gave the product of molecular weight 381, 48 (C22H27N303); MS (ESI): 382 (M + H +).
Beispiel 238Example 238
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-isobutoxy-phenyl)- acetamidN- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-isobutoxy-phenyl) -acetamide
Figure imgf000149_0002
Figure imgf000149_0002
Nach Methode H wurde N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4- hydroxy-phenyl)-acetamid mit Isobutylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 423,56 (C25H33N303); MS(ESI): 424 (M+H+). APD62429PCBy method H, N- {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxy-phenyl) -acetamide was reacted with isobutyl bromide. This gave the product with the molecular weight 423.56 (C25H33N303); MS (ESI): 424 (M + H +). APD62429PC
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-hydroxy-phenyl)- acetamid Methode IN- {4- [3- (Acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxyphenyl) -acetamide Method I
4-Hydroxyphenylessigsäure (305 mg), 1 -Hydroxybenzotriazol (300 mg) und 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimid Hydrochlorid (480 mg) in DMF (5 mL) wurden mit N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid (470 mg) für 3 Stunden bei Raumtemperatur gerührt. Dann wurde der Ansatz mit Wasser versetzt und mit Ethylacetat extrahiert. Die organische Phase wurde mit ges. Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet, eingeengt und aus Diethylether kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 367,45 (C21H25N303); MS(ESI): 368 (M+H+).4-hydroxyphenylacetic acid (305mg), 1-hydroxybenzotriazole (300mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (480mg) in DMF (5mL) were treated with N- [1- (4-amino- phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide (470 mg) for 3 hours at room temperature. Then, the reaction was added with water and extracted with ethyl acetate. The organic phase was washed with sat. Washed sodium chloride solution, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This gave the product with the molecular weight 367.45 (C21H25N303); MS (ESI): 368 (M + H +).
Beispiel 239Example 239
(/?)-N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-butoxy-phenyl)- acetamid(/?) - N- {4- [3- (Acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-butoxy-phenyl) -acetamide
Figure imgf000150_0001
Figure imgf000150_0001
Nach Methode E wurde (fl)-N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl- acetamid mit 4-Butoxyphenylessigsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 423,56 (C25H33N303); MS(ESI): 424 (M+H+).According to method E, (fl) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 4-butoxyphenylacetic acid. This gave the product with the molecular weight 423.56 (C25H33N303); MS (ESI): 424 (M + H +).
Beispiel 240Example 240
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-cyclopropylmethoxy- phenyl)-propionamidN- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-cyclopropylmethoxy-phenyl) -propionamide
Figure imgf000150_0002
APD62429PC
Figure imgf000150_0002
APD62429PC
Nach Methode H wurde N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1 -yl]-phenyl}-2-(4- hydroxy-phenyl)-propionamid mit Brommethylcyclopropan umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 435,57 (C26H33N303); MS(ESI): 436 (M+H+).By Method H, N- {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxy-phenyl) -propionamide was reacted with bromomethylcyclopropane. This gave the product with the molecular weight 435.57 (C26H33N303); MS (ESI): 436 (M + H +).
Beispiel 241Example 241
N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-2-(4-cyclobutylmethoxy- phenyl)-propionamidN- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-cyclobutylmethoxy-phenyl) -propionamide
Figure imgf000151_0001
Figure imgf000151_0001
Nach Methode H wurde N-{4-[3-(Acetyl-methyl-amino)~pyrrolidin-1 -yl]-phenyl}-2-(4- hydroxy-phenyl)-propionamid mit Brommethylcyclobutan umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 449,60 (C27H35N303); MS(ESI): 450 (M+H+).By Method H, N- {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -2- (4-hydroxy-phenyl) -propionamide was reacted with bromomethylcyclobutane. This gave the product of molecular weight 449.60 (C27H35N303); MS (ESI): 450 (M + H +).
Beispiel 242Example 242
1-(4-Methoxy-phenyl)-cyclopropancarbonsäure {4-[3-(acetyl-methyl~amino)- pyrrolidin-1 -yl]-phenyl}-amid1- (4-Methoxy-phenyl) -cyclopropanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000151_0002
Figure imgf000151_0002
Nach Methode E wurde N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 1-(4-Methoxyphenyl)-1 -cyclopropancarbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 407,52 (C24H29N303); MS(ESI): 408 (M+H+). APD62429PCAccording to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 1- (4-methoxyphenyl) -1-cyclopropanecarboxylic acid. This gave the product of molecular weight 407.52 (C24H29N303); MS (ESI): 408 (M + H +). APD62429PC
Beispiel 243Example 243
1-(4-Butoxy-phenyl)-cyclopropancarbonsäure {4-[3-(acetyl-methyl-amino)- pyrrolidin-1 -yl]-phenyl}-amid1- (4-Butoxy-phenyl) -cyclopropanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000152_0001
Figure imgf000152_0001
Nach Methode H wurde 1-(4-Hydroxy-phenyl)-cyclopropancarbonsäure {4-[3- (acetyl-methyl-amino)-pyrrolidin-l -yl]-phenyl}-amid mit n-Butylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 449,60 (C27H35N303); MS(ESI): 450 (M+H+).In Method H, 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide was reacted with n-butylbromide. This gave the product of molecular weight 449.60 (C27H35N303); MS (ESI): 450 (M + H +).
1 -(4-Hydroxy-phenyl)-cyclopropancarbonsäure {4-[3-(acetyl-methyl-amino)- pyrrolidin-1 -yl]-phenyl}-amid1- (4-Hydroxy-phenyl) -cyclopropanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Zu einer Lösung von 1-(4-Methoxy-phenyl)-cyclopropancarbonsäure {4-[3-(acetyl- methyl-amino)-pyrrolidin-1-yl]-phenyl}-amid (540 mg) in Dichlormethan (5,5 mL) wurde bei 0°C Bortribromid-Dimethylsulfid (460 mg) zugegeben. Nach 12 Stunden Reaktionszeit bei Raumtemperatur wurde der Ansatz mit Wasser versetzt, die Phasen getrennt und die wäßrige Phase mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, eingeengt und durch Chromatographie (Kieselgel, Toluol/Ethanol/Ethylacetat 8:1 :1 unter Zusatz von 0,1% Triethylamin) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 393,49 (C23H27N303); MS(ESI): 394 (M+H+).To a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide (540 mg) in dichloromethane (5.5 mL) boron tribromide-dimethylsulfide (460 mg) was added at 0 ° C. After 12 hours reaction time at room temperature, the mixture was treated with water, the phases were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene / ethanol / ethyl acetate 8: 1: 1 with the addition of 0.1% triethylamine). This gave the product with the molecular weight 393.49 (C23H27N303); MS (ESI): 394 (M + H +).
Beispiel 244Example 244
(fl)-4-(4-Fluor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)- pyrrolidin-1-yl]-phenyl}-N-methyl-amid(fl) -4- (4-Fluoro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -N-methyl-amide
Figure imgf000152_0002
APD62429PC
Figure imgf000152_0002
APD62429PC
Eine Suspension von Natriumhydrid (95%ig in Öl; 0,005 g) in DMF (1 mL) wurde mit (fl)-4-(4-Fluor-phenyl)-piperidin-1 -carbonsäure {4-[3-(acetyl-methyl-amino)- pyrrolidin-1-yl]-phenyl}-amid (22 mg) versetzt. Nach beendeter Gasentwicklung wurde lodmethan (0,02 mL) zugesetzt. Nach zwei Stunden wurde die Reaktionsmischung vorsichtig mit Wasser hydrolysiert und mit Dichlormethan extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt und der Rückstand aus Pentan kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 452,58 (C26H33FN402); MS (ESI): 453 (M+H+).A suspension of sodium hydride (95% in oil, 0.005 g) in DMF (1 mL) was treated with (fl) -4- (4-fluoro-phenyl) -piperidine-1-carboxylic acid {4- [3- (acetyl- methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide (22 mg). When gas evolution ceased, iodomethane (0.02 mL) was added. After two hours, the reaction mixture was carefully hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This gave the product of molecular weight 452.58 (C26H33FN402); MS (ESI): 453 (M + H +).
Beispiel 245Example 245
5-2-[(2-Fluor-phenyl)-ethinyl]-furan-2-carbonsäure{4-[3-(acetyl-methyl-amino)- pyrrolidin-1 -yl]-phenyl}-amid5-2 - [(2-Fluoro-phenyl) -ethynyl] -furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000153_0001
Figure imgf000153_0001
Methode JMethod J
Unter inerten Bedingungen wurden zu einer Suspension von Palladium bis(tri-tert.- butylphosphin)dichlorid (3,8 mg) und Kupfer(l)-iodid (0,9 mg) in DMF (0,5 mL) zunächst Diisopropylamin (14,9 mg) und dann eine Lösung von 5-Bromfuran-2- carbonsäure{4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]-phenyl}-amid (50,0 mg) und 1 -Ethinyl-2-fluorbenzol (17,7 mg) in Dioxan (0,5 mL) und DMF (0,2 mL) zugegeben. Nach 12 Stunden Reaktionszeit bei Raumtemperatur wurde mit Ethylacetat verdünnt, über Kieselgel filtriert, das Filtrat eingeengt und über präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 445,18 (C26H24FN303); MS(ESI): 446 (M+H+) als Hydrotrifluoracetat.Under inert conditions, to a suspension of palladium bis (tri-tert-butylphosphine) dichloride (3.8 mg) and copper (I) iodide (0.9 mg) in DMF (0.5 mL), diisopropylamine (14 , 9 mg) and then a solution of 5-bromofuran-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide (50.0 mg) and 1 - Ethinyl-2-fluorobenzene (17.7 mg) in dioxane (0.5 mL) and DMF (0.2 mL) were added. After 12 hours reaction time at room temperature was diluted with ethyl acetate, filtered through silica gel, the filtrate was concentrated and purified by preparative HPLC. This gave the product with the molecular weight 445.18 (C26H24FN303); MS (ESI): 446 (M + H +) as hydrotrifluoroacetate.
5-Bromfuran-2-carbonsäure{4-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}- amid APD62429PC5-Bromo-furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide APD62429PC
Nach Methode E wurde N-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid mit 5-Brom-2-furancarbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 406,28 (C18H20BrN3O3); MS(ESI): 407 (M+H+).According to method E, N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide was reacted with 5-bromo-2-furancarboxylic acid. This gave the product with the molecular weight 406.28 (C18H20BrN3O3); MS (ESI): 407 (M + H +).
Beispiel 246Example 246
5-2-[(4-Fluor-phenyl)-ethinyl]-furan-2-carbonsäure{4-[3-(acetyl-methyl-amino)- pyrrolidin-1 -yl]-phenyl}-amid5-2 - [(4-Fluoro-phenyl) -ethynyl] -furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Nach Methode J wurde 5-Bromfuran-2-carbonsäure{4-[3-(acetyl-methyl-amino)- pyrrolidin-1-yl]-phenyl}-amid mit 1 -Ethinyl-4-fluorbenzol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 445,18 (C26H24FN303); MS(ESI): 446 (M+H+) als Hydrotrifluoracetat. By method J, 5-bromo-furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide was reacted with 1-ethynyl-4-fluorobenzene. This gave the product with the molecular weight 445.18 (C26H24FN303); MS (ESI): 446 (M + H +) as hydrotrifluoroacetate.
Beispiel 247Example 247
5-2-[(2-Chlor-phenyl)-ethinyl]-furan-2-carbonsäure{4-[3-(acetyl-methyl-amino)- pyrrolidin-1 -yl]-phenyl}-amid5-2 - [(2-Chloro-phenyl) -ethynyl] -furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000154_0002
Figure imgf000154_0002
Nach Methode J wurde 5-Bromfuran-2-carbonsäure{4-[3-(acetyl-methyl-amino)- pyrrolidin-1-yl]-phenyl}-amid mit 1 -Ethinyl-2-chlorbenzol umgesetzt. Man erhielt so APD62429PCBy method J, 5-bromo-furan-2-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide was reacted with 1-ethynyl-2-chlorobenzene. You got like that APD62429PC
das Produkt mit dem Molekulargewicht 461 ,15 (C26H24CIN303); MS(ESI): 462 (M+H+) als Hydrotrifluoracetat.the product of molecular weight 461, 15 (C26H24CIN303); MS (ESI): 462 (M + H +) as hydrotrifluoroacetate.
Beispiel 248Example 248
R-4-Butoxy-N-(3-fluor-4-{3-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-pyrrolidin- 1 -yl}-phenyl) -benzamidR-4-butoxy-N- (3-fluoro-4- {3 - [(2-hydroxy-2-methyl-propyl) -methyl-amino] -pyrrolidin-1-yl} -phenyl) -benzamide
Figure imgf000155_0001
Figure imgf000155_0001
Eine Lösung von (R)-4-Butoxy-N-[3-fluor-4-(3-methylamino-pyrrolidin-1-yl)-phenyl]- benzamid (0,03 g) und Isobutylenoxid in Ethanol (5 mL) wurden 3 Stunden unter Rückfluß erhitzt. Anschließend wurde im Vakuum eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 457,59 (C26H36FN303); MS (ESI): 458 (M+H+).A solution of (R) -4-butoxy-N- [3-fluoro-4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -benzamide (0.03 g) and isobutylene oxide in ethanol (5 mL) were refluxed for 3 hours. It was then concentrated in vacuo. This gave the product with the molecular weight 457.59 (C26H36FN303); MS (ESI): 458 (M + H +).
Beispiel 249Example 249
R-4-Butoxy-N-(3-fluor-4-{3-[(3-hydroxy-3-methyl-butyl)-methyl-amino]-pyrrolidin-1- yl}-phenyl)-N-methyl-benzamidR-4-butoxy-N- (3-fluoro-4- {3 - [(3-hydroxy-3-methylbutyl) -methyl-amino] -pyrrolidin-1-yl} -phenyl) -N-methyl- benzamide
Figure imgf000155_0002
Figure imgf000155_0002
Eine Lösung von (R)-4-Butoxy-N-[3-fluor-4-(3-methylamino-pyrrolidin-1-yl)-phenyl]- benzamid (0,03 g), Triethylamin (0,02 g) und 4-Brom-2-methyl-butan-2-ol (0,03 g) APD62429PCA solution of (R) -4-butoxy-N- [3-fluoro-4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -benzamide (0.03 g), triethylamine (0.02 g) and 4-bromo-2-methylbutan-2-ol (0.03 g) APD62429PC
in DMF (2 mL) wurde 16 Stunden auf 80 QC erwärmt. Nach dem Abkühlen wurde Ethylacetat (100 mL) hinzugegeben, mit Wasser (2 x 50 mL) gewaschen, die organische Phase mit Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde mit präparativer HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 471 ,62 (C27H38FN303); MS (ESI): 472 (M+H+).in DMF (2 mL) was heated at 80 ° C. for 16 hours. After cooling, ethyl acetate (100 mL) was added, washed with water (2 x 50 mL), the organic phase dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This gave the product of molecular weight 471, 62 (C27H38FN303); MS (ESI): 472 (M + H +).
4-Brom-2-methyl-butan-2-ol4-bromo-2-methyl-butan-2-ol
Eine Lösung von 3-Brompropionsäure-ethylester (10 g) in Diethylether (100 mL) wurde bei Raumtemperatur unter Argon mit Methylmagnesiumbromid (3M in Diethylether; 46 mL) versetzt. Hierbei wurde der Ansatz über 20 SC und unter 35 QC gehalten. Nach 2 Stunden wurde die Mischung auf eine gesättigte Ammoniumchloridlösung gegossen. Dann wurde mit Diethylether extrahiert, mit Natriumsulfat getrocknet, filtriert und eingeengt. Man erhielt so das gewünschte Produkt.A solution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 mL) at room temperature under argon was added methylmagnesium bromide (3M in diethyl ether, 46 mL). Here, the approach over 20 S C and was kept below 35 Q C. After 2 hours, the mixture was poured onto a saturated ammonium chloride solution. It was then extracted with diethyl ether, dried with sodium sulfate, filtered and concentrated. This gave the desired product.
Beispiel 250 R-4-Butoxy-N-[6-(3-dicyclopropylamino-pyrrolidin-1-yl)-pyridin-3-yl]-benzamidExample 250 R-4-Butoxy-N- [6- (3-dicyclopropylamino-pyrrolidin-1-yl) -pyridin-3-yl] -benzamide
Figure imgf000156_0001
Methode K
Figure imgf000156_0001
Method K
Eine Lösung aus (R)-N-[6-(3-Amino-pyrrolidin-1-yl)-pyridin-3-yl]-4-butoxy- benzamid (0,065 g) in Methanol (2 mL) wurde mit Eisessig (0,11 mL), und [(1- ethoxycyclopropyl)-oxy]-trimethylsilan (0,19 g) versetzt. Anschließend wurde Natriumcyanoborhydrid (0,051 g) zugegeben und 16 Stunden unter Rückfluß erhitzt. Dann wurde die Mischung filtriert, konzentriert, in Dichlormethan aufgenommen, mit Natriumhydroxid (2N; 20 mL) und Natriumchloridlösung (20 mL) gewaschen, mit Magnesiumsulfat getrocknet und eingeengt. Der Rückstand APD62429PCA solution of (R) -N- [6- (3-amino-pyrrolidin-1-yl) -pyridin-3-yl] -4-butoxybenzamide (0.065 g) in methanol (2 mL) was treated with glacial acetic acid ( 0.11 mL), and [(1-ethoxycyclopropyl) oxy] trimethylsilane (0.19 g). Then, sodium cyanoborohydride (0.051 g) was added and heated at reflux for 16 hours. The mixture was filtered, concentrated, taken up in dichloromethane, washed with sodium hydroxide (2N; 20 mL) and sodium chloride solution (20 mL), dried with magnesium sulfate and concentrated. The residue APD62429PC
wurde mit präparativer HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 434,59 (C26H34N402); MS (ESI): 435 (M+H+).was purified by preparative HPLC. This gave the product with the molecular weight 434.59 (C26H34N402); MS (ESI): 435 (M + H +).
Beispiel 251Example 251
R-4-Butoxy-N-[6-(3-dicyclopropylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl- benzamidR-4-butoxy-N- [6- (3-dicyclopropylamino-pyrrolidin-1-yl) -pyridin-3-yl] -N-methyl-benzamide
Figure imgf000157_0001
Figure imgf000157_0001
Nach Methode F wurde (R)-4-Butoxy-N-[6-(3-dicyclopropylamino-pyrrolidin-1-yl)- pyridin-3-yl]-benzamid methyliert. Man erhielt so das Produkt mit dem Molekulargewicht 448,61 (C27H36N402); MS (ESI): 449 (M+H+).Method F methylated (R) -4-butoxy-N- [6- (3-dicyclopropylamino-pyrrolidin-1-yl) -pyridin-3-yl] -benzamide. This gave the product of molecular weight 448.61 (C27H36N402); MS (ESI): 449 (M + H +).
Beispiel 252Example 252
R-4-Butoxy-N-{6-[3-(cyclopropyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}- benzamidR-4-butoxy-N- {6- [3- (cyclopropylmethyl-amino) -pyrrolidin-1-yl] -pyridin-3-yl} -benzamide
Figure imgf000157_0002
Figure imgf000157_0002
Nach Methode K wurde (R)-4-Butoxy-N-[6-(3-methylamino-pyrrolidin-1-yl)-pyridin- 3-yl]-benzamid cyclopropyliert. Man erhielt so das Produkt mit dem Molekulargewicht 408,551 (C24H32N402); MS (ESI): 409 (M+H+). APD62429PCIn method K, (R) -4-butoxy-N- [6- (3-methylamino-pyrrolidin-1-yl) -pyridin-3-yl] -benzamide was cyclopropylated. This gave the product with the molecular weight 408.551 (C24H32N402); MS (ESI): 409 (M + H +). APD62429PC
Beispiel 253Example 253
{1-[4-(2-Amino-4-butoxy-benzoylamino)-3-fluor-phenyl]-pyrrolidin-3-yl}-methyl- carbaminsäure tert-butylester{1- [4- (2-Amino-4-butoxybenzoylamino) -3-fluoro-phenyl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester
Nach Methode E wurde [1 -(4-Amino-3-fluor-phenyl)-pyrrolidin-3-yl]-methyl- carbaminsäure tert-butylester mit 4-Butoxy-2-riitro-benzoesäure umgesetzt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 500,62 (C27H37FN4O4); MS (ESI): 501 (M+H+).According to method E, tert-butyl [1- (4-amino-3-fluorophenyl) -pyrrolidin-3-yl] -methylcarbamate was reacted with 4-butoxy-2-nitrobenzoic acid and then hydrogenated. This gave the product of molecular weight 500.62 (C27H37FN4O4); MS (ESI): 501 (M + H +).
4-Butoxy-2-nitro-benzoesäure4-Butoxy-2-nitro-benzoic acid
Eine Lösung aus 4-Fluor-2-nitro-benzoesäure (1 ,81 g) in Butanol (20 mL) wurde mit Schwefelsäure (3 mL) versetzt und 4 Stunden bei 110 QC gerührt. Es wurde Ethylacetat (100 mL) hinzugefügt, mit gesättigter Natriumhydrogencarbonat Lösung (3 x 50 mL) gewaschen, mit Natriumsulfat getrocknet, filtriert und im Vakuum eingeengt. Der Rückstand (2,2 g) wurde bei -10 QC zu einerA solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 mL) was added with sulfuric acid (3 mL) and stirred at 110 ° C. for 4 hours. Ethyl acetate (100 mL) was added, washed with saturated sodium bicarbonate solution (3 x 50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue (2.2 g) became at -10 ° C
Natriumbutoxylat Lösung, hergestellt aus Butanol (20 mL) und Natriumhydrid (2,18 g) bei -10 QC, unter Argon zugetropft und anschließend 20 Stunden gerührt. Es wurde Ethylacetat (100 mL) hinzugegeben, mit Wasser (2 x 50 mL) gewaschen, über Natriumsulfat getrocknet, filtriert und im Vakuum eingeengt. Der Rückstand wurde mit präparativer HPLC gereinigt. Der 4-Butoxy-2-nitro- benzoesäurebutylester wurde bei Raumtemperatur über 3 Stunden mit Natriumhydroxid (5N; 100 mL) in Ethanol verseift. Es wurde mit Salzsäure (10N; 100 mL) sauer gestellt, mit Dichlormethan extrahiert, die organische Phase über Natriumsulfat getrocknet, filtriert und konzentriert. Man erhielt so das Produkt mit dem Molekulargewicht 239,23 (C11 H13N05); MS (ESI): 240 (M+H+). APD62429PCSodium butoxylate solution, prepared from butanol (20 mL) and sodium hydride (2.18 g) at -10 Q C, added dropwise under argon and then stirred for 20 hours. Ethyl acetate (100 mL) was added, washed with water (2 x 50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was saponified at room temperature for 3 hours with sodium hydroxide (5N, 100 mL) in ethanol. It was acidified with hydrochloric acid (10 N, 100 mL), extracted with dichloromethane, the organic phase dried over sodium sulfate, filtered and concentrated. This gave the product of molecular weight 239.23 (C11 H13N05); MS (ESI): 240 (M + H +). APD62429PC
Beispiel 254Example 254
N-{4-[3-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-oxo-pyrrolidin-1-yl]-phenyl}-4-cyclohexyl-N- {4- [3- (7-aza-bicyclo [2.2.1] hept-7-yl) -2-oxo-pyrrolidin-1-yl] -phenyl} -4-cyclohexyl-
N-methyl-benzamidN-methyl-benzamide
Figure imgf000159_0001
Figure imgf000159_0001
Methode LMethod L
Eine Mischung von N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl-N- methyl-benzamid (100 mg), Kaliumcarbonat (60 mg), 7-Aza-bicyclo[2.2.1]heptan (44 mg) und DMF (2 mL) wurde für 6 Stunden bei 50°C gehalten. Die Mischung wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 471 ,65 (C30H37N3O2); MS (ESI): 472 (M+H+).A mixture of N- [4- (3-bromo-2-oxo-pyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide (100 mg), potassium carbonate (60 mg), 7-aza bicyclo [2.2.1] heptane (44 mg) and DMF (2 mL) were kept at 50 ° C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 471, 65 (C30H37N3O2); MS (ESI): 472 (M + H +).
N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl-N-methyl-benzamid N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benzamid (3,0 g) in Acetonitril (30 mL) wurde mit Trinatriumphosphat (0,95 g) versetzt und bei 0°C 2-Brom-4- chlorbutyrylbromid (2,9 g) zugesetzt. Nach einer Stunde wurde eine Lösung von Natriumhydroxid (0,85 g) in Wasser (10 mL) zugesetzt und die Mischung 6 Stunden bei Raumtemperatur intensiv gerührt. Danach wurde die gleiche Menge Natronlauge zugesetzt und weitere 48 Stunden gerührt. Die Reaktionslösung wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel (Laufmittel Ethylacetat/Heptan 1 :2) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 455,40 (C24H27BrN202); MS (ESI): 456 (M+H+).N- [4- (3-Bromo-2-oxo-pyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide N- (4-Amino-phenyl) -4-cyclohexyl-N-methyl -benzamide (3.0 g) in acetonitrile (30 mL) was added trisodium phosphate (0.95 g) and 2-bromo-4-chlorobutyryl bromide (2.9 g) was added at 0 ° C. After one hour, a solution of sodium hydroxide (0.85 g) in water (10 mL) was added and the mixture stirred vigorously for 6 hours at room temperature. Thereafter, the same amount of sodium hydroxide solution was added and stirred for a further 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent ethyl acetate / heptane 1: 2). This gave the product with the molecular weight 455.40 (C24H27BrN202); MS (ESI): 456 (M + H +).
N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benzamid APD62429PCN- (4-Amino-phenyl) -4-cyclohexyl-N-methyl-benzamide APD62429PC
4-Cyclohexylcarbonsäure (5,0 g) und 4-Nitrophenylisocyanat (4,0 g) wurden in Toluol (150 mL) für 3 Stunden gerührt und dann über Nacht stehen gelassen. Der Niederschlag wurde abgesaugt und mit Diethylether gewaschen. Das erhaltene Amid wurde nach Methode F methyliert und nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 308,43 (C20H24N2O); MS (ESI): 309 (M+H+).4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenyl isocyanate (4.0 g) were stirred in toluene (150 mL) for 3 hours and then allowed to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was methylated by Method F and hydrogenated by Method B. This gave the product with the molecular weight 308.43 (C20H24N2O); MS (ESI): 309 (M + H +).
Beispiel 255 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxo-pyrrolidin-1-yl)-phenyl]- benzamidExample 255 4-Cyclohexyl-N-methyl-N- [4- (3-morpholin-4-yl-2-oxopyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000160_0001
Figure imgf000160_0001
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Morphölin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 461 ,61 (C28H35N303); MS (ESI): 462 (M+H+).By method L, N- [4- (3-bromo-2-oxo-pyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methyl-benzamide was reacted with morpholine. This gave the product of molecular weight 461, 61 (C28H35N303); MS (ESI): 462 (M + H +).
Beispiel 256Example 256
4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1-yl-pyrrolidin-1-yl)-phenyl]- benzamid4-Cyclohexyl-N-methyl-N- [4- (2-oxo-3-piperidin-1-yl-pyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000160_0002
APD62429PC
Figure imgf000160_0002
APD62429PC
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Piperidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 459,64 (C29H37N302); MS (ESI): 460 (M+H+).By method L, N- [4- (3-bromo-2-oxopyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide was reacted with piperidine. This gave the product of molecular weight 459.64 (C29H37N302); MS (ESI): 460 (M + H +).
Beispiel 257 4-Cyclohexyl-N-methyl-N-[4-(2'-oxo-[1 ,3']bipyrrolidinyl-1,-yl)-phenyl]-benzamidExample 257 4-cyclohexyl-N-methyl-N- [4- (2'-oxo- [1, 3 '] bipyrrolidinyl-1 -yl) -phenyl] -benzamide
Figure imgf000161_0001
Figure imgf000161_0001
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1 -yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Pyrrolidin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 445,61 (C28H35N302); MS (ESI): 446 (M+H+).By method L, N- [4- (3-bromo-2-oxopyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide was reacted with pyrrolidine. This gave the product with a molecular weight of 445.61 (C28H35N302); MS (ESI): 446 (M + H +).
Beispiel 258 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxo-pyrrolidin-1-yl)-phenyl]- benzamidExample 258 4-Cyclohexyl-N-methyl-N- [4- (3-methylamino-2-oxopyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000161_0002
Figure imgf000161_0002
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Methylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 405,54 (C25H31 N302); MS (ESI): 406 (M+H+). APD62429PCBy method L, N- [4- (3-bromo-2-oxo-pyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methyl-benzamide was reacted with methylamine. This gave the product with the molecular weight 405.54 (C25H31 N302); MS (ESI): 406 (M + H +). APD62429PC
Beispiel 259Example 259
4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxo-pyrrolidin-1-yl)-phenyl]-N-methyl- benzamid4-Cyclohexyl-N- [4- (3-cyclohexylamino-2-oxopyrrolidin-1-yl) -phenyl] -N-methylbenzamide
Figure imgf000162_0001
Figure imgf000162_0001
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Cyclohexylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 473,66 (C30H39N3O2); MS (ESI): 474 (M+H+).According to method L, N- [4- (3-bromo-2-oxopyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine. This gave the product with the molecular weight 473.66 (C30H39N3O2); MS (ESI): 474 (M + H +).
Beispiel 260Example 260
4-Cyclohexyl-N-{4-[3-(cyclopropylmethyl-amino)-2-oxo-pyrrolidin-1-yl]-phenyl}-N- methyl-benzamid4-Cyclohexyl-N- {4- [3- (cyclopropylmethyl-amino) -2-oxopyrrolidin-1-yl] -phenyl} -N-methylbenzamide
Figure imgf000162_0002
Figure imgf000162_0002
Nach Methode L wurde N-[4-(3-Brom-2-oxo-pyrrolidin-1-yl)-phenyl]-4-cyclohexyl- N-methyl-benzamid mit Cyclopropylmethylamin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 445,61 (C28H35N302); MS (ESI): 446 (M+H+). APD62429PCBy method L, N- [4- (3-bromo-2-oxopyrrolidin-1-yl) -phenyl] -4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine. This gave the product with a molecular weight of 445.61 (C28H35N302); MS (ESI): 446 (M + H +). APD62429PC
Beispiel 261Example 261
N-{4-[3-(Acetyl-methyl-amino)-2-oxo-pyrrolidin-1-yl]-phenyl}-4-cyclohexyl-N- methyl-benzamidN- {4- [3- (acetylmethyl-amino) -2-oxopyrrolidin-1-yl] -phenyl} -4-cyclohexyl-N-methylbenzamide
Figure imgf000163_0001
Figure imgf000163_0001
4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxo-pyrrolidin-1-yl)-phenyl]- benzamid (52 mg) wurde mit Pyridin (0.5 mL) und Acetanhydrid (130 mg) versetzt und nach 3 Stunden flüchtige Anteile im Vakuum entfernt. Man erhielt so das Produkt mit dem Molekulargewicht 447,58 (C27H33N303); MS (ESI): 448 (M+H+).4-Cyclohexyl-N-methyl-N- [4- (3-methylamino-2-oxopyrrolidin-1-yl) -phenyl] -benzamide (52 mg) was treated with pyridine (0.5 mL) and acetic anhydride (130 mg). added and removed after 3 hours of volatile components in vacuo. This gave the product of molecular weight 447.58 (C27H33N303); MS (ESI): 448 (M + H +).
Beispiel 262Example 262
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidin-1-yl)-phenyl]- benzamid4-Cyclohexyl-N-methyl-N- [4- (4-methylamino-2-oxopyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000163_0002
Figure imgf000163_0002
1 -{4-[(4-Cyclohexyl-benzoyl)-methyl-amino]-phenyl}-5-oxo-pyrrolidin-3- carbonsäure (1 ,5 g) wurde mit tert-Butanol (8 mL), Triethylamin (350 mg) und schliesslich mit Diphenylphosphorylazid (1 ,18 g) versetzt und für 48 Stunden auf 95°C erhitzt. Die Reaktionslösung wurde mit Ethylacetat verdünnt und zweimal mit Wasser gewaschen. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde nach Methode G weiter APD62429PC1 - {4 - [(4-Cyclohexyl-benzoyl) -methyl-amino] -phenyl} -5-oxo-pyrrolidine-3-carboxylic acid (1.5 g) was treated with tert-butanol (8 mL), triethylamine (350 mg) and finally with diphenylphosphorylazide (1.18 g) and heated to 95 ° C for 48 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was further to method G. APD62429PC
umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 405,54 (C25H31N302); MS (ESI): 406 (M+H+).implemented. This gave the product with the molecular weight 405.54 (C25H31N302); MS (ESI): 406 (M + H +).
1-{4-[(4-Cyclohexyl-benzoyl)-methyl-amino]-phenyl}-5-oxo-pyrrolidin-3- carbonsäure1- {4 - [(4-Cyclohexyl-benzoyl) -methyl-amino] -phenyl} -5-oxo-pyrrolidine-3-carboxylic acid
N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benzamid (3,0 g) wurde mit Itaconsäure (1.27 g) für 3 Stunden auf 100 °C erwärmt. Die Reinigung erfolgte durch Filtration über Kieselgel (Laufmittel Ethylacatat/Methanol 5:1). Man erhielt so das Produkt mit dem Molekulargewicht 420,51 (C25H28N204); MS (ESI): 421 (M+H+).N- (4-Amino-phenyl) -4-cyclohexyl-N-methylbenzamide (3.0 g) was heated at 100 ° C with itaconic acid (1.27 g) for 3 hours. The purification was carried out by filtration through silica gel (mobile phase ethyl acetate / methanol 5: 1). This gave the product of molecular weight 420.51 (C25H28N204); MS (ESI): 421 (M + H +).
Beispiel 263Example 263
N-{4-[4-(Acetyl-methyl-amino)-2-oxo-pyrrolidin-1-yl]-phenyl}-4-cyclohexyl-N- methyl-benzamidN- {4- [4- (acetylmethyl-amino) -2-oxopyrrolidin-1-yl] -phenyl} -4-cyclohexyl-N-methylbenzamide
Figure imgf000164_0001
Figure imgf000164_0001
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidin-1-yl)-phenyl]- benzamid (101 mg) wurde mit Pyridin (20mg) und Acetanhydrid (25 mg) versetzt und nach 3 Stunden flüchtige Anteile im Vakuum entfernt. Man erhielt so das Produkt mit dem Molekulargewicht 447,58 (C27H33N303); MS (ESI): 448 (M+H+).4-Cyclohexyl-N-methyl-N- [4- (4-methylamino-2-oxopyrrolidin-1-yl) -phenyl] -benzamide (101 mg) was added with pyridine (20 mg) and acetic anhydride (25 mg) and after 3 hours volatiles removed in vacuo. This gave the product of molecular weight 447.58 (C27H33N303); MS (ESI): 448 (M + H +).
Beispiel 264 APD62429PCExample 264 APD62429PC
(1-{5-[(4-Cyclohexyl-benzoyl)-propyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl- carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) -propyl-amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Figure imgf000165_0001
Figure imgf000165_0001
Methode F-aMethod F-a
{1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]-pyrrolidin-3-yl}-methyl- carbaminsäure tert-butylester (50 mg), Cäsiumcarbonat (249 mg), Kaliumiodid (17 mg), N-Methylpyrrolidon (1 ,5 mL) und Propyliodid (40 mg) wurden für 5 Stunden bei 60°C gerührt. War der Umsatz unvollständig wurde auf 100°C erhitzt, weiteres Propyliodid (40 mg) zugegeben und für 12 Stunden auf 140°C erhitzt. Das Reaktionsgemisch wurde mit Ethylacetat verdünnt, mit Wasser und Natriumhydrogencarbonatlosung gewaschen, über Chromabond XTR getrocknet und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 520,72 (C31 H44N4O3); MS (ESI): 521 (M+H+).{1- [5- (4-Cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-carbamic acid tert -butyl ester (50 mg), cesium carbonate (249 mg), potassium iodide (17 mg) , N-methylpyrrolidone (1.5 mL) and propyl iodide (40 mg) were stirred for 5 hours at 60 ° C. When the conversion was incomplete, it was heated to 100 ° C, additional propyl iodide (40 mg) added and heated to 140 ° C for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and sodium bicarbonate solution, dried over Chromabond XTR and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 520.72 (C31 H44N4O3); MS (ESI): 521 (M + H +).
Beispiel 265Example 265
(1-{5-[(4-Cyclohexyl-benzoyl)-(1-ethyl-propyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)- methyl-carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) - (1-ethyl-propyl) -amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Figure imgf000165_0002
APD62429PC
Figure imgf000165_0002
APD62429PC
Nach Methode F-a wurde {1 -[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]- pyrrolidin-3-yl}-methyl-carbaminsäure tert-butylester mit 2-Ethylbutylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 548,78 (C33H48N403); MS (ESI): 549 (M+H+).According to method F-a, {1- [5- (4-cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester was reacted with 2-ethyl-butylbromide. This gave the product of molecular weight 548.78 (C33H48N403); MS (ESI): 549 (M + H +).
Beispiel 266Example 266
(1-{5-[(4-Cyclohexyl-benzoyl)-(3-methyl-but-2-enyl)-amino]-pyridin-2-yl}-pyrrolidin- 3-yl)-methyl-carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) - (3-methyl-but-2-enyl) -amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Figure imgf000166_0001
Figure imgf000166_0001
Nach Methode F-a wurde {1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]- pyrrolidin-3-yl}-methyl-carbaminsäure tert-butylester mit 3-Methyl-2-butenylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 546,76 (C33H46N403); MS (ESI): 547 (M+H+).By method F-a, {1- [5- (4-cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester was reacted with 3-methyl-2-butenylbromide. This gave the product of molecular weight 546.76 (C33H46N403); MS (ESI): 547 (M + H +).
Beispiel 267Example 267
(1-{5-[(4-Cyclohexyl-benzoyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl- carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) -methyl-amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Figure imgf000166_0002
APD62429PC
Figure imgf000166_0002
APD62429PC
Nach Methode F-a wurde {1 -[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]~ pyrrolidin-3-yl}-methyl-carbaminsäure tert-butylester mit Methyliodid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 492,67 (C29H40N4O3); MS (ESI): 493 (M+H+).According to method F-a, {1- [5- (4-cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester was reacted with methyl iodide. This gave the product with the molecular weight 492.67 (C29H40N4O3); MS (ESI): 493 (M + H +).
Weiter wurden nach Methode F-a aus {1 -[5-(4-Cyclohexyl-benzoylamino)-pyridin- 2-yl]-pyrrolidin-3-yl}-methyl-carbaminsäure tert-butylester und dem entsprechenden Alkylierungsmittel folgende Verbindungen erhalten:Furthermore, the following compounds were obtained by method F-a from {1- [5- (4-cyclohexyl-benzoylamino) -pyridin-2-yl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester and the corresponding alkylating agent:
(1-{5-[sec-Butyl-(4-cyclohexyl-benzoyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl- carbaminsäure tert-butylester(1- {5- [sec-Butyl- (4-cyclohexyl-benzoyl) -amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
(1-{5-[(4-Cyclohexyl-benzoyl)-isopropyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl- carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) -isopropyl-amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
(1-{5-[(4-Cyclohexyl-benzoyl)-prop-2-inyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)- methyl-carbaminsäure tert-butylester(1- {5 - [(4-Cyclohexyl-benzoyl) -prop-2-ynyl-amino] -pyridin-2-yl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Beispiel 268Example 268
5-p-Tolylethinyl-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]- amid5-p-Tolylethynyl-furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000167_0001
Figure imgf000167_0001
Unter Argon wurden zu 3,8 mg Pd(tBu)2CI2 und 0,95 mg Cul in 0,2 mL DMF 0,042 mL Diisopropylamin gegeben. Anschließend wurden eine Lösung aus 94,6 mg 5- Brom-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid in 0,3 mL DMF und eine Lösung aus 4-Ethinyltoluol in 0,3 mL DMF zugetropft. Die APD62429PCUnder argon, 0.042 ml of diisopropylamine was added to 3.8 mg of Pd (tBu) 2 Cl 2 and 0.95 mg of CuI in 0.2 ml of DMF. Subsequently, a solution of 94.6 mg of 5-bromofuran-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide in 0.3 mL of DMF and a solution of 4-ethynyltoluene added dropwise in 0.3 mL DMF. The APD62429PC
Lösung wurde über Nacht bei Raumtemperatur gerührt. Der ausgefallene Niederschlag abgesaugt und das Filtrat durch präparative HPLC gereinigt. Das gewünschte Produkt mit dem Molekurlargewicht 413,52; MS (ESI): 414 wurde als Hydrotrifluoracetat erhalten.Solution was stirred at room temperature overnight. The precipitate was filtered off with suction and the filtrate was purified by preparative HPLC. The desired product with molecular weight 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.
5-Brom-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid Nach Methode E wurde [1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin mit 5- Brom-2-furancarbonsäure umgesetzt. Es wurde das Produkt mit einem Molekulargewicht von 378,27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) als Hydrotrifluoracetat erhalten.5-Bromo-furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide According to Method E, [1- (4-amino-phenyl) -pyrrolidin-3-yl] - dimethyl-amine reacted with 5-bromo-2-furancarbonsäure. It was the product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M + H +) as hydrotrifluoroacetate.
Analog wurden die Beispiele 269-273 dargestellt:Analogously, Examples 269-273 were shown:
Figure imgf000168_0001
APD62429PC
Figure imgf000168_0001
APD62429PC
Figure imgf000169_0002
Figure imgf000169_0002
Beispiel 274Example 274
(R)-4'-Fluor-biphenyl-4-carbonsäure [6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3- yl]-amid(R) -4'-Fluoro-biphenyl-4-carboxylic acid [6- (3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl] -amide
Figure imgf000169_0001
Figure imgf000169_0001
Methode MMethod M
(R)-4'-Fluor-biphenyl-4-carbonsäure [6-(3-methylamino-pyrrolidin-1-yl)-pyridin-3- yl]-amid (390 mg) gelöst in Ameisensäure (230 mg) wurde mit Formaldehydiösung (37% aq.; 0.4 mL) versetzt und die Mischung für 3 Stunden auf 80°C erwärmt. Die abgekühlte Reaktionslösung wurde eingeengt und zwischen Ethylacetat und einer gesättigten Natriumcarbonatlösung verteilt. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 404,49 (C24H25FN40); MS (ESI): 405 (M+H+).(R) -4'-Fluoro-biphenyl-4-carboxylic acid [6- (3-Methylamino-pyrrolidin-1-yl) -pyridin-3-yl] -amide (390 mg) dissolved in formic acid (230 mg) was washed with Formaldehydiösung (37% aq, 0.4 mL) and the mixture heated to 80 ° C for 3 hours. The cooled reaction solution was concentrated and partitioned between ethyl acetate and a saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 404.49 (C24H25FN40); MS (ESI): 405 (M + H +).
Beispiel 275Example 275
1-(4-Fluor-phenyl)-piperidin-4-carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin- 1 -yl]-phenyl}-amid APD62429PC1- (4-Fluoro-phenyl) -piperidine-4-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide APD62429PC
Figure imgf000170_0001
Figure imgf000170_0001
Methode E-aMethod E-a
Eine Mischung aus 0,048 g 1-(4-Fluor-phenyl)-piperidin-4-carbonsäure und 0,5 mL SOCI2 und einem Tropfen DMF wurden 2 Stunden bei Raumtemperatur gerührt. Anschließend wurde das überschüssige SOCI2 im Vakuum entfernt. Der Rückstand wurde in 0,4 mL DMF gelöst und mit 0,033 mL Triethylamin und 0,048 g N-[1 -(4-Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid versetzt. Die Lösung wurde über Nacht bei Raumtemperatur gerührt. Danach wurde die Lösung abfiltriert und über päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 438,20 (C25H31FN402); MS (ESI): 439 (M+H+) als Hydrotrifluoracetat.A mixture of 0.048 g of 1- (4-fluoro-phenyl) -piperidine-4-carboxylic acid and 0.5 mL of SOCl 2 and one drop of DMF were stirred for 2 hours at room temperature. Subsequently, the excess SOCl 2 was removed in vacuo. The residue was dissolved in 0.4 ml of DMF and admixed with 0.033 ml of triethylamine and 0.048 g of N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide. The solution was stirred at room temperature overnight. Thereafter, the solution was filtered off and purified by preparative HPLC. This gave the product with the molecular weight 438.20 (C25H31FN402); MS (ESI): 439 (M + H +) as hydrotrifluoroacetate.
1-(4-Fluor-phenyl)-piperidin-4-carbonsäure1- (4-fluoro-phenyl) -piperidine-4-carboxylic acid
In einem ausgeheizten und mit Argon gespülten Kolben wurden 0,875 g 4- Bromfluorbenzol, 0,016 g Pd(dba)3*CHCI3, 0,022 g 2-In a heated and argon purged flask, 0.875 g of 4-bromofluorobenzene, 0.016 g of Pd (dba) 3 * CHCl 3, 0.022 g of 2-
(Dicyclohexylphosphino)biphenyl und 2,28 g Cäsiumcarbonat gegeben und mit 0,943 g 4-Piperidincarbonsäureethylester in 5 mL entgastem Toluol versetzt. Die Lösung wurde über Nacht auf 100 °C erhitzt. Nach dem Abkühlen wurde die Mischung im Vakuum eingeengt. Der Rückstand wurde in Ethylacetat/ Wasser aufgenommen. Die organische Phase wurde mit 10% NaHC03-Lsg. gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wurde durch päparative HPLC gereinigt.(Dicyclohexylphosphino) biphenyl and 2.28 g of cesium carbonate and treated with 0.943 g of 4-Piperidincarbonsäureethylester in 5 mL of degassed toluene. The solution was heated at 100 ° C overnight. After cooling, the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate / water. The organic phase was washed with 10% NaHCO 3 solution. washed, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC.
Zu einer Lösung aus 1,1 g 1-(4-Fluor-phenyl)-piperidin-4-carbonsäureethylester in 100 mL Methanol wurden 4,4 mL einer 2N Kaliumhydroxidlösung gegeben. Es wurde über Nacht bei Raumtemperatur gerührt. Anschließend wurde mit 5% APD62429PCTo a solution of 1.1 g of 1- (4-fluoro-phenyl) -piperidine-4-carboxylic acid ethyl ester in 100 mL of methanol was added 4.4 mL of a 2N potassium hydroxide solution. It was stirred overnight at room temperature. Subsequently, with 5% APD62429PC
Salzsäure ein pH-Wert von 6 eingestellt und die Lösung im Vakuum eingeengt. Der Rückstand wurde durch päparative HPLC gereinigt.Hydrochloric acid adjusted to a pH of 6 and the solution concentrated in vacuo. The residue was purified by preparative HPLC.
Beispiel 276Example 276
4-Phenoxy-cyclohexancarbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]- phenyl}-amid4-Phenoxy-cyclohexanecarboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000171_0001
Figure imgf000171_0001
Eine Lösung aus 0,106 g 4-Phenoxy-cyclohexancarbonsäure und 0,113 g N-[1-(4- Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid in 9 mL DMF wurde bei 0°C mit 0,251 g PyBOP und 0,135 mL Triethylamin versetzt. Nach 10 Minuten ließ man die Lösung auf Raumtemperatur kommen und rührte über Nacht bei dieser Temperatur. Anschließend wurde das Lösungsmittel im Vakuum entfernt und der Rückstand in Wasser / Ethylacetat aufgenommen. Die Ethylacetatphase wurde mit 10% Zitronensäure und 10% NaHC03-Lösung gewaschen, über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Der Rückstand wurde durch päparative HPLC gereinigt. Das gewünschte Produkt wurde erhalten. Molekulargewicht 435,25 (C26H33N303), MS: 436 (M+H+).A solution of 0.106 g of 4-phenoxy-cyclohexanecarboxylic acid and 0.113 g of N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide in 9 mL of DMF was added 0.251 g at 0 ° C PyBOP and 0.135 mL triethylamine were added. After 10 minutes, the solution was allowed to come to room temperature and stirred overnight at this temperature. The solvent was then removed in vacuo and the residue taken up in water / ethyl acetate. The ethyl acetate phase was washed with 10% citric acid and 10% NaHCO 3 solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 435.25 (C26H33N303), MS: 436 (M + H +).
4-Phenoxy-cyclohexancarbonsäure4-Phenoxy-cyclohexanecarboxylic acid
Zu einer Lösung aus 0,522 g 4-Hydroxycyclohexancarbonsäureethylester in 5,0 mL Pyridin wurden 0,63 g p-Toluolsulfonylchlorid gegeben. Die Reaktion wurde 3 Stunden bei Raumtemperatur gerührt. Die Reaktionsmischung wurde im Vakuum eingeengt. Der erhaltene Feststoff wurde in Wasser und Ethylacetat aufgenommen und die organische Phase dreimal mit 2 N Salzsäure und einmal mit gesättigter NaCI-Lösung gewaschen. Die organische Phase wurde über APD62429PCTo a solution of 0.522 g of 4-hydroxycyclohexanecarboxylic acid ethyl ester in 5.0 mL of pyridine was added 0.63 g of p-toluenesulfonyl chloride. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting solid was taken up in water and ethyl acetate, and the organic phase was washed three times with 2N hydrochloric acid and once with saturated NaCl solution. The organic phase was over APD62429PC
Natriumsulfat getrocknet und im Vakuum eingeengt. Das erhaltene Produkt wurde ohne weitere Reinigung im nächsten Schritt eingesetzt.Dried sodium sulfate and concentrated in vacuo. The product obtained was used in the next step without further purification.
Das erhaltene Produkt (0,55 g) wurde in 11 ,2 mL DMF gelöst, mit 0,159 g Phenol und 0,549 g Cäsiumcarbonat versetzt. Dann wurde die Lösung 6 Stunden auf 80 °C erhitzt. Nach dem Abkühlen wurde die Mischung im Vakuum eingeengt und säulenchromatographisch an Kieselgel gereinigt (Eluent: Ethylacetat / n-Heptan 1 :1). Das gewünschte Produkt wurde erhalten. Molekulargewicht 248,32 (C15H20O3), MS: 249 (M+H+). Zu einer Lösung aus 0,12 g 4-Phenoxy-cyclohexancarbonsäureethylester in 8 mL WASSER/THF (1:1) wurden 0,06 mL 2 N Kaliumhydroxidlösung gegeben. Die Lösung wurde 3 Stunden auf 60 °C erwärmt. Der Ansatz wurde mit Ethylacetat und 10% Zitronensäure versetzt. Die wässrige Phase wurde dreimal mit Ethylacetat extrahiert, über Natriumsulfat getrocknet und im Vakuum eingeengt. Die erhaltene Verbindung wurde ohne weitere Reinigung in die nächste Stufe eingesetzt.The product obtained (0.55 g) was dissolved in 11.2 ml of DMF, to which 0.159 g of phenol and 0.549 g of cesium carbonate were added. Then, the solution was heated at 80 ° C for 6 hours. After cooling, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: ethyl acetate / n-heptane 1: 1). The desired product was obtained. Molecular weight 248.32 (C15H20O3), MS: 249 (M + H +). To a solution of 0.12 g of 4-phenoxy-cyclohexanecarboxylic acid ethyl ester in 8 mL of WATER / THF (1: 1) was added 0.06 mL of 2N potassium hydroxide solution. The solution was heated to 60 ° C for 3 hours. The reaction was treated with ethyl acetate and 10% citric acid. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The resulting compound was used in the next step without further purification.
Beispiel 277 N-[4-(3-Cyclohexylamino-pyrrolidin-1-yl)-phenyl]-4-isobutoxy-benzamidExample 277 N- [4- (3-Cyclohexylamino-pyrrolidin-1-yl) -phenyl] -4-isobutoxy-benzamide
Figure imgf000172_0001
Figure imgf000172_0001
(4-lsobutoxy-N-[4-(3-oxo-pyrrolidin-1-yl)-phenyl]-benzamid (50 mg) in Methanol (2 mL) wurde mit Aminocyclohexan (28 mg) und Eisessig (10 mg) versetzt und eine Lösung von Natriumcyanoborhydrid (1M in Toluol; 0,17 mL) zugegeben. Nach 8 Stunden wurde die Reaktionslösung eingeengt und zwischen Ethylacetat und Wasser verteilt. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 435,61 (C27H37N302); MS (ESI): 436 (M+H+). APD62429PC(4-Iso-Butoxy-N- [4- (3-oxo-pyrrolidin-1-yl) -phenyl] -benzamide (50 mg) in methanol (2 mL) was added with aminocyclohexane (28 mg) and glacial acetic acid (10 mg) and a solution of sodium cyanoborohydride (1M in toluene, 0.17 mL) was added After 8 hours, the reaction solution was concentrated and partitioned between ethyl acetate and water The organic phase was dried over magnesium sulfate and concentrated The crude product was purified by preparative HPLC thus obtained the product with molecular weight 435.61 (C27H37N302); MS (ESI): 436 (M + H +). APD62429PC
4-lsobutoxy-N-[4-(3-oxo-pyrrolidin-1-yl)-phenyl]-benzamid Nach Methode E-a wurde 4-lsobutoxybenzoesäure mit 4-(1 ,4-Dioxa-7-aza- spiro[4.4]non-7-yl)-phenylamin umgesetzt. Das erhaltene Amid (0,25 g) in Aceton (10 mL) wurde mit para-Toluolsulfonsäure (Monohydrat, 109 mg) versetzt und die Mischung für 8 Stunden am Ruckfluss gekocht. Nach Zusatz von Triethylamin (0,5 mL) wurde die Mischung mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 352,44 (C21H24N203); MS (ESI): 353 (M+H+). Auf analoge Weise wurde unter Verwendung von 4-Butoxybenzoesäure 4-Butoxy- N-[4-(3-oxo-pyrrolidin-1-yl)-phenyl]-benzamid erhalten. Ebenso wurde aus 4- Butoxybenzoesäure und 4-(1 ,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluor-phenylamin zunächst 4-Butoxy-N-[4-(1 ,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluor-phenyl]- benzamid erhalten, das nach Methylierung nach Methode F und Behandeln mit para-Toluolsulfonsäure, wie oben beschrieben, 4-Butoxy-N-[3-fluor-4-(3-oxo- pyrrolidin-1 -yl)-phenyl]-benzamid ergab.4-Isobutoxy-N- [4- (3-oxopyrrolidin-1-yl) -phenyl] -benzamide According to Method Ea, 4-isobutoxybenzoic acid was treated with 4- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -phenylamine reacted. The obtained amide (0.25 g) in acetone (10 mL) was added with para-toluenesulfonic acid (monohydrate, 109 mg), and the mixture was refluxed for 8 hours. After addition of triethylamine (0.5 mL), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This gave the product of molecular weight 352.44 (C21H24N203); MS (ESI): 353 (M + H +). In an analogous manner, 4-butoxy-N- [4- (3-oxopyrrolidin-1-yl) -phenyl] -benzamide was obtained using 4-butoxybenzoic acid. Likewise, from 4-butoxybenzoic acid and 4- (1,4-dioxa-7-aza-spiro [4.4] non-7-yl) -3-fluoro-phenylamine, initially 4-butoxy-N- [4- (1,4 -dioxa-7-aza-spiro [4.4] non-7-yl) -3-fluoro-phenyl] - benzamide, which after methylation according to method F and treatment with para-toluenesulfonic acid, as described above, 4-butoxy-N - [3-fluoro-4- (3-oxopyrrolidin-1-yl) -phenyl] -benzamide.
4-(1,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-phenylamin4- (1,4-dioxa-7-aza-spiro [4.4] non-7-yl) -phenylamine
Eine Lösung von 1 -Benzyl-3-pyrrolidinon (5.0 g) in Dichlormethan (30 mL) und Etyhlenglykol (2,67 g) wurde langsam mit Trimethylchlorsilan (9.3 g) versetzt. Nach 18 Stunden wurde das Gemisch in Natronlauge (1N) gegossen. Die organische Phase wurde abgetrennt, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde in Methanol (30 mL) gelöst und Ammoiumformiat (5.2 g) sowie Palladiumhydroxid (10% auf Kohle, 300 mg) zugegeben. Die Mischung wurde für 8 Stunden am Ruckfluss gekocht, filtriert und eingeengt. Der Rückstand wurde nach Methode C mit 4-Fluornitrobenzol umgesetzt. Schliesslich wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 220,27 (C12H16N202); MS (ESI): 221 (M+H+). Analog wurde 4-(1 ,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluor-phenylamin unter Verwendung von 3,4-Difluornitrobenzol erhalten. APD62429PCA solution of 1-benzyl-3-pyrrolidinone (5.0 g) in dichloromethane (30 mL) and ethylene glycol (2.67 g) was added slowly with trimethylchlorosilane (9.3 g). After 18 hours, the mixture was poured into sodium hydroxide solution (1N). The organic phase was separated, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (30 mL) and ammonium formate (5.2 g) and palladium hydroxide (10% on carbon, 300 mg) added. The mixture was refluxed for 8 hours, filtered and concentrated. The residue was reacted by method C with 4-fluoronitrobenzene. Finally, hydrogenation was carried out according to Method B. This gave the product with the molecular weight 220.27 (C12H16N202); MS (ESI): 221 (M + H +). Analogously, 4- (1,4-dioxa-7-aza-spiro [4.4] non-7-yl) -3-fluoro-phenylamine was obtained using 3,4-difluoronitrobenzene. APD62429PC
Beispiel 278Example 278
(R)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure {4-[3-(methyl-pyrimidin-2-yl- amino)-pyrrolidin-1-yl]-phenyl}-amid(R) -4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid {4- [3- (methyl-pyrimidin-2-yl-amino) -pyrrolidin-1-yl] -phenyl} -amide
Figure imgf000174_0001
Figure imgf000174_0001
(R)-4-(4-Chlor-phenyl)-piperidin-1 -carbonsäure [4-(3-methylamino-pyrrolidin-1 -yl)- phenyl]-amid (100 mg) wurde in N-Methylpyrrolidon (3 mL) mit Kaliumcarbonat (100 mg) und 2-Brompyrimidin (50 mg) für 4 Stunden bei 100°C umgesetzt. Dann wurde die Reaktionslösung zwischen Ethylacetat und Wasser verteilt. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 491 ,04 (C27H31CIN60); MS (ESI): 491 (M+H+).(R) -4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid [4- (3-methyl-aminopyrrolidin-1-yl) -phenyl] -amide (100 mg) was dissolved in N-methylpyrrolidone (3 mL ) were reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) for 4 hours at 100 ° C. Then, the reaction solution was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 491, 04 (C27H31CIN60); MS (ESI): 491 (M + H +).
Beispiel 279Example 279
[1-(4-{[5-(2-Fluor-phenyl)-furan-2-carbonyl]-amino}-phenyl)-pyrrolidin-3-yl]-methyl- carbaminsäure-tert-butylester[1- (4 - {[5- (2-Fluoro-phenyl) -furan-2-carbonyl] -amino} -phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Figure imgf000174_0002
Figure imgf000174_0002
Methode OMethod O
In einem 10 mL Zwei-Hals-Kolben wurde zu einer Lösung aus (1 -{4-[(5-Brom- furan-2-carbonyl)-amino]-phenyl}-pyrrolidin-3-yl)-methyl-carbaminsäure tert- butylester (252 mg) in entgastem Toluol (4 mL) unter Argon APD62429PCIn a 10 mL two-necked flask tert to a solution of (1 - {4 - [(5-bromofuran-2-carbonyl) -amino] -phenyl} -pyrrolidin-3-yl) -methyl-carbamic acid - butyl ester (252 mg) in degassed toluene (4 mL) under argon APD62429PC
Tetrakis(triphenylphosphin)palladium(0) (20 mg) gegeben und 10 Minuten bei Raumtemperatur gerührt. Anschließend wurde mit einer Lösung von 2- Fluorbenzolboronsäure (73 mg in 1 mL Ethanol) und 0,35 mL 2M Natriumcarbonatlösung versetzt und der Ansatz 24 Stunden bei 100 °C gerührt. Danach wurde das Reaktionsgemisch mit Wasser (5 mL) und Ethylacetat (5ml) versetzt, die organische Phase abgetrennt und die wässrige Phase 2x mit Ethylacetat (10 mL) extrahiert. Die vereinigten organischen Phasen wurden eingeengt und der Rückstand durch präparative HPLC gereinigt. Man erhielt das gewünschte Produkt mit dem Molekulargewicht 479,56 (C27H30FN3O4); MS (ESI): 480 (M+H+) als Hydrotrifluoracetat. Alternativ kann als BaseTetrakis (triphenylphosphine) palladium (0) (20 mg) and stirred for 10 minutes at room temperature. Subsequently, a solution of 2-fluorobenzeneboronic acid (73 mg in 1 ml of ethanol) and 0.35 ml of 2M sodium carbonate solution was added and the mixture was stirred at 100 ° C. for 24 hours. Thereafter, the reaction mixture was treated with water (5 mL) and ethyl acetate (5 mL), the organic phase separated and the aqueous phase extracted 2x with ethyl acetate (10 mL). The combined organic phases were concentrated and the residue was purified by preparative HPLC. The desired product of molecular weight 479.56 (C27H30FN3O4) was obtained; MS (ESI): 480 (M + H +) as hydrotrifluoroacetate. Alternatively, as a base
Cäsiumcarbonat verwendet und die Reaktion in einer Mikrowellenapparatur für 3 Minuten auf 150°C erwärmt werden.Cesium carbonate is used and the reaction is heated in a microwave apparatus for 3 minutes at 150 ° C.
(1-{4-[(5-Brom-furan-2-carbonyl)-amino]-phenyl}-pyrrolidin-3-yl)-methyl- carbaminsäure-tert-butylester(1- {4 - [(5-Bromo-furan-2-carbonyl) -amino] -phenyl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
Nach Methode E wurde 5-Brom-furan-2-carbonsäure mit [1-(4-Amino-phenyl)- pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 464,36 (C21 H26BrN304); MS (ESI): 464 (M+H+).According to method E, 5-bromo-furan-2-carboxylic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester. This gave the product of molecular weight 464.36 (C21 H26BrN304); MS (ESI): 464 (M + H +).
Analog wurden folgende Verbindungen hergestellt:The following compounds were prepared analogously:
5-Brom-furan-2-carbonsäure-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid5-bromo-furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
(1-{4-[(5-Brom-thiophen-2-carbonyl)-amino]-phenyl}-pyrrolidin-3-yl)-methyl- carbaminsäure-tert-butylester(1- {4 - [(5-Bromo-thiophene-2-carbonyl) -amino] -phenyl} -pyrrolidin-3-yl) -methyl-carbamic acid tert-butyl ester
2-Brom-thiazol-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid2-Bromo-thiazole-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
4-lod-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-benzamid4-iodo-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide
(R)-N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluor-phenyl]-4-iod-benzamid(R) -N- [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -4-iodo-benzamide
4-Brom-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-3-fluor-benzamid APD62429PC4-bromo-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -3-fluoro-benzamide APD62429PC
Beispiel 280Example 280
(3R)-3'-Cyano-biphenyl-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-3-fluor- phenyl]-amid(3R) -3'-Cyano-biphenyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -amide
Figure imgf000176_0001
Figure imgf000176_0001
Methode O-bMethod O-b
Zu einer Lösung aus 0,022 g (R)-N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluor- phenyl]-4-iod-benzamid in 0,45 mL entgastem DMF wurden 0,002 mg Pd(PPh3)4 gegeben und 10 Minuten bei Raumtemperatur gerührt. Anschließend wurde die Lösung mit 0,035 mL Wasser, 0,021 g K3P04 und 0,008 g 3-To a solution of 0.022 g of (R) -N- [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -4-iodo-benzamide in 0.45 mL of degassed DMF was added 0.002 mg Pd (PPh3) 4 and stirred for 10 minutes at room temperature. The solution was then treated with 0.035 mL water, 0.021 g K3PO4 and 0.008 g 3
Cyanophenylboronsäure versetzt. Die Reaktionslösung wurde über Nacht auf 80 °C erhitzt. Danach wurde die Lösung abfiltriert und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 428,20 (C26H25FIN40); MS (ESI): 429 (M+H+) als Hydrotrifluoracetat.Cyanophenylboronic added. The reaction solution was heated at 80 ° C overnight. Thereafter, the solution was filtered off and purified by preparative HPLC. This gave the product with a molecular weight of 428.20 (C26H25FIN40); MS (ESI): 429 (M + H +) as hydrotrifluoroacetate.
Beispiel 281Example 281
3,2',4'-Trifluor-biphenyl-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]- amid3,2 ', 4'-trifluoro-biphenyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000176_0002
Figure imgf000176_0002
Nach Methode O-b wurde 1-Brom-2,4-difluorbenzol mit N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-2-fluor-4-boronsäure-benzamid umgesetzt. Man erhielt so APD62429PCAccording to method I, 1-bromo-2,4-difluorobenzene was reacted with N- [4- (3-dimethylaminopyrrolidin-1-yl) phenyl] -2-fluoro-4-boronic acid benzamide. You got like that APD62429PC
das Produkt mit dem Molekulargewicht 439,19 (C25H24F3N30); MS (ESI): 440 (M+H+) als Hydrotrifluoracetatthe product of molecular weight 439.19 (C25H24F3N30); MS (ESI): 440 (M + H +) as hydrotrifluoroacetate
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-2-fluor-4-boronsäure-benzamidN- [4- (3-dimethylamino-pyrrolidin-1-yl) phenyl] -2-fluoro-4-boronic acid-benzamide
Nach Methode E-b wurde 4-Carboxy-3-fluorphenylboronsäure mit [1 -(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 371 ,18 (C19H23BFN303); MS (ESI): 372 (M+H+) als Hydrotrifluoracetat.According to method E-b, 4-carboxy-3-fluorophenylboronic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product of molecular weight 371, 18 (C19H23BFN303); MS (ESI): 372 (M + H +) as hydrotrifluoroacetate.
Beispiel 282Example 282
5-(2,4-Difluor-phenyl)-thiophen-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyl]-amid5- (2,4-Difluoro-phenyl) -thiophene-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000177_0001
Nach Methode O-b wurde 1 -Brom-2,4-difluorbenzol mit 2-Boronsäure-thiophen-5- carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 427,52 (C23H23F2N30S); MS (ESI): 428 (M+H+) als Hydrotrifluoracetat.
Figure imgf000177_0001
By Method Ob, 1-bromo-2,4-difluorobenzene was reacted with 2-boronic acid-thiophene-5-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide. This gave the product with the molecular weight 427.52 (C23H23F2N30S); MS (ESI): 428 (M + H +) as hydrotrifluoroacetate.
2-Boronsäure-thiophen-5-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)- phenyl]-amid2-boronic acid-thiophene-5-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Nach Methode E-b wurde 5-Carboxy-2-thiophenboronsäure mit [1-(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 359,15 (C17H22BN303S); MS (ESI): 360 (M+H+) als Hydrotrifluoracetat. APD62429PCBy method Eb, 5-carboxy-2-thiopheneboronic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product with the molecular weight 359.15 (C17H22BN303S); MS (ESI): 360 (M + H +) as hydrotrifluoroacetate. APD62429PC
Beispiel 283 N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-(4-fluor-phenyl)-nicotinamidExample 283 N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -nicotinamide
Figure imgf000178_0001
[Trifluor-methansulfonsäure 5-[4-(3-dimethylamino-pyrrolidin-1 -yl)- phenylcarbamoyl]-pyridin-2-yl ester wurde mit 4-Fluorbenzolboronsäure unter den Bedingungen von Methode O-b umgesetzt. (Erhitzt wurde 15 Minuten in einer Mikrowellenapparatur bei 140 °C). Man erhielt so das Produkt mit dem Molekulargewicht 404,20 (C24H25FN40); MS (ESI): 405 (M+H+) als Hydrotrifluoracetat.
Figure imgf000178_0001
[Trifluoro-methanesulfonic acid 5- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenylcarbamoyl] -pyridin-2-yl ester was reacted with 4-fluorobenzeneboronic acid under the conditions of Method Ob. (Heated for 15 minutes in a microwave oven at 140 ° C). This gave the product with the molecular weight 404.20 (C24H25FN40); MS (ESI): 405 (M + H +) as hydrotrifluoroacetate.
[Trifluor-methansulfonsäure 5-[4-(3-dimethylamino-pyrrolidin-1-yl)- phenylcarbamoyl]-pyridin-2-yl ester[Trifluoro-methanesulfonic acid 5- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenylcarbamoyl] -pyridin-2-yl ester
Eine Lösung aus 0,084 mL LDA-Lösung (2M) in 0,4 mL DME wurde bei 0°C mit einer Suspension aus 0,0,5 g N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6- hydroxy-nicotinamid in 0,4 mL DME versetzt. Es wurde 2 Stunden bei 0°C nachgerührt. Anschließend versetzte man die Mischung mit einer Lösung aus 0,055 g N-Phenyltrifluormethansulfonimid in 0,2 mL DME. Man ließ die Reaktionslösung auf Raumtemperatur kommen und erhitzte 3 Stunden auf 80 °C. Nach dem Abkühlen wurde die Lösung im Vakuum eingeengt. Der Rückstand wurde in Ethylacetat /Wasser aufgenommen und die wässrige Phase dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, im Vakuum eingeengt und durch päparative HPLC gereinigt.A solution of 0.084 mL LDA solution (2M) in 0.4 mL DME was incubated at 0 ° C with a suspension of 0.05 g of N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl ] -6-hydroxy-nicotinamide in 0.4 mL DME. It was stirred for 2 hours at 0 ° C. Subsequently, the mixture was admixed with a solution of 0.055 g of N-phenyltrifluoromethanesulfonimide in 0.2 ml of DME. The reaction solution was allowed to come to room temperature and heated to 80 ° C for 3 hours. After cooling, the solution was concentrated in vacuo. The residue was taken up in ethyl acetate / water and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC.
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamid Nach Methode E-b wurde 6-Hydroxynicotinsäure mit [1 -(4-Amino-phenyl)- pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem APD62429PCN- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -6-hydroxy-nicotinamide According to Method Eb, 6-hydroxynicotinic acid was treated with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine implemented. One received thus the product with the APD62429PC
Molekulargewicht 326,17 (C18H22N402); MS (ESI): 327 (M+H+) als Hydrotrifluoracetat.Molecular weight 326.17 (C18H22N402); MS (ESI): 327 (M + H +) as hydrotrifluoroacetate.
Beispiel 284Example 284
N-[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-6-(2,4-difluor-phenyl)-nicotinamidN- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -6- (2,4-difluoro-phenyl) -nicotinamide
Figure imgf000179_0001
Figure imgf000179_0001
Nach Methode O-b wurde 2,4-Difluorphenylboronsäure mit [Trifluor- methansulfonsaure 5-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenylcarbamoyl]- pyridin-2-yl ester umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 422,00 (C24H24F2N40); MS (ESI): 423 (M+H+) als Hydrotrifluoracetat.By method O-b, 2,4-difluorophenylboronic acid was reacted with [trifluoromethanesulfonic acid 5- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenylcarbamoyl] -pyridin-2-yl ester. This gave the product with a molecular weight of 422.00 (C24H24F2N40); MS (ESI): 423 (M + H +) as hydrotrifluoroacetate.
Beispiel 285Example 285
2,,4'-Difluor-biphenyl-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]- amid2 , 4'-Difluoro-biphenyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000179_0002
Figure imgf000179_0002
Nach Methode E-a wurde 2',4'-Difluor-biphenyl-4-carbonsäure mit [1 -(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit APD62429PCAccording to method Ea, 2 ', 4'-difluoro-biphenyl-4-carboxylic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product with APD62429PC
dem Molekulargewicht 421 ,20 (C25H25F2N30); MS (ESI): 422 (M+H+) als Hydrotrifluoracetatthe molecular weight 421, 20 (C25H25F2N30); MS (ESI): 422 (M + H +) as hydrotrifluoroacetate
2',4'-Difluor-biphenyl-4-carbonsäure Methode P2 ', 4'-Difluoro-biphenyl-4-carboxylic acid Method P
Zu einer Lösung aus 0,051 g 2',4'-Difluor-biphenyl-4-carbonsäureethylester in 1 mL THF/WASSER (1 :1) wurden 0,098 mL 1 N Lithiumhydroxidlösung gegeben, es wurde über Nacht bei Raumtemperatur gerührt. Mit 5 % Salzsäure wurde die Lösung neutral gestellt, im Vakuum eingeengt und der Rückstand über päparative HPLC gereinigt.To a solution of 0.051 g of ethyl 2 ', 4'-difluoro-biphenyl-4-carboxylate in 1 mL THF / WATER (1: 1) was added 0.098 mL 1 N lithium hydroxide solution, it was stirred overnight at room temperature. With 5% hydrochloric acid, the solution was made neutral, concentrated in vacuo and the residue purified by preparative HPLC.
2,,4'-Difluor-biphenyl-4-carbonsäureethylester2 , 4'-Difluoro-biphenyl-4-carboxylic acid ethyl ester
Zu einer Lösung aus 0,091 g 4-lodbenzoesäureethylester in 0,96 mL entgastemTo a solution of 0.091 g of ethyl 4-iodobenzoate in 0.96 mL degassed
Toluol wurden 0,009 g Pd(PPh3)4 gegeben und 10 Minuten bei Raumtemperatur gerührt. Dann wurde die Reaktionslösung mit einer Lösung aus 0,047 g 2,4- Difluorphenylboronsäure in 0,114 mL Ethanol und 0,201 mL einer 2N Na2C03- Lösung versetzt. Die Lösung wurde über Nacht auf 100 °C erhitzt. Anschließend wurde das Reaktionsgemisch im Vakuum eingeengt und der Rückstand mit Wasser / Ethylacetat versetzt. Die wässrige Phase wurde dreimal mit Ethylacetat extrahiert, über Natriumsulfat getrocknet, das Lösungsmittel im Vakuum entfernt und über päparative HPLC gereinigt.Toluene was added to 0.009 g of Pd (PPh3) 4 and stirred at room temperature for 10 minutes. Then, a solution of 0.047 g of 2,4-difluorophenylboronic acid in 0.114 ml of ethanol and 0.201 ml of a 2N Na 2 CO 3 solution were added to the reaction solution. The solution was heated at 100 ° C overnight. The reaction mixture was then concentrated under reduced pressure and the residue was combined with water / ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulfate, the solvent removed in vacuo and purified by preparative HPLC.
Beispiel 286 2',4'-Difluor-biphenyl-4-carbonsäure {4-[3-(acetyl-methyl-amino)-pyrrolidin-1 -yl]- phenyl}-amid APD62429PCExample 286 2 ', 4'-Difluoro-biphenyl-4-carboxylic acid {4- [3- (acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -amide APD62429PC
Figure imgf000181_0001
Figure imgf000181_0001
Methode E-bMethod E-b
Eine Lösung aus 0,047 g 2',4'-Difluor-biphenyl-4-carbonsäure und 0,058 g N-[1-(4- Amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamid in 2 mL DMF wurde bei 0°C mit 0,095 g HATU, 0,068 g HOBT und 0,035 mL Triethylamin versetzt. Nach 10 Minuten ließ man die Lösung auf Raumtemperatur kommen und rührte über Nacht bei dieser Temperatur. Anschließend wurde das Lösungsmitel im Vakuum entfernt und der Rückstand in Wasser / Ethylacetat aufgenommen. Die Ethylacetatphase wurde mit 10% NaHC03-Lösung und Wasser gewaschen. Die Ethylacetatphase wurde über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Der Rückstand wurde durch präparative HPLC gereinigt. Das gewünschte Produkt wurde erhalten. Molekulargewicht 449,19 (C26H25F2N3O2), MS: 450 (M+H+).A solution of 0.047 g of 2 ', 4'-difluoro-biphenyl-4-carboxylic acid and 0.058 g of N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide in 2 mL of DMF 0.095 g HATU, 0.068 g HOBT and 0.035 mL triethylamine were added at 0 ° C. After 10 minutes, the solution was allowed to come to room temperature and stirred overnight at this temperature. Then the solvent was removed in vacuo and the residue was taken up in water / ethyl acetate. The ethyl acetate phase was washed with 10% NaHCO 3 solution and water. The ethyl acetate phase was dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 449.19 (C26H25F2N3O2), MS: 450 (M + H +).
Beispiel 287Example 287
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-3-fluor-4-(4-methyl-piperidin-1-yl)- benzamid APD62429PCN- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -3-fluoro-4- (4-methylpiperidin-1-yl) -benzamide APD62429PC
Figure imgf000182_0001
Figure imgf000182_0001
Nach Methode E-a wurde 3-Fluor-4-(4-methyl-piperidin-1-yl)-benzoesäure mit [1- (4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 424,00 (C25H33FN40); MS (ESI): 425 (M+H+) als Hydrotrifluoracetat.According to method E-a, 3-fluoro-4- (4-methyl-piperidin-1-yl) -benzoic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product of molecular weight 424.00 (C25H33FN40); MS (ESI): 425 (M + H +) as hydrotrifluoroacetate.
3-Fluor-4-(4-methyl-piperidin-1-yl)-benzoesäure3-fluoro-4- (4-methyl-piperidin-1-yl) benzoic acid
3-Fluor-4-(4-methyl-piperidin-1-yl)-benzoesäuremethylester wurde nach Methode P mit Lithiumhydroxid behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 237,28 (C13H16FN02); MS (ESI): 238 (M+H+).Methyl 3-fluoro-4- (4-methyl-piperidin-1-yl) benzoate was treated by method P with lithium hydroxide. This gave the product with the molecular weight 237.28 (C13H16FN02); MS (ESI): 238 (M + H +).
3-Fluor-4-(4-methyl-piperidin-1-yl)-benzoesäuremethylester Zu einer Lösung aus 0,086 g 3,4-Difluorbenzoesäuremethyiester und 0,050 g 4- Methylpiperidin in 0,5 mL DMF wurden 0,076 g Kaliumcarbonat gegeben. Die Reaktion wurde 2 Tage auf 60 °C erwärmt, abfiltriert und durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 251 ,3 (C14H18FN02); MS (ESI): 252 (M+H+) als Hydrotrifluoracetat.Methyl 3-fluoro-4- (4-methyl-piperidin-1-yl) benzoate To a solution of 0.086 g of 3,4-difluorobenzoic acid methyl ester and 0.050 g of 4-methylpiperidine in 0.5 mL of DMF was added 0.076 g of potassium carbonate. The reaction was heated at 60 ° C for 2 days, filtered off and purified by preparative HPLC. This gave the product with the molecular weight 251, 3 (C14H18FN02); MS (ESI): 252 (M + H +) as hydrotrifluoroacetate.
Beispiel 288Example 288
4-Butoxy-N-(4-{3-[(2-dimethylamino-acetyl)-methyl-amino]-pyrrolidin-1-yl}-phenyl)- N-methyl-benzamid APD62429PC4-Butoxy-N- (4- {3 - [(2-dimethylamino-acetyl) -methyl-amino] -pyrrolidin-1-yl} -phenyl) -N-methylbenzamide APD62429PC
Figure imgf000183_0001
Figure imgf000183_0001
Nach Methode E wurde 4-Butoxy-N-methyl-N-[4-(3-methylamino-pyrrolidin-1-yl)- phenyl]-benzamid mit N,N-Dimethylglycin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 466,63 (C27H38N403); MS (ESI): 467 (M+H+). Analog wurde (R)-4-Butoxy-N-(4-{3-[(2-dimethylamino-acetyl)-methyl-amino]- pyrrolidin-1 -yl}-phenyl) -N-methyl-benzamid erhalten.According to method E, 4-butoxy-N-methyl-N- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -benzamide was reacted with N, N-dimethylglycine. This gave the product with the molecular weight 466.63 (C27H38N403); MS (ESI): 467 (M + H +). Analogously, (R) -4-butoxy-N- (4- {3 - [(2-dimethylamino-acetyl) -methyl-amino] -pyrrolidin-1-yl} -phenyl) -N-methyl-benzamide was obtained.
Beispiel 289 N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-phenyl}-4-butoxy-N-methyl-benzamidExample 289 N- {4- [3- (Acetyl-methyl-amino) -pyrrolidin-1-yl] -phenyl} -4-butoxy-N-methyl-benzamide
Figure imgf000183_0002
Figure imgf000183_0002
4-Butoxy-N-methyl-N-[4-(3-methylamino-pyrrolidin-1-yl)-phenyl]-benzamid wurde mit Pyridin und Acetanhydrid versetzt. Flüchtige Anteile wurden nach 2 Stunden entfernt. Man erhielt so das Produkt mit dem Molekulargewicht 423,56 (C25H33N303); MS (ESI): 424 (M+H+).4-Butoxy-N-methyl-N- [4- (3-methylamino-pyrrolidin-1-yl) -phenyl] -benzamide was added with pyridine and acetic anhydride. Volatiles were removed after 2 hours. This gave the product with the molecular weight 423.56 (C25H33N303); MS (ESI): 424 (M + H +).
Beispiel 290 4-Butyrylamino-N-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-benzamidExample 290 4-Butyrylamino-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000183_0003
APD62429PC
Figure imgf000183_0003
APD62429PC
Methode QMethod Q
4-Amino-N-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-benzamid (32 mg) in Dichlormethan (2 mL) wurde mit Kaliumcarbonat (50 mg) und Butyrylchlorid (11 mg) versetzt. Die Mischung wurde nach 12 Stunden filtriert und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 394,52 (C23H30N4O3); MS (ESI): 395 (M+H+). Alternativ kann man nach Methode E 4-Amino-N-[4-(3-dimethylamino-pyrrolidin-1- yl)-phenyl]-benzamid mit Buttersäure umsetzen.To 4-amino-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide (32 mg) in dichloromethane (2 mL) was added potassium carbonate (50 mg) and butyryl chloride (11 mg). The mixture was filtered after 12 hours and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 394.52 (C23H30N4O3); MS (ESI): 395 (M + H +). Alternatively, by method E, 4-amino-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide can be reacted with butyric acid.
4-Amino-N-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-benzamid4-amino-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide
Nach Methode E wurde 4-tert-Butoxycarbonylamino-benzoesäure mit [1-(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt und das Produkt nach Methode G behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 324,43 (C19H24N40); MS (ESI): 325 (M+H+).According to Method E, 4-tert-butoxycarbonylamino-benzoic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine and the product was treated according to Method G. This gave the product with the molecular weight 324.43 (C19H24N40); MS (ESI): 325 (M + H +).
Beispiel 291Example 291
2-Phenylethinyl-thiazol-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]- amid2-phenylethynyl-thiazole-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000184_0001
Figure imgf000184_0001
2-Brom-thiazol-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid2-Bromo-thiazole-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
(100 mg) wurde in Tetrahydrofuran (2 mL) gelöst und mit Phenylacetylen (52 mg),(100 mg) was dissolved in tetrahydrofuran (2 mL) and washed with phenylacetylene (52 mg),
Triethylamin (52 mg), Triphenylphosphin (17 mg),Triethylamine (52 mg), triphenylphosphine (17 mg),
Bis(triphenylphosphin)palladiumdichlorid (89 mg) und Kupfer(l)-iodid (9,6 mg) versetzt. Die Reaktion wurde für 3 Minuten in einer Mikrowellenapparatur aufBis (triphenylphosphine) palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction was carried out in a microwave apparatus for 3 minutes
150°C erhitzt und anschließend eingegengt. Der Rückstand wurde durch APD62429PCHeated to 150 ° C and then eingegengt. The residue was through APD62429PC
präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 416,55 (C24H24N4OS); MS (ESI): 417 (M+H+).purified by preparative HPLC. This gave the product with the molecular weight 416.55 (C24H24N4OS); MS (ESI): 417 (M + H +).
Beispiel 292Example 292
5-(4-Fluor-phenyl)-pyridin-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyl]-amid5- (4-Fluoro-phenyl) -pyridine-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000185_0001
Figure imgf000185_0001
Methode O-a 5-Chlor-pyridin-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid (100 mg) gelöst in Toluol wurde mit 4-Fluorphenylboronsäure (81 mg), POPD (15 mg) und Cäsiumcarbonat (2M aq.; 0.5 mL) versetzt. Die Reaktion wurde für 10 Minuten in einer Mikrowellenapparatur auf 150°C erhitzt und anschließend eingegeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 404,49 (C24H25FN40); MS (ESI): 405 (M+H+).Method Oa 5-Chloro-pyridine-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (100 mg) dissolved in toluene was treated with 4-fluorophenylboronic acid (81 mg), POPD (15 mg) and cesium carbonate (2M aq, 0.5 mL). The reaction was heated for 10 minutes in a microwave apparatus at 150 ° C and then concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 404.49 (C24H25FN40); MS (ESI): 405 (M + H +).
5-Chlor-pyridin-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid5-Chloro-pyridine-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin wurde nach Methode E mit 5- chlor-pyridin-2-carbonsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 344,85 (C18H21 CIN40); MS (ESI): 345 (M+H+).[1- (4-Amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine was reacted by method E with 5-chloro-pyridine-2-carboxylic acid. This gave the product with the molecular weight 344.85 (C18H21 CIN40); MS (ESI): 345 (M + H +).
Beispiel 293 APD62429PCExample 293 APD62429PC
5-(4-Fluor-phenyl)-pyridin-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)- phenyl]-amid5- (4-Fluoro-phenyl) -pyridine-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000186_0001
Figure imgf000186_0001
Nach Methode O-a wurde 5-Chlor-pyridin-2-carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amid mit 4-Methylphenylboronsäure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 400,53 (C25H28N40); MS (ESI): 401 (M+H+).According to method O-a, 5-chloro-pyridine-2-carboxylic acid [4- (3-dimethylaminopyrrolidin-1-yl) -phenyl] -amide was reacted with 4-methylphenylboronic acid. This gave the product with a molecular weight of 400.53 (C25H28N40); MS (ESI): 401 (M + H +).
Beispiel 294Example 294
1 -Benzolsulfonyl-piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)- phenyl]-amid1-Benzenesulfonyl-piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000186_0002
Figure imgf000186_0002
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid (70 mg) gelöst in N-Methylpyrrolidon (2 mL) wurde versetzt mit Kaliumcarbonat (45 mg) und Benzolsulfonyl Chlorid (35 mg). Nach 12 Stunden wurde die Mischung filtriert und das Filtrat durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 456,61 (C24H32N403S); MS (ESI): 457 (M+H+).Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (70 mg) dissolved in N-methylpyrrolidone (2 mL) was combined with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave the product of molecular weight 456.61 (C24H32N403S); MS (ESI): 457 (M + H +).
Beispiel 295 APD62429PCExample 295 APD62429PC
1-(4-Fluor-benzolsulfonyl)-piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin- 1-yl)-phenyl]-amid1- (4-Fluoro-benzenesulfonyl) -piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000187_0001
Figure imgf000187_0001
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid (70 mg) gelöst in N-Methylpyrrolidon (2 mL) wurde versetzt mit Kaliumcarbonat (45 mg) und 4-Fluor-benzolsulfonyl chlorid (40 mg). Nach 12 Stunden wurde die Mischung filtriert und das Filtrat durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 474,60 (C24H31 FN403S); MS (ESI): 475 (M+H+).Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (70 mg) dissolved in N-methylpyrrolidone (2 mL) was combined with potassium carbonate (45 mg) and 4-fluoro benzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave the product of molecular weight 474.60 (C24H31 FN403S); MS (ESI): 475 (M + H +).
Beispiel 296Example 296
1 -(Butane-1 -sulfonyl)-piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)- phenyl]-amid1 - (Butane-1-sulfonyl) -piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000187_0002
Figure imgf000187_0002
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid (70 mg) gelöst in N-Methylpyrrolidon (2 mL) wurde versetzt mit Kaliumcarbonat (45 mg) und Butylsulfonylchlorid (30 mg). Nach 12 Stunden wurde die Mischung filtriert und das Filtrat durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 436,62 (C22H36N403S); MS (ESI): 437 (M+H+). APD62429PCPiperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (70 mg) dissolved in N-methylpyrrolidone (2 mL) was added potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg ). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave the product of molecular weight 436.62 (C22H36N403S); MS (ESI): 437 (M + H +). APD62429PC
Beispiel 297Example 297
5-(4-Butoxy-phenylethinyl)-furan-2-carbonsäure-[4-(3-dimethylamino-pyrrolidin-1- yl)-phenyl]-amid5- (4-Butoxy-phenylethynyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000188_0001
Methode J-a
Figure imgf000188_0001
Method Yes
5-Brom-furan-2-carbonsäure-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid (75 mg) wurde zusammen mit 1-Butoxy-4-ethinyl-benzol (35 mg) in N,N- Dimethylformamid (1 mL) gelöst und unter Argon zu einer Suspension von Pd(tBu3P)2CI2 (4 mg), Kupfer(l)-iodid (75 mg) und N,N-Diisopropylamin (20 mg) in Wasserfreiem Tetrahydrofuran (3 mL) getropft. Der Ansatz wird 8 Stunden bei Raumtemperatur gerührt. Zur Aufarbeitung wurde die Reakion über einen Spritzenfilter filtriert, eingeengt und das Rohprodukt über präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 471 ,6 (C29H33N303); MS (ESI): 472 (M+H+) als Hydrotrifluoracetat.5-Bromo-furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (75 mg) was co-extracted with 1-butoxy-4-ethynyl-benzene (35 mg) N, N-dimethylformamide (1 mL) and added under argon to a suspension of Pd (tBu3P) 2Cl 2 (4 mg), copper (I) iodide (75 mg) and N, N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 mL) was added dropwise. The batch is stirred for 8 hours at room temperature. For workup, the reaction was filtered through a syringe filter, concentrated and the crude product purified by preparative HPLC. This gave the product of molecular weight 471.6 (C29H33N303); MS (ESI): 472 (M + H +) as hydrotrifluoroacetate.
Beispiel 298 6-Butoxy-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-nicotinamidExample 298 6-Butoxy-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -nicotinamide
Figure imgf000188_0002
Methode H-a
Figure imgf000188_0002
Method Ha
Eine Lösung aus 0,1 g Kaliumhydroxid in 1 mL DMSO wurde 10 Minuten bei Raumtemperatur geruht und anschließend mit 0,1 g N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamid versetzt. Die Reaktionslösung wurde 10 Minuten gerührt und anschließend mit 0,084 g 1 -Brombutan versetzt. Es wurde über Nacht bei Raumtemperatur gerührt. Nach Zugabe von Wasser und APD62429PCA solution of 0.1 g of potassium hydroxide in 1 mL of DMSO was stirred for 10 minutes at room temperature and then with 0.1 g of N- [4- (3-dimethylaminopyrrolidin-1-yl) -phenyl] -6-hydroxy-nicotinamide added. The reaction solution was stirred for 10 minutes and then admixed with 0.084 g of 1-bromobutane. It was stirred overnight at room temperature. After adding water and APD62429PC
Ethylacetat, wurde die wässrige Phase dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, im Vakuum eingeengt und durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 382,24 (C22H30N4O2); MS (ESI): 383 (M+H+) als Hydrotrifluoracetat.Ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This gave the product of molecular weight 382.24 (C22H30N4O2); MS (ESI): 383 (M + H +) as hydrotrifluoroacetate.
Beispiel 299 6-Cyclopropylmethoxy-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-nicotinamidExample 299 6-Cyclopropylmethoxy-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -nicotinamide
Figure imgf000189_0001
Figure imgf000189_0001
Nach Methode H-a wurde (Brommethyl)cyclopropan mit N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 380,22 (C22H28N402); MS (ESI): 381 (M+H+) als Hydrotrifluoracetat.By method H-a, (bromomethyl) cyclopropane was reacted with N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -6-hydroxy-nicotinamide. This gave the product with a molecular weight of 380.22 (C22H28N402); MS (ESI): 381 (M + H +) as hydrotrifluoroacetate.
Beispiel 300 N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-isobutoxy-nicotinamidExample 300 N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -6-isobutoxy-nicotinamide
Figure imgf000189_0002
Nach Methode H-a wurde 1-Brom-2-methylpropan mit N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 382,24 (C22H30N4O2); MS (ESI): 383 (M+H+) als Hydrotrifluoracetat. APD62429PC
Figure imgf000189_0002
According to method Ha, 1-bromo-2-methylpropane was reacted with N- [4- (3-dimethylaminopyrrolidin-1-yl) -phenyl] -6-hydroxy-nicotinamide. This gave the product of molecular weight 382.24 (C22H30N4O2); MS (ESI): 383 (M + H +) as hydrotrifluoroacetate. APD62429PC
Beispiel 301 N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-6-(4-fluor-phenoxy)-nicotinamidExample 301 N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -6- (4-fluoro-phenoxy) -nicotinamide
Figure imgf000190_0001
Figure imgf000190_0001
Zu einer Lösung aus 0,041 g 6-Chlor-N-[4-(3-dimethylamino-pyrrolidin-1-yl)- phenyl]-nicotinamid und 4-Fluorphenol (30 mg) in 0,8 mL DMF wurden 49 mg Kaliumcarbonat gegeben und die Reaktion 90 Minuten bei 140 °C in einer Mikrowellenapparatur erwärmt. Nach Zugabe von Wasser und Ethylacetat wurde die wassrige Phase dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, im Vakuum eingeengt und durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 420,2 (C24H25FN402); MS (ESI): 421 (M+H+) als Hydrotrifluoracetat.To a solution of 0.041 g of 6-chloro-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -nicotinamide and 4-fluorophenol (30 mg) in 0.8 mL of DMF was added 49 mg of potassium carbonate and the reaction heated at 140 ° C for 90 minutes in a microwave oven. After adding water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This gave the product with a molecular weight of 420.2 (C24H25FN402); MS (ESI): 421 (M + H +) as hydrotrifluoroacetate.
6-Chlor-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-nicotinamid6-chloro-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -nicotinamide
Nach Methode E-b wurde 6-Chlornicotinsäure mit [1-(4-Amino-phenyl)-pyrrolidin-According to method E-b, 6-chloronicotinic acid was treated with [1- (4-amino-phenyl) -pyrrolidine
3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem3-yl] -dimethyl-amine reacted. One received thus the product with the
Molekulargewicht 344,14 (C18H21CIN40); MS (ESI): 345 (M+H+) alsMolecular weight 344.14 (C18H21CIN40); MS (ESI): 345 (M + H +) as
Hydrotrifluoracetat.Hydrotrifluoroacetate.
Die folgenden Beispiele wurden analog dargestellt.The following examples were presented analogously.
Figure imgf000190_0002
APD62429PC
Figure imgf000190_0002
APD62429PC
Figure imgf000191_0002
Figure imgf000191_0002
Beispiel 305 N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-2-fluor-4-phenoxy-benzamidExample 305 N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -2-fluoro-4-phenoxy-benzamide
Figure imgf000191_0001
Figure imgf000191_0001
Zu einer Lösung aus 0,008 g Phenol in 0,5 mL Methylenchlorid wurde gepulvertes Molekularsieb (4 A), 0,01 g Kupferacetat und 0,02 g N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-2-fluor-4-boronsäure-benzamid gegeben und 24 Stunden bei 40 °C gerührt. Anschließend wurde das Lösungsmittel im Vakuum entfernt, der Rückstand in Wasser / Ethylacetat aufgenommen und die wassrige Phase dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet, im Vakuum eingeengt und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 419,2 (C25H26FN302); MS (ESI): 420 (M+H+) als Hydrotrifluoracetat.To a solution of 0.008 g of phenol in 0.5 mL of methylene chloride was powdered molecular sieve (4 A), 0.01 g of copper acetate and 0.02 g of N- [4- (3-dimethylaminopyrrolidin-1-yl) -phenyl]. 2-fluoro-4-boronic acid benzamide and stirred at 40 ° C for 24 hours. The solvent was then removed in vacuo, the residue taken up in water / ethyl acetate and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This gave the product with the molecular weight 419.2 (C25H26FN302); MS (ESI): 420 (M + H +) as hydrotrifluoroacetate.
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-2-fluor-4-boronsäure-benzamid Nach Methode E-b wurde 4-Carboxy-3-fluorphenylboronsäure mit [1-(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 371 ,18 (C19H23BFN303); MS (ESI): 372 (M+H+) als Hydrotrifluoracetat. APD62429PCN- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -2-fluoro-4-boronic acid benzamide According to Method Eb, 4-carboxy-3-fluorophenylboronic acid was treated with [1- (4-amino-phenyl ) -pyrrolidin-3-yl] -dimethyl-amine reacted. This gave the product of molecular weight 371, 18 (C19H23BFN303); MS (ESI): 372 (M + H +) as hydrotrifluoroacetate. APD62429PC
Beispiel 306Example 306
4-(3-Cyano-phenyl)-3,6-dihydro-2H-pyridin-1 -carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amid4- (3-Cyano-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000192_0001
Figure imgf000192_0001
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid wurde nach Methode O-a mit 3-Brombenzonitril umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 415,54 (C25H29N50); MS (ESI): 416 (M+H+)4- (4,4,5,5-Tetramethyl- [1,2,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidine 1-yl) -phenyl] -amide was reacted by method Oa with 3-bromobenzonitrile. This gave the product of molecular weight 415.54 (C25H29N50); MS (ESI): 416 (M + H +)
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- carboxylic acid [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid Nach Methode A wurde 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 ,2,3,6- tetrahydro-pyridin mit [1-(4-amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 440,40 (C24H37BN4O3); MS (ESI): 441 (M+H+)4- (4,4,5,5-Tetramethyl- [1,2,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidine 1 -yl) -phenyl] -amide According to Method A, 4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -1,2,3,6-tetrahydro -pyridine reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product with the molecular weight 440.40 (C24H37BN4O3); MS (ESI): 441 (M + H +)
Beispiel 307Example 307
4-(2-Cyano-phenyl)-3,6-dihydro-2H-pyridin-1 -carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amid4- (2-Cyano-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000192_0002
Figure imgf000192_0002
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid wurde nach APD62429PC4- (4,4,5,5-Tetramethyl- [1,2,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidine 1-yl) -phenyl] -amide was after APD62429PC
Methode O-a mit 2-Brombenzonitril umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 415,54 (C25H29N50); MS (ESI): 416 (M+H+)Method O-a reacted with 2-bromobenzonitrile. This gave the product of molecular weight 415.54 (C25H29N50); MS (ESI): 416 (M + H +)
Beispiel 308Example 308
4-(3-Methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridin-1 -carbonsäure [4-(3- dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid4- (3-Methylsulfanylphenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000193_0001
Figure imgf000193_0001
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid wurde nach4- (4,4,5,5-Tetramethyl- [1,2,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid [4- (3-dimethylamino-pyrrolidine 1-yl) -phenyl] -amide was after
Methode O-a mit 3-Bromthioanisol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 436,62 (C25H32N4OS); MS (ESI): 437 (M+H+)Method O-a reacted with 3-Bromthioanisol. This gave the product with the molecular weight 436.62 (C25H32N4OS); MS (ESI): 437 (M + H +)
Beispiel 309Example 309
4-(5-Chlor-pyridin-2-yloxy)-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]- benzamid4- (5-Chloro-pyridin-2-yloxy) -N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide
Figure imgf000193_0002
Figure imgf000193_0002
Zu einer Lösung aus 0,19 g Essigsäure 4-[4-(3-dimethylamino-pyrrolidin-1-yl)- phenylcarbamoyl]-phenylester in 2 mL DMF wurden 0,143 g Kaliumcarbonat gegeben und die Lösung 15 Minuten bei 130 °C in einer Mikrowellenapparatur erhitzt. Anschließend wurde die Lösung mit Wasser und Ethylacetat versetzt, die Wasserphase gefriergetrocknet und der Rückstand ohne weitere Aufreinigung in der nächsten Stufe eingesetzt.To a solution of 0.19 g of acetic acid 4- [4- (3-dimethylamino-pyrrolidin-1-yl) - phenylcarbamoyl] -phenylester in 2 mL of DMF were added 0.133 g of potassium carbonate and the solution for 15 minutes at 130 ° C in a Microwave apparatus heated. Subsequently, the solution was mixed with water and ethyl acetate, the water phase was freeze-dried and the residue used without further purification in the next stage.
Methode R APD62429PCMethod R APD62429PC
Eine Lösung aus 0,05 g N-[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-4-hydroxy- benzamid, 0,017 g 2,5-Dichlorpyridin, 0,064 g Kaliumcarbonat in 0,8 mL DMF wurde 30 Minuten auf 230 °C in einer Mikrowellenapparatur erwärmt. Die Lösung wurde abfiltriert und durch päperative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 436,17 (C24H25CIN402); MS (ESI): 437 (M+H+) als Hydrotrifluoracetat.A solution of 0.05 g of N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine, 0.064 g of potassium carbonate in 0.8 mL of DMF was heated at 230 ° C for 30 minutes in a microwave oven. The solution was filtered off and purified by preparative HPLC. This gave the product with the molecular weight 436.17 (C24H25CIN402); MS (ESI): 437 (M + H +) as hydrotrifluoroacetate.
Essigsäure 4-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenylcarbamoyl]-phenylester Nach Methode E-b wurde 4-Acetoxybenzoesäure mit [1-(4-Amino-phenyl)- pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 367,19 (C21 H25N303); MS (ESI): 368 (M+H+) als Hydrotrifluoracetat.Acetic acid 4- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenylcarbamoyl] -phenyl ester According to Method Eb, 4-acetoxybenzoic acid was treated with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl- reacted amine. This gave the product with the molecular weight 367.19 (C21 H25N303); MS (ESI): 368 (M + H +) as hydrotrifluoroacetate.
Beispiel 310Example 310
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-4-(5-fluor-pyridin-2-yloxy)-benzamidN- [4- (3-dimethylamino-pyrrolidin-1-yl) phenyl] -4- (5-fluoro-pyridin-2-yloxy) -benzamide
Figure imgf000194_0001
Figure imgf000194_0001
Nach Methode R wurde 2-Chlor-5-fluorpyridin mit N-[4-(3-Dimethylamino- pyrrolidin-1-yl)-phenyl]-4-hydroxy-benzamid umgesetzt. Man erhielt so das Produktmit dem Molekulargewicht 420,2 (C24H25FN402); MS (ESI): 421 (M+H+) als Hydrotrifluoracetat.By method R, 2-chloro-5-fluoropyridine was reacted with N- [4- (3-dimethylaminopyrrolidin-1-yl) phenyl] -4-hydroxybenzamide. This gave the product of molecular weight 420.2 (C24H25FN402); MS (ESI): 421 (M + H +) as hydrotrifluoroacetate.
Beispiel 311 4-(6-Chlor-pyridin-3-yloxy)-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]- benzamid APD62429PCExample 311 4- (6-Chloro-pyridin-3-yloxy) -N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -benzamide APD62429PC
Figure imgf000195_0001
Figure imgf000195_0001
Wurde als Nebenprodukt der Umsetzung im Beispiel 310 erhalten. Man erhielt so das Produkt mit dem Molekulargewicht 436,95 (C24H25CIN402); MS (ESI): 437 (M+H+) als Hydrotrifluoracetat.Was obtained as a by-product of the reaction in Example 310. This gave the product with the molecular weight 436.95 (C24H25CIN402); MS (ESI): 437 (M + H +) as hydrotrifluoroacetate.
Beispiel 312 δ-Chlor-S'.δ'-dihydro^'H-p^'lbipyridinyl-l'-carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amidExample 312 δ-Chloro-S'.δ'-dihydro ^ 'H-p''-1-bipyridinyl-1-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000195_0002
Figure imgf000195_0002
[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin (32 mg) und Carbonyldiimidazol (27,1 mg) wurden in Acetonitril (1 ,5 mL) gelöst und die Mischung für 3 Stunden gerührt. Zu einer Lösung von δ-Chlor-l'^'^'.δ'- tetrahydro-[2,4']bipyridin (40,7 mg) in THF (1 mL) und Chloroform (0,5 mL) wurde Triethylamin (63,4 μL) gegeben. Nach 15 Minuten wurde die Mischung zur ersten Lösung getropft und über Nacht gerührt. Die Mischung wurde eingeengt und der Rückstand zwischen Dichlormethan und Wasser verteilt. Die organische Phase wurde über Natriumsulfat getrocknet, filtriert und eingeengt. Um Verunreinigungen durch das primäre und / oder sekundäre Amin zu entfernen wurde der Rückstand in Dichlormethan (1 ,5 mL) gelöst und die Lösung zu einer gerührten Suspension von polymergebundem p-Toluolsulfonsäurechlorid (0,5 g) in Dichlormethan (6 mL) und Triethylamin (128 μL) gegeben. Nach 3 Stunden wurde filtriert und das Harz mehrmals mit Dichlormethan gewaschen. Die kombinierten organischen Phasen wurden eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Laufmittel: Ethylacetat / Dichlormethan (5%), Ammoniak (7N in Methanol, 2%) später Ethylacetat / Dichlormethan (5%), Ammoniak (7N in Methanol, 3%) APD62429PC[1- (4-Amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine (32 mg) and carbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 mL) and the mixture was stirred for 3 hours , To a solution of δ-chloro-l '^' ^ ', δ'-tetrahydro- [2,4'] bipyridine (40.7 mg) in THF (1 mL) and chloroform (0.5 mL) was added triethylamine ( 63.4 μL). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated. To remove impurities by the primary and / or secondary amine, the residue was dissolved in dichloromethane (1.5 mL) and the solution added to a stirred suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 mL) and triethylamine (128 μL). After 3 hours, filtered and the resin washed several times with dichloromethane. The combined organic phases were concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate / dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl acetate / dichloromethane (5%), ammonia (7N in methanol, 3%). APD62429PC
gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 425,97 (C23H28CIN50); MS (ESI): 426 (M+H+).cleaned. This gave the product with a molecular weight of 425.97 (C23H28CIN50); MS (ESI): 426 (M + H +).
5-Chlor-1 ',2',3',&- tetrahydro-[2,4']bipyridin5-chloro-1 ', 2', 3 ', & -tetrahydro- [2,4'] bipyridine
Eine Lösung von δ-Chlor-S'.e'-dihydro^'H-p^bipyridin-l '-carbonsäure tert- butylester (50 mg) in Chloroform (2,4 mL) wurde mit Chlorwasserstoff (4N in Dioxan; 0,8 mL) versetzt und die Mischung nach 13 Stunden eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 194,67 (C10H11 CIN2); MS (ESI): 195 (M+H+).A solution of δ-chloro-S'.e'-dihydro ^ 'Hp ^ bipyridine-1'-carboxylic acid tert-butyl ester (50 mg) in chloroform (2.4 mL) was treated with hydrogen chloride (4N in dioxane, 0.8 mL) and the mixture is concentrated after 13 hours. This gave the product with the molecular weight 194.67 (C10H11 CIN2); MS (ESI): 195 (M + H +).
δ-Chlor-S'.e'-dihydro^Η-ß^^bipyridin-l '-carbaminsäure tert-butylester Zu einem Gemisch aus 4-(4,4,5,δ-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridin-1-carbaminsäure tert-butylester (Eastwood, Paul R., Tetrahedron Leti, 41, 19, 2000, 370δ-3708; 200 mg), Kaliumcarbonat (0.26δ g) und Pd(dppf)CI2 (50 mg) wurde eine Lösung von von 2-Brom-5-chlorpyridin (131 mg) in DMF (entgast mit Stickstoff; 4,δ mL) gegeben. Die Mischung wurde für 8 Stunden auf 80 °C erwärmt. Nach dem Abkühlen wurde die Mischung mit Dichlormethan verdünnt und mit Natriumcarbonatlösung und Wasser gewaschen. Die organische Phase wurde über Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Laufmittel: Heptan / Ethylacetat (2%) / Dichlormethan (δ%) später Heptan / Ethylacetat (δ%) / Dichlormethan (δ%) gereinigt.tert-Butyl bipyridine-1'-carbamic acid to a mixture of 4- (4,4,5, δ-tetramethyl- [1, 3, 2] δ-chloro-S'.e'-dihydro) dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carbamic acid tert -butyl ester (Eastwood, Paul R., Tetrahedron Leti, 41, 19, 2000, 370δ-3708, 200 mg), potassium carbonate (0.26 δ g) and Pd (dppf) CI 2 (50 mg) was added a solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed with nitrogen, 4, δ mL). The mixture was heated to 80 ° C for 8 hours. After cooling, the mixture was diluted with dichloromethane and washed with sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: heptane / ethyl acetate (2%) / dichloromethane (δ%) later heptane / ethyl acetate (δ%) / dichloromethane (δ%).
Beispiel 313 δ-(2-Amino-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin- 1 -yl)- phenyl]-amidExample 313 δ- (2-Amino-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000196_0001
APD62429PC
Figure imgf000196_0001
APD62429PC
δ-(2-Nitro-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 - yl)- phenyl]-amid wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 404,22 (C24H28N402); MS (ESI): 40δ (M+H+).δ- (2-nitro-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide was hydrogenated by Method B. This gave the product with the molecular weight 404.22 (C24H28N402); MS (ESI): 40δ (M + H +).
Beispiel 314 δ-(2-Acetylamino-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino- pyrrolidin- 1-yl)-phenyl]-amidExample 314 δ- (2-Acetylamino-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000197_0001
δ-(2-Amino-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin- 1-yl)- phenyl]-amid wurde nach Methode Q mit Acetylchlorid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 446,23 (C26H30N4O3); MS (ESI): 447 (M+H+).
Figure imgf000197_0001
δ- (2-Amino-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide was reacted according to method Q with acetyl chloride. This gave the product with the molecular weight 446.23 (C26H30N4O3); MS (ESI): 447 (M + H +).
Beispiel 31 δExample 31 δ
5-(2-lsobutyrylamino-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amid5- (2-isobutyrylamino-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000197_0002
5-(2-Amino-4-methyl-phenyl)-furan-2-carbonsäure [4-(3-dimethylamino-pyrrolidin- 1-yl)- phenyl]-amid wurde nach Methode Q mit Isobutyrylchlorid umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 474,26 (C28H34N403); MS (ESI): 47δ (M+H+). APD62429PC
Figure imgf000197_0002
5- (2-Amino-4-methyl-phenyl) -furan-2-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide was reacted with isobutyryl chloride according to Method Q. This gave the product of molecular weight 474.26 (C28H34N403); MS (ESI): 47δ (M + H +). APD62429PC
Beispiel 316 δ'-Chlor-3,4,δ,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carbonsäure [4-(3-dimethylamino- pyrrolidin-1-yl)-phenyl]-methyl-amidExample 316 δ'-Chloro-3,4, δ, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl- amide
Figure imgf000198_0001
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-methyl-amid (44,4 mg) und 2,5-Dichlorpyridin (60 mg) wurden für 15 Minuten auf 160°C erhitzt. Es wurde o-Xylen (0,5 mL) zugesetzt und für weitere 2 Stunden auf 160°C erhitzt. Das abgekühlte Rohgemisch wurde durch Chromatographie (Kieselgel, Eluent: Ethylacetat / Ammoniak (7N in Methanol)) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 442,01 (C24H32CIN50); MS (ESI): 442 (M+H+).
Figure imgf000198_0001
Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl-amide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at 160 ° C for 15 minutes heated. O-xylene (0.5 mL) was added and heated to 160 ° C for an additional 2 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate / ammonia (7N in methanol)). This gave the product of molecular weight 442.01 (C24H32CIN50); MS (ESI): 442 (M + H +).
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-methyl-amid Nach Methode G wurde 4-{[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-methyl- carbamoyl}-piperidine-1 -carbonsäure tert-butylester mit Trifluoressigsaure behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 330,48 (C19H30N4O); MS (ESI): 331 (M+H+).Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl-amide According to Method G, 4 - {[4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] Methyl-carbamoyl} -piperidine-1-carboxylic acid tert-butyl ester treated with trifluoroacetic acid. This gave the product with the molecular weight 330.48 (C19H30N4O); MS (ESI): 331 (M + H +).
Analog läßt sich Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)- phenyl]-amid herstellen. 4-{[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-methyl-carbamoyl}-piperidine-1- carbonsäure tert-butylesterAnalogously, piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide can be prepared. 4 - {[4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl-carbamoyl} -piperidine-1-carboxylic acid tert-butyl ester
Eine Lösung von N-Boc-piperidin-4-carbonsäure (δδO mg) und Pyridin (0,47 mL) in Dichlormethan (1δ mL) wurde mit Thinoylchlorid (0,21 mL) versetzt und nach 30 Minuten eine Lösung von Dimethyl-[1-(4-methylamino-phenyl)-pyrrolidin-3-yl]-amin (0,δ g), Triethylamin (1 ,17 mL), DMAP (0,44 g) und Dichlormethan (10 mL) tropfenweise zugesetzt. Nach 16 Stunden wurde die Mischung mit Dichlormethan verdünnt, mit Wasser und gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Eluent: Ethylacetat / Ammoniak (7N in Methanol)) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 430,60 (C24H38N403); MS (ESI): 431 (M+H+). APD62429PCA solution of N-Boc-piperidine-4-carboxylic acid (δδO mg) and pyridine (0.47 mL) in dichloromethane (1δ mL) was treated with thinoyl chloride (0.21 mL) and after 30 minutes a solution of dimethyl [ Add 1- (4-methylamino-phenyl) -pyrrolidin-3-yl] -amine (0, δ g), triethylamine (1, 17 mL), DMAP (0.44 g) and dichloromethane (10 mL) dropwise. After 16 hours, the mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate / ammonia (7N in methanol)). This gave the product with the molecular weight 430.60 (C24H38N403); MS (ESI): 431 (M + H +). APD62429PC
Analog läßt sich 4-{[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-carbamoyl}- piperidin-1 -carbonsäure tert-butylester herstellen.Analogously, tert-butyl 4 - {[4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -carbamoyl} -piperidine-1-carboxylate can be prepared.
Die folgenden Beispiele wurden analog dargestellt.The following examples were presented analogously.
Figure imgf000199_0002
Figure imgf000199_0002
Beispiel 320 3,4,δ,6-Tetrahydro-2H-[1 ,2']bipyridinyl-4-carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amidExample 320 3,4, δ, 6-Tetrahydro-2H- [1, 2 '] bipyridinyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000199_0001
Figure imgf000199_0001
Piperidine-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid (30 mg) und 2-Chlorpyridin (90 mg) wurden für 2 Stunden auf 160°C erhitzt. Es wurde 2-Chlorpyridin (0,2 mL) zugesetzt und nochmals für 4 Stunden auf 160°C erhitzt. Das abgekühlte Rohgemisch wurde durch Chromatographie (Kieselgel, Eluent: APD62429PCPiperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160 ° C for 2 hours. 2-Chloropyridine (0.2 mL) was added and heated again at 160 ° C for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: APD62429PC
Ethylacetat / Ammoniak (3N in Methanol)) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 393,δ4(C23H31 NδO); MS (ESI): 394 (M+H+).Ethyl acetate / ammonia (3N in methanol)). This gave the product with the molecular weight 393, δ4 (C23H31 NδO); MS (ESI): 394 (M + H +).
Die folgenden Beispiele wurden analog dargestellt.The following examples were presented analogously.
Figure imgf000200_0002
Figure imgf000200_0002
Beispiel 323 5'-Chlor-3,4,δ,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carbonsäure [4-(3-dimethylamino- pyrrolidin-1 -yl)-phenyl]-amidExample 323 5'-Chloro-3,4, δ, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide
Figure imgf000200_0001
Figure imgf000200_0001
Piperidine-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid (30 mg), 2,δ-Dichlorpyridin (30 mg) und Tributylamin (0,2 mL) wurden für 2 Stunden auf 160°C erhitzt. Das abgekühlte Rohgemisch wurde mit Heptan gewaschen und durch Chromatographie (Kieselgel, Eluent: Ethylacetat / Ammoniak (3N in Methanol)) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 427,98 (C23H30CINδO); MS (ESI): 428 (M+H+). APD62429PCPiperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide (30 mg), 2, δ-dichloropyridine (30 mg) and tributylamine (0.2 mL) were added for 2 hours heated to 160 ° C. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate / ammonia (3N in methanol)). This gave the product with the molecular weight 427.98 (C23H30CINδO); MS (ESI): 428 (M + H +). APD62429PC
Beispiel 324Example 324
1-(4-Chlor-2-cyano-phenyl)-piperidin-4-carbonsäure [4-(3-dimethylamino- pyrrolidin-1- yl)-phenyl]-amid1- (4-Chloro-2-cyano-phenyl) -piperidine-4-carboxylic acid [4- (3-dimethylaminopyrrolidin-1-yl) -phenyl] -amide
Figure imgf000201_0001
Figure imgf000201_0001
Piperidine-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-amid wurde wie im Beispiel 323 beschrieben mit 2,δ-Dichlorbenzonitril umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 4δ2,00 (C2δH30CINδO); MS (ESI): 4δ2 (M+H+).Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide was reacted with 2, δ-dichlorobenzonitrile as described in Example 323. This gave the product with the molecular weight 4δ2.00 (C2δH30CINδO); MS (ESI): 4δ2 (M + H +).
Beispiel 32δExample 32δ
1-(2-Acetylamino-4-chlor-phenyl)-piperidin-4-carbonsäure [4-(3-dimethylamino- pyrrolidin-1-yl)-phenyl]-methyl-amid1- (2-Acetylamino-4-chlorophenyl) -piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl-amide
Figure imgf000201_0002
Zu einer Lösung von 1-(4-Chlor-2-nitro-phenyl)-piperidin-4-carbonsäure [4-(3- dimethylamino-pyrrolidin-1- yl)-phenyl]-methyl-amid (50 mg) in Eisessig (5 mL) wurde Palladium auf Kohle (10%ig; 10 mg) hinzugefügt. Die Lösung wurde unter einer Atmosphäre von Wasserstoff (1 bar) gerührt und mit Acetanhydrid (14μL) versetzt. Nach einer Stunde wurde weiteres Acetanhydrid (6μL) zugesetzt und die Mischung noch 1δ Minuten gerührt. Die Suspension wurde filtriert und das Filtrat eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Eluent: Ethylacetat / Ammoniak (7N in Methanol)) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 498,07 (C27H36CINδ02); MS (ESI): 498 (M+H+).
Figure imgf000201_0002
To a solution of 1- (4-chloro-2-nitro-phenyl) -piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -methyl-amide (50 mg) in glacial acetic acid (5 mL) was added to palladium on carbon (10%, 10 mg). The solution was stirred under an atmosphere of hydrogen (1 bar) and acetic anhydride (14μL) was added. After one hour, further acetic anhydride (6 .mu.L) was added and the mixture was stirred for 1 δ minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate / ammonia (7N in methanol)). This gave the product with the molecular weight 498.07 (C27H36CINδ02); MS (ESI): 498 (M + H +).
Die folgenden Beispiele wurden analog dargestellt. APD62429PCThe following examples were presented analogously. APD62429PC
Figure imgf000202_0002
Figure imgf000202_0002
Beispiel 329Example 329
(R)-N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-2-(4-phenyl-piperidin-1-yl)- acetamid(R) -N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -2- (4-phenyl-piperidin-1-yl) -acetamide
Figure imgf000202_0001
Figure imgf000202_0001
Zu einer Lösung von (R)-2-Chlor-N-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]- acetamid (80 mg) in Acetonitril (δ mL) und DMF (1 mL) wurden Cäsiumcarbonat (100 mg) und 4-Phenylpiperidin (48 mg) gegeben und die Mischung für 12 Stunden bei 6δ°C gehalten. Die Mischung wurde von flüchtigen Anteilen befreit und der Rückstand zwischen Wasser und Dichlormethan verteilt. Die organische Phase wurde über Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Eluent: Methanol / Dichlormethan) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 406,58 (C25H34N40); MS (ESI): 407 (M+H+). APD62429PCTo a solution of (R) -2-chloro-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -acetamide (80 mg) in acetonitrile (δ mL) and DMF (1 mL) Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added and the mixture kept at 6 ° C for 12 hours. The mixture was freed of volatiles and the residue partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol / dichloromethane). This gave the product with the molecular weight 406.58 (C25H34N40); MS (ESI): 407 (M + H +). APD62429PC
Alternativ können Kaliumcarbonat oder Pyridin als Hilfsbasen eingesetzt, Kaliumiodid als Katalysator zugesetzt, oder die Reaktion bei 1δ0°C in einer Mikrowellenapparatur durchgeführt werden.Alternatively, potassium carbonate or pyridine can be used as auxiliary bases, potassium iodide can be added as catalyst, or the reaction can be carried out at 110 ° C. in a microwave apparatus.
(R)-2-Chlor-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-acetamid(R) -2-chloro-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -acetamide
Zu einer Lösung von (R)- [1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin (3,1δ g) in Dichlormethan (120 mL) wurde Triethylamin (2.03 g) gegeben und dann Chloracetylchlorid (2,26 g) zugetropft. Nach 3 Stunden wurde die Mischung mit Dichlormethan verdünnt und mit Wasser und einer Kochsalzlösung gewaschen. Die organische Phase wurde über Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde durch Chromatographie (Kieselgel, Eluent: Methanol / Dichlormethan) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 281 ,79 (C14H20CIN3O); MS (ESI): 282 (M+H+). Analog wurden erhalten: N-{4-[3-(Acetyl-methyl-amino)-pyrrolidin-1 -yl]-phenyl}-2-chlor-acetamid 2-Chlor-N-[4-(3-dimethylamino-pyrrolidin-1 -yl)-phenyl]-acetamid (R)-2-Chlor-N-[6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3-yl]-acetamidTo a solution of (R) - [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine (3.1 g) in dichloromethane (120 mL) was added triethylamine (2.03 g) and then Chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol / dichloromethane). This gave the product of molecular weight 281, 79 (C14H20CIN3O); MS (ESI): 282 (M + H +). The following were obtained analogously: N- {4- [3- (acetylmethyl-amino) -pyrrolidin-1-yl] -phenyl} -2-chloro-acetamide 2-chloro-N- [4- (3-dimethylamino-pyrrolidine 1 -yl) -phenyl] -acetamide (R) -2-chloro-N- [6- (3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl] -acetamide
Die folgenden Beispiele wurden analog der in Beispiel 329 gegeben Vorschrift hergestellt:The following examples were prepared analogously to the procedure given in Example 329:
Figure imgf000203_0001
APD62429PC
Figure imgf000203_0001
APD62429PC
Figure imgf000204_0002
Figure imgf000204_0002
Beispiel 340Example 340
(R)-4-Benzyl-piperidin-1 -carbonsäure [6-(3-dimethylamino-pyrrolidin-1 -yl)-pyridin-(R) -4-Benzyl-piperidine-1-carboxylic acid [6- (3-dimethylamino-pyrrolidin-1-yl) -pyridine]
3-yl]-amid3-yl] -amide
Figure imgf000204_0001
APD62429PC
Figure imgf000204_0001
APD62429PC
Zu einer Lösung von Carbonyldiimidazol (δ3 mg) in DMF (0,δ mL) bei 0°C wurde (R)-6-(3-Dimethylamino-pyrrolidin-1-yl)-pyridin-3-ylamine gegeben. Nach 1δ Minuten wurde 4-Benzylpiperidin (δ7 mg) zugesetzt und die Mischung für eine Stunde auf 90°C erhitzt. Die abgekühlte Mischung wurde von flüchtigen Anteilen befreit. Der Rückstand wurde durch Chromatographie (Kieselgel, Eluent: Methanol / Dichlormethan) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 407,δ6 (C24H33NδO); MS (ESI): 408 (M+H+).To a solution of carbonyldiimidazole (δ3 mg) in DMF (0, δ mL) at 0 ° C was added (R) -6- (3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-ylamine. After 1 δ minutes, 4-benzylpiperidine (δ7 mg) was added and the mixture heated to 90 ° C for one hour. The cooled mixture was freed of volatiles. The residue was purified by chromatography (silica gel, eluent: methanol / dichloromethane). This gave the product with the molecular weight 407, δ6 (C24H33NδO); MS (ESI): 408 (M + H +).
Analog wurden folgende Beispiele dargestellt:The following examples were presented analogously:
Figure imgf000205_0001
APD62429PC
Figure imgf000205_0001
APD62429PC
Figure imgf000206_0002
Figure imgf000206_0002
Beispiel 348Example 348
(R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-3-fluor-phenyl]- benzamid(R) -4-Cyclopropylmethoxy-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -benzamide
Figure imgf000206_0001
Figure imgf000206_0001
(R)-4-Benzyloxy-N-[4-(3-dimethylamino-pyrrolidin-1-yl)-3-fluor-phenyl]-benzamid wurde nach Methode B debenzylierend hydriert. Das erhaltene (R)-N-[4-(3- Dimethylamino-pyrrolidin-1 -yl)-3-fluoro-phenyl]-4-hydroxy-benzamid wurde nach Methode H mit Cyclopropylmethylbromid alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 397,δ0 (C23H28N302); MS (ESI): 398 (M+H+).(R) -4-Benzyloxy-N- [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -benzamide was hydrogenated by Method B by debenzylation. The obtained (R) -N- [4- (3-dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -4-hydroxybenzamide was alkylated by method H with cyclopropylmethylbromide. This gave the product with the molecular weight 397, δ0 (C23H28N302); MS (ESI): 398 (M + H +).
Nach Methode H wurden ebenfalls folgende Beispiele erhalten:Method H also gave the following examples:
Figure imgf000206_0003
APD62429PC
Figure imgf000206_0003
APD62429PC
Figure imgf000207_0002
Figure imgf000207_0002
Beispiel 352Example 352
(R)-N-[4-(3-Dimethylamino-pyrrolidin-1 -yl)-3-fluor-phenyl]-4-(pyridin-2-yloxy)- benzamid(R) -N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -4- (pyridin-2-yloxy) -benzamide
Figure imgf000207_0001
Figure imgf000207_0001
(R)-N-[4-(3-Dimethylamino-pyrrolidin-1 -yl)-3-fluoro-phenyl]-4-hydroxy-benzamid wurde nach Methode R mit 2-Chlorpyridin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 434,52 (C25H27N402); MS (ESI): 43δ (M+H+).(R) -N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -3-fluoro-phenyl] -4-hydroxybenzamide was reacted with 2-chloropyridine by Method R. This gave the product with the molecular weight 434.52 (C25H27N402); MS (ESI): 43δ (M + H +).
Beispiel 3δ3 - Beispiel δ07Example 3δ3 - Example δ07
Nach Methode A wurden verschiedene Pyrrolidinylaniline mit diversen Aminen umgesetzt. Die erhaltenen Produkte sind in Tabelle 6 zusammengefasst.By method A, various pyrrolidinylanilines were reacted with various amines. The products obtained are summarized in Table 6.
Beispiel δ08 - Beispiel 1130Example δ08 - Example 1130
Nach den Methoden E wurden verschiedene Pyrrolidinylaniline mit diversenAfter the methods E were different Pyrrolidinylaniline with various
Säuren umgesetzt. Die erhaltenen Produkte sind in Tabelle 7 zusammengefasst.Converted acids. The products obtained are summarized in Table 7.
Beispiel 1131 - Beispiel 1232Example 1131 - Example 1232
Nach den Methoden O wurden verschiedene (Hetero-)Arylhalogenide mit diversen Boronsäuren umgesetzt. Die erhaltenen Produkte sind in Tabelle 8 zusammengefasst.According to the methods O, various (hetero) aryl halides were reacted with various boronic acids. The products obtained are summarized in Table 8.
Beispiel 1233 - Beispiel 1237 APD62429PCExample 1233 - Example 1237 APD62429PC
Nach den Methoden J wurden verschiedene Arylhalogenide mit diversen Acetylenen umgesetzt. Die erhaltenen Produkte sind in Tabelle 9 zusammengefasst.By methods J, various aryl halides were reacted with various acetylenes. The products obtained are summarized in Table 9.
Beispiel 1238 - Beispiel 1403Example 1238 - Example 1403
Nach der Methode N wurden verschiedene Aminopyrrolidine und N- Arylpyrrolidinone mit diversen Aldehyden, Ketonen bzw. Aminen umgesetzt. Die erhaltenen Produkte sind in Tabelle 10 zusammengefasst.By method N, various aminopyrrolidines and N-arylpyrrolidinones were reacted with various aldehydes, ketones or amines. The products obtained are summarized in Table 10.
Beispiel 1404 - Beispiel 1423Example 1404 - Example 1423
Nach der Methode E wurden verschiedene Aminopyrrolidine mit Formaldehyd reduktiv methyliert. Die erhaltenen Produkte sind in Tabelle 11 zusammengefasst.According to the method E, various aminopyrrolidines were reductively methylated with formaldehyde. The products obtained are summarized in Table 11.
Beispiel 1424 - Beispiel 1443 Nach der Methode F wurden verschiedene Amide alkyliert. Die erhaltenen Produkte sind in Tabelle 12 zusammengefasst.Example 1424 - Example 1443 Method F was used to alkylate various amides. The products obtained are summarized in Table 12.
Beispiel 1444 - Beispiel 1618Example 1444 - Example 1618
Nach der Methode G wurden verschiedene Carbaminsäure tert-butylester gespalten. Die erhaltenen Produkte sind in Tabelle 13 zusammengefasst.According to the method G, various carbamic acid tert-butyl ester were cleaved. The products obtained are summarized in Table 13.
Tabelle 6Table 6
Figure imgf000208_0001
APD62429PC
Figure imgf000208_0001
APD62429PC
Figure imgf000209_0001
APD62429PC
Figure imgf000209_0001
APD62429PC
Figure imgf000210_0001
APD62429PC
Figure imgf000210_0001
APD62429PC
Figure imgf000211_0001
APD62429PC
Figure imgf000211_0001
APD62429PC
Figure imgf000212_0001
APD62429PC
Figure imgf000212_0001
APD62429PC
Figure imgf000213_0001
APD62429PC
Figure imgf000213_0001
APD62429PC
Figure imgf000214_0001
APD62429PC
Figure imgf000214_0001
APD62429PC
Figure imgf000215_0001
APD62429PC
Figure imgf000215_0001
APD62429PC
Figure imgf000216_0001
APD62429PC
Figure imgf000216_0001
APD62429PC
Figure imgf000217_0001
APD62429PC
Figure imgf000217_0001
APD62429PC
Figure imgf000218_0001
APD62429PC
Figure imgf000218_0001
APD62429PC
Figure imgf000219_0001
APD62429PC
Figure imgf000219_0001
APD62429PC
Figure imgf000220_0001
APD62429PC
Figure imgf000220_0001
APD62429PC
Figure imgf000221_0001
APD62429PC
Figure imgf000221_0001
APD62429PC
Figure imgf000222_0001
APD62429PC
Figure imgf000222_0001
APD62429PC
Figure imgf000223_0001
Figure imgf000223_0001
Tabelle 7Table 7
Figure imgf000223_0002
APD62429PC
Figure imgf000223_0002
APD62429PC
Figure imgf000224_0001
APD62429PC
Figure imgf000224_0001
APD62429PC
Figure imgf000225_0001
APD62429PC
Figure imgf000225_0001
APD62429PC
Figure imgf000226_0001
APD62429PC
Figure imgf000226_0001
APD62429PC
Figure imgf000227_0001
APD62429PC
Figure imgf000227_0001
APD62429PC
Figure imgf000228_0001
APD62429PC
Figure imgf000228_0001
APD62429PC
Figure imgf000229_0001
APD62429PC
Figure imgf000229_0001
APD62429PC
Figure imgf000230_0001
APD62429PC
Figure imgf000230_0001
APD62429PC
Figure imgf000231_0001
APD62429PC
Figure imgf000231_0001
APD62429PC
Figure imgf000232_0001
APD62429PC
Figure imgf000232_0001
APD62429PC
Figure imgf000233_0001
APD62429PC
Figure imgf000233_0001
APD62429PC
Figure imgf000234_0001
APD62429PC
Figure imgf000234_0001
APD62429PC
Figure imgf000235_0001
APD62429PC
Figure imgf000235_0001
APD62429PC
Figure imgf000236_0001
APD62429PC
Figure imgf000236_0001
APD62429PC
Figure imgf000237_0001
APD62429PC
Figure imgf000237_0001
APD62429PC
Figure imgf000238_0001
APD62429PC
Figure imgf000238_0001
APD62429PC
Figure imgf000239_0001
APD62429PC
Figure imgf000239_0001
APD62429PC
Figure imgf000240_0001
APD62429PC
Figure imgf000240_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
695 C23H24CIN302 409,16 410695 C23H24CIN302 409.16 410
696 C22H24CIN30S 413,13 414696 C22H24CIN30S 413,13 414
697 C21 H21 CIFN30S 417,11 418697 C21 H21 CIFN30S 417.11 418
Figure imgf000241_0001
Figure imgf000241_0001
698 C21 H21 CI2N30S 433,08 434698 C21 H21 CI2N30S 433.08 434
699 C21 H21CIN403S 444,10 445699 C21 H21CIN403S 444.10 445
Figure imgf000241_0002
Figure imgf000241_0002
700 C22H23CI2N302S 463,09 464700 C22H23CI2N302S 463.09 464
cici
701 C22H24CIN302S 429,13 430701 C22H24CIN302S 429.13 430
702 C23H26CIN30S 427,15 428702 C23H26CIN30S 427.15 428
703 C24H26CIN302S 455,14 456703 C24H26CIN302S 455.14 456
704 C22H24F3N50S 463,17 464704 C22H24F3N50S 463.17 464
705 C24H23CIF3N302 477,14 478705 C24H23CIF3N302 477.14 478
Figure imgf000241_0003
APD62429PC
Figure imgf000241_0003
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
706 C24H24F3N302 443,18 444706 C24H24F3N302 443.18 444
707 C23H28BrN502 485,14 486707 C23H28BrN502 485.14 486
708 C24H25F3N402S 490,17 491708 C24H25F3N402S 490.17 491
Figure imgf000242_0001
Figure imgf000242_0001
709 C22H22N4OS 390,15 391709 C22H22N4OS 390.15 391
N-N-
710 C23H25N3O2 375,20 376710 C23H25N3O2 375.20 376
711 C24H27N3O2S 421 ,18 422711 C24H27N3O2S 421, 18 422
Figure imgf000242_0002
Figure imgf000242_0002
712 C24H26CIN303 439,17 440712 C24H26CIN303 439.17 440
713 C21 H22CIN30S 399,12 400713 C21 H22CIN30S 399.12 400
714 C25H23F6N302 511 ,17 512714 C25H23F6N302 511, 17 512
715 C23H30FN3O2 399,51 400715 C23H30FN3O2 399.51 400
Figure imgf000242_0003
APD62429PC
Figure imgf000242_0003
APD62429PC
Figure imgf000243_0001
APD62429PC
Figure imgf000243_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
727 C26H28FN30 417,22 418727 C26H28FN30 417.22 418
728 C27H31 N3O2 429,24 430728 C27H31 N3O2 429.24 430
Figure imgf000244_0001
Figure imgf000244_0001
729 C26H28CIN30 433,19 434 a OJrCr'°N~ 729 C26H28CIN30 433.19 434 a O J rCr '° N ~
730 C26H28CIN30 433,19 434730 C26H28CIN30 433.19 434
" yQXrOr0""yQXrOr 0 "
731 C26H28CIN30 433,19 434731 C26H28CIN30 433.19 434
732 C24H25CIN404 468,16 469732 C24H25CIN404 468.16 469
Figure imgf000244_0002
Figure imgf000244_0002
733 C26H28FN30 417,22 418733 C26H28FN30 417.22 418
F^ ^°N~ F ^ ^ ° N ~
734 C27H29N303 443,22 444734 C27H29N303 443.22 444
735 C27H31N3O 413,25 414735 C27H31N3O 413.25 414
736 C27H31 N30 413,25 414736 C27H31 N30 413.25 414
737 C26H26FN302 431 ,20 432737 C26H26FN302 431, 20 432
Figure imgf000244_0003
APD62429PC
Figure imgf000244_0003
APD62429PC
Figure imgf000245_0001
APD62429PC
Figure imgf000245_0001
APD62429PC
Figure imgf000246_0001
APD62429PC
Figure imgf000246_0001
APD62429PC
Figure imgf000247_0001
APD62429PC
Figure imgf000247_0001
APD62429PC
Figure imgf000248_0001
APD62429PC
Figure imgf000248_0001
APD62429PC
Figure imgf000249_0001
APD62429PC
Figure imgf000249_0001
APD62429PC
Figure imgf000250_0001
APD62429PC
Figure imgf000250_0001
APD62429PC
Figure imgf000251_0001
APD62429PC
Figure imgf000251_0001
APD62429PC
Figure imgf000252_0001
APD62429PC
Figure imgf000252_0001
APD62429PC
Figure imgf000253_0001
APD62429PC
Figure imgf000253_0001
APD62429PC
Figure imgf000254_0001
APD62429PC
Figure imgf000254_0001
APD62429PC
Figure imgf000255_0001
APD62429PC
Figure imgf000255_0001
APD62429PC
Figure imgf000256_0001
APD62429PC
Figure imgf000256_0001
APD62429PC
Figure imgf000257_0001
APD62429PC
Figure imgf000257_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
870 C26H32N4O2 432,25 433870 C26H32N4O2 432.25 433
871 C24H27N3O2 389,21 390871 C24H27N3O2 389.21 390
872 C27H29N5O 439,24 440872 C27H29N5O 439.24 440
873 C23H28N4O3S 440,19 441873 C23H28N4O3S 440.19 441
874 C28H34N4OS 474,24 475874 C28H34N4OS 474.24 475
875 C24H28N4O3S 452,19 453875 C24H28N4O3S 452.19 453
876 C23H23CIN403 438,15 439876 C23H23CIN403 438.15 439
877 C23H26FN50 407,21 408877 C23H26FN50 407.21 408
878 C25H27CIN402 450,18 451878 C25H27CIN402 450.18 451
879 C24H27N5O 401 ,22 402879 C24H27N5O 401, 22 402
880 C24H30F3N5O 461 ,24 462880 C24H30F3N5O 461, 24 462
Figure imgf000258_0001
APD62429PC
Figure imgf000258_0001
APD62429PC
Figure imgf000259_0001
APD62429PC
Figure imgf000259_0001
APD62429PC
Figure imgf000260_0001
APD62429PC
Figure imgf000260_0001
APD62429PC
Figure imgf000261_0001
APD62429PC
Figure imgf000261_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
912 C24H31 FN4O4 458,23 459912 C24H31 FN4O4 458.23 459
913 C24H31CIFN302 447,21 448913 C24H31CIFN302 447.21 448
914 C26H36FN302 441 ,28 442914 C26H36FN302 441, 28 442
915 C25H32CI2FN303 511 ,18 512915 C25H32CI2FN303 511, 18 512
916 C24H28F5N302 485,21 486916 C24H28F5N302 485.21 486
917 C24H31 F2N302 431 ,24 432917 C24H31 F2N302 431, 24 432
918 C26H34FN303 455,26 456918 C26H34FN303 455.26 456
919 C28H40FN3O3 485,30 486919 C28H40FN3O3 485.30 486
920 C25H34FN50 439,27 4A0920 C25H34FN50 439.27 4A0
921 C23H31 FN402 414,24 415921 C23H31 FN402 414.24 415
Figure imgf000262_0001
APD62429PC
Figure imgf000262_0001
APD62429PC
Figure imgf000263_0001
APD62429PC
Figure imgf000263_0001
APD62429PC
Figure imgf000264_0001
APD62429PC
Figure imgf000264_0001
APD62429PC
Figure imgf000265_0001
APD62429PC
Figure imgf000265_0001
APD62429PC
Figure imgf000266_0001
APD62429PC
Figure imgf000266_0001
APD62429PC
Figure imgf000267_0001
APD62429PC
Figure imgf000267_0001
APD62429PC
Figure imgf000268_0001
APD62429PC
Figure imgf000268_0001
APD62429PC
Figure imgf000269_0001
APD62429PC
Figure imgf000269_0001
APD62429PC
Figure imgf000270_0001
APD62429PC
Figure imgf000270_0001
APD62429PC
Figure imgf000271_0001
APD62429PC
Figure imgf000271_0001
APD62429PC
Figure imgf000272_0001
APD62429PC
Figure imgf000272_0001
APD62429PC
Figure imgf000273_0001
APD62429PC
Figure imgf000273_0001
APD62429PC
Figure imgf000274_0001
APD62429PC
Figure imgf000274_0001
APD62429PC
Figure imgf000275_0001
APD62429PC
Figure imgf000275_0001
APD62429PC
Figure imgf000276_0001
APD62429PC
Figure imgf000276_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1066 C20H21CIN4O2S 416,11 4171066 C20H21CIN4O2S 416.11 417
Figure imgf000277_0001
Figure imgf000277_0001
1067 C25H26N403S 462,17 4631067 C25H26N403S 462.17 463
1068 C26H28N404 460,21 4611068 C26H28N404 460.21 461
1069 C30H42FN3O4 527,32 5281069 C30H42FN3O4 527.32 528
1070 C31 H42FN304 539,32 5401070 C31 H42FN304 539.32 540
1071 C27H30N4O2 442,24 4431071 C27H30N4O2 442.24 443
1072 C28H32N4O3 472,25 4731072 C28H32N4O3 472.25 473
1073 C25H32FN302 425,25 4261073 C25H32FN302 425.25 426
1074 C27H30FN3O2 447,23 4481074 C27H30FN3O2 447.23 448
1075 C27H30FN3O 431 ,24 4321075 C27H30FN3O 431, 24 432
Figure imgf000277_0002
APD62429PC
Figure imgf000277_0002
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1076 C28H27FN403 486,21 4871076 C28H27FN403 486.21 487
1077 C28H28BrFN4O2 550,14 5511077 C28H28BrFN4O2 550.14 551
1078 C28H31FN402 474,24 4751078 C28H31FN402 474.24 475
1079 C26H31 FN40 434,25 4351079 C26H31 FN40 434.25 435
1080 C26H29FN402 448,23 4491080 C26H29FN402 448.23 449
1081 C28H30FN5O 471 ,24 4721081 C28H30FN5O 471, 24 472
1082 C29H31 FN40 470,25 4711082 C29H31 FN40 470.25 471
1083 C27H30FN3OS 463,21 4641083 C27H30FN3OS 463.21 464
1084 C25H28FN50S 465,20 4661084 C25H28FN50S 465,20 466
1085 C26H29FN40S 464,20 4651085 C26H29FN40S 464,20 465
Figure imgf000278_0001
APD62429PC
Figure imgf000278_0001
APD62429PC
Figure imgf000279_0001
APD62429PC
Figure imgf000279_0001
APD62429PC
Figure imgf000280_0001
APD62429PC
Figure imgf000280_0001
APD62429PC
Figure imgf000281_0001
APD62429PC
Figure imgf000281_0001
APD62429PC
Figure imgf000282_0001
Figure imgf000282_0001
Tabelle 8Table 8
Figure imgf000282_0002
APD62429PC
Figure imgf000282_0002
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1133 C24H26FN302 407,20 4081133 C24H26FN302 407.20 408
1134 C28H33N304 475,25 4761134 C28H33N304 475.25 476
1135 C29H34N405 518,25 5191135 C29H34N405 518.25 519
1136 C33H41 N304 543,31 5441136 C33H41 N304 543.31 544
1137 C29H36N404 504,27 5051137 C29H36N404 504.27 505
1138 C29H32N404 500,24 5011138 C29H32N404 500.24 501
1139 C28H30F3N3O4 529,22 5301139 C28H30F3N3O4 529.22 530
1140 C22H22CI2N40S 460,09 4611140 C22H22CI2N40S 460,09 461
1141 C22H23CIN4OS 426,13 4271141 C22H23CIN4OS 426.13 427
Figure imgf000283_0001
APD62429PC
Figure imgf000283_0001
APD62429PC
Figure imgf000284_0001
APD62429PC
Figure imgf000284_0001
APD62429PC
Figure imgf000285_0001
APD62429PC
Figure imgf000285_0001
APD62429PC
Figure imgf000286_0001
APD62429PC
Figure imgf000286_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1172 C23H26N40S2 438,15 4391172 C23H26N40S2 438.15 439
Q -.s^ sAnjy "Q -.s ^ s to j y "
1173 C24H28N40S2 452,17 4531173 C24H28N40S2 452.17 453
1174 C24H28N40S 420,20 4211174 C24H28N40S 420,20 421
1175 C23H23F3N402S 476,15 4771175 C23H23F3N402S 476.15 477
Figure imgf000287_0001
Figure imgf000287_0001
1176 C24H28N403S 452,19 4531176 C24H28N403S 452.19 453
.o..O.
^r-^ r-
6 s- to Ö 6 to Ö
1177 C25H30N4OS 434,21 4351177 C25H30N4OS 434.21 435
1178 C25H30N4OS 434,21 4351178 C25H30N4OS 434.21 435
1179 C23H26N402S 422,18 4231179 C23H26N402S 422.18 423
1180 C22H25N502S 423,17 4241180 C22H25N502S 423.17 424
1181 C24H24N40S2 448,14 4491181 C24H24N40S2 448.14 449
1182 C23H23F3N4O2S 476,15 4771182 C23H23F3N4O2S 476.15 477
Figure imgf000287_0002
APD62429PC
Figure imgf000287_0002
APD62429PC
Figure imgf000288_0001
APD62429PC
Figure imgf000288_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1193 C27H29N3O2 427,23 4281193 C27H29N3O2 427.23 428
Figure imgf000289_0001
Figure imgf000289_0001
1194 C25H25F2N30 421 ,20 4221194 C25H25F2N30 421, 20 422
FryOJ» X F Ryo J »X
1195 C25H25F2N30 421 ,20 4221195 C25H25F2N30 421, 20 422
1196 C26H28N403 444,22 4451196 C26H28N403 444.22 445
1197 C27H32N40 428,26 4291197 C27H32N40 428.26 429
1198 C25H28N4O2 416,22 4171198 C25H28N4O2 416.22 417
Figure imgf000289_0002
Figure imgf000289_0002
1199 C27H29N303 443,22 4441199 C27H29N303 443.22 444
1200 C24H28N402 404,22 4051200 C24H28N402 404.22 405
1201 C23H25N302 375,20 3761201 C23H25N302 375.20 376
1202 C24H25FN40 404,20 4051202 C24H25FN40 404.20 405
Figure imgf000289_0003
APD62429PC
Figure imgf000289_0003
APD62429PC
Figure imgf000290_0001
APD62429PC
Figure imgf000290_0001
APD62429PC
Figure imgf000291_0001
APD62429PC
Figure imgf000291_0001
APD62429PC
Figure imgf000292_0001
Figure imgf000292_0001
Tabelle 9Table 9
Figure imgf000292_0002
APD62429PC
Figure imgf000292_0002
APD62429PC
1233 C31 H29N302 475,23 4761233 C31 H29N302 475.23 476
1234 C30H35N3O2 469,27 4701234 C30H35N3O2 469.27 470
1235 C28H30N4O3S 502,20 5031235 C28H30N4O3S 502.20 503
1236 C29H30FN3O3S 519,20 5201236 C29H30FN3O3S 519,20 520
1237 C28H30N4O3S 502,20 5031237 C28H30N4O3S 502.20 503
Figure imgf000293_0001
Figure imgf000293_0001
Tabelle 10Table 10
Figure imgf000293_0002
APD62429PC
Figure imgf000293_0002
APD62429PC
Figure imgf000294_0001
APD62429PC
Figure imgf000294_0001
APD62429PC
Figure imgf000295_0001
APD62429PC
Figure imgf000295_0001
APD62429PC
Figure imgf000296_0001
APD62429PC
Figure imgf000296_0001
APD62429PC
Figure imgf000297_0001
APD62429PC
Figure imgf000297_0001
APD62429PC
Figure imgf000298_0001
APD62429PC
Figure imgf000298_0001
APD62429PC
Figure imgf000299_0001
APD62429PC
Figure imgf000299_0001
APD62429PC
Figure imgf000300_0001
APD62429PC
Figure imgf000300_0001
APD62429PC
Figure imgf000301_0001
APD62429PC
Figure imgf000301_0001
APD62429PC
Figure imgf000302_0001
APD62429PC
Figure imgf000302_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+ * No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + * No. Mw.
1343 C25H34FN303 443,26 4441343 C25H34FN303 443.26 444
1344 C27H36FN302 453,28 4541344 C27H36FN302 453.28 454
1345 C27H38FN302 455,30 4561345 C27H38FN302 455.30 456
1346 C27H38FN302 455,30 4561346 C27H38FN302 455.30 456
1347 C27H38FN302 455,30 4561347 C27H38FN302 455.30 456
1348 C26H36FN303 457,27 4581348 C26H36FN303 457.27 458
1349 C26H36FN303 457,27 4581349 C26H36FN303 457.27 458
1350 C25H34FN304 459,25 4601350 C25H34FN304 459.25 460
1351 C25H34FN304 459,25 4601351 C25H34FN304 459.25 460
Figure imgf000303_0001
Figure imgf000303_0001
1352 38FN302 467,30 4681352 38FN302 467.30 468
*o ό >X> C28H* o ό > X> C28H
1353 C27H38FN303 471 ,29 4721353 C27H38FN303 471, 29 472
Figure imgf000303_0002
APD62429PC
Figure imgf000303_0002
APD62429PC
Figure imgf000304_0001
APD62429PC
Figure imgf000304_0001
APD62429PC
Figure imgf000305_0001
APD62429PC
Figure imgf000305_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1376 C26H34FN302S 471 ,24 4721376 C26H34FN302S 471, 24,472
1377 C26H36FN304 473,27 4741377 C26H36FN304 473.27 474
1378 C28H41 FN402 484,32 4851378 C28H41 FN402 484.32 485
1379 C28H37FN403 496,29 4971379 C28H37FN403 496.29 497
1380 C28H37FN403 496,29 4971380 C28H37FN403 496.29 497
1381 C32H38FN302 515,29 5161381 C32H38FN302 515.29 516
1382 C31 H38FN303 519,29 5201382 C31 H38FN303 519.29 520
1383 C31 H43FN402 522,34 5231383 C31 H43FN402 522.34 523
Figure imgf000306_0001
Figure imgf000306_0001
1384 C27H36FN303 469,27 4701384 C27H36FN303 469.27 470
1385 C27H36FN303 469,27 4701385 C27H36FN303 469.27 470
Figure imgf000306_0002
APD62429PC
Figure imgf000306_0002
APD62429PC
Figure imgf000307_0001
APD62429PC
Figure imgf000307_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1397 - C26H36FN303 457,27 4581397 - C26H36FN303 457.27 458
1398 C26H34FN304 471 ,25 4721398 C26H34FN304 471, 25,472
1399 C28H38FN304 499,29 5001399 C28H38FN304 499.29 500
1400 C27H38FN3Q3 471 ,29 4721400 C27H38FN3Q3 471, 29 472
1401 C28H40FN3O3 485,30 4861401 C28H40FN3O3 485.30 486
1402 C27H36FN304 485,27 4861402 C27H36FN304 485.27 486
1403 C27H36FN303 469,27 4701403 C27H36FN303 469.27 470
Figure imgf000308_0001
Figure imgf000308_0001
Tabelle 11Table 11
Figure imgf000308_0002
APD62429PC
Figure imgf000308_0002
APD62429PC
Figure imgf000309_0001
APD62429PC
Figure imgf000309_0001
APD62429PC
Figure imgf000310_0001
Figure imgf000310_0001
Tabelle 12Table 12
Figure imgf000310_0002
APD62429PC
Figure imgf000310_0002
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1425 C28H39N304 481 ,29 4821425 C28H39N304 481, 29 482
1426 C27H38N404 482,29 4831426 C27H38N404 482.29 483
1427 C24H32N403 424,25 4251427 C24H32N403 424.25 425
Figure imgf000311_0001
Figure imgf000311_0001
1428 C24H33N302 395,26 3961428 C24H33N302 395.26 396
Y χyγXX°Y χy γ XX °
1429 C24H31 N303 409,24 4101429 C24H31 N303 409.24 410
X 0m < ^X 0 m <^
1430 C29H33FN4O3 504,25 5051430 C29H33FN4O3 504.25 505
1431 C27H38N404 482,29 4831431 C27H38N404 482.29 483
Figure imgf000311_0002
Figure imgf000311_0002
1432 C30H43N3O5 525,32 5261432 C30H43N3O5 525.32 526
oO
1433 C25H33N303 423,25 4241433 C25H33N303 423.25 424
1434 C29H41 N305 511 ,30 5121434 C29H41 N305 511, 30 512
1435 C26H28FN30 417,22 4181435 C26H28FN30 417.22 418
Figure imgf000311_0003
Figure imgf000311_0003
1436 C27H30FN3O 431 ,24 4321436 C27H30FN3O 431, 24 432
:^ ^ ' APD62429PC : ^ ^ ' APD62429PC
Tabelle 13Table 13
Figure imgf000312_0002
APD62429PC
Figure imgf000312_0002
APD62429PC
Figure imgf000313_0001
APD62429PC
Figure imgf000313_0001
APD62429PC
Figure imgf000314_0001
APD62429PC
Figure imgf000314_0001
APD62429PC
Figure imgf000315_0001
APD62429PC
Figure imgf000315_0001
APD62429PC
Figure imgf000316_0001
APD62429PC
Figure imgf000316_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1485 C22H28FN302 385,22 3861485 C22H28FN302 385.22 386
1486 C22H29N302 367,23 3681486 C22H29N302 367.23 368
Figure imgf000317_0001
Figure imgf000317_0001
1487 C22H28N40 364,23 365 o-o-tcrtf1487 C22H28N40 364.23 365 o-o-tcrtf
1488 C25H35N303 425,27 4261488 C25H35N303 425.27 426
1489 C24H33N303 411 ,25 4121489 C24H33N303 411, 25 412
1490 C22H29N502 395,23 3961490 C22H29N502 395.23 396
Figure imgf000317_0002
Figure imgf000317_0002
1491 C23H25N502 403,20 4041491 C23H25N502 403.20 404
<x<x
O0-a σ' MO 0 -a σ 'M
1492 C23H25N502 403,20 4041492 C23H25N502 403.20 404
1493 C20H22N6O 362,19 3631493 C20H22N6O 362.19 363
1494 C25H25N502 427,20 4281494 C25H25N502 427.20 428
Figure imgf000317_0003
APD62429PC
Figure imgf000317_0003
APD62429PC
Figure imgf000318_0001
APD62429PC
Figure imgf000318_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H4 No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H 4 no. Mw.
1505 C23H24FN502 421 ,19 4221505 C23H24FN502 421, 19 422
1506 C23H22F3N302 429,17 4301506 C23H22F3N302 429.17 430
1507 C24H28N402 404,22 4051507 C24H28N402 404.22 405
1508 C28H33N302 443,26 4441508 C28H33N302 443.26 444
1509 C24H24N402 400,19 4011509 C24H24N402 400.19 401
1510 C24H26N403 418,20 4191510 C24H26N403 418,20 419
1511 C23H30FN3O2 399,23 4001511 C23H30FN3O2 399.23 400
1512 C22H27FN404 430,20 4311512 C22H27FN404 430,20 431
1513 C22H29FN402 400,23 4011513 C22H29FN402 400.23 401
1514 C24H26N403 418,20 4191514 C24H26N403 418,20 419
Figure imgf000319_0001
APD62429PC
Figure imgf000319_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1515 C23H30FN3O2 399,23 4001515 C23H30FN3O2 399.23 400
1516 C24H29FN40 408,23 4091516 C24H29FN40 408.23 409
1517 C25H26FN302 419,20 4201517 C25H26FN302 419,20 420
1518 C25H26FN302 419,20 4201518 C25H26FN302 419.20 420
1519 C24H26FN302S 439,17 4401519 C24H26FN302S 439.17 440
1520 C24H30FN3O 395,24 396
Figure imgf000320_0001
1520 C24H30FN3O 395.24 396
Figure imgf000320_0001
1521 C25H32FN30 409,25 4101521 C25H32FN30 409.25 410
H.NH.N
Q-Jζ rόA Q -Jζ rόA
1522 C26H27F2N3O 435,21 4361522 C26H27F2N3O 435.21 436
Figure imgf000320_0002
Figure imgf000320_0002
1523 ci C22H21CIFN302 413,13 4141523 ci C22H21CIFN302 413.13 414
Ax jyoAx Jyo
1524 C22H22FN302 379,17 3801524 C22H22FN302 379.17 380
1525 C23H25N303 391 ,19 392
Figure imgf000320_0003
APD62429PC1525 C23H25N303 391, 19 392
Figure imgf000320_0003
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1526 C23H25N303 391 ,19 3921526 C23H25N303 391, 19 392
1527 C22H22FN302 379,17 3801527 C22H22FN302 379.17 380
1528 C23H25N302S 407,17 4081528 C23H25N302S 407.17 408
1529 C23H25N302 375,20 3761529 C23H25N302 375.20 376
1530 C24H27N303 405,20 4061530 C24H27N303 405.20 406
1531 C23H30FN3O2 399,23 4001531 C23H30FN3O2 399.23 400
1532 C25H31 CIFN3O 443,21 4441532 C25H31 CIFN3O 443.21 444
1533 C24H25CIFN3O3 457,16 4581533 C24H25CIFN3O3 457.16 458
1534 C24H30FN3O2 411 ,23 4121534 C24H30FN3O2 411, 23 412
1535 C24H27N303 405,20 4061535 C24H27N303 405.20 406
Figure imgf000321_0001
Figure imgf000321_0001
1536 •^ C23H22N402 386,17 3871536 • ^ C23H22N402 386.17 387
ÜKGAT APD62429PCÜKGAT APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1537 C24H25N303 403,19 4041537 C24H25N303 403.19 404
1538 C24H27N304 421 ,20 4221538 C24H27N304 421, 20 422
1539 C24H25N303 403,19 4041539 C24H25N303 403.19 404
1540 C24H25FN404 452,19 4531540 C24H25FN404 452.19 453
1541 C23H30FN3O2 399,23 4001541 C23H30FN3O2 399.23 400
1542 C25H26FN30 403,21 4041542 C25H26FN30 403.21 404
1543 C26H28FN302 433,22 4341543 C26H28FN302 433.22 434
1544 C28H29FN402 472,23 4731544 C28H29FN402 472.23 473
1545 C26H28FN30 417,22 4181545 C26H28FN30 417.22 418
1546 C24H32FN302 413,25 414
Figure imgf000322_0001
APD62429PC1546 C24H32FN302 413.25 414
Figure imgf000322_0001
APD62429PC
Figure imgf000323_0001
APD62429PC
Figure imgf000323_0001
APD62429PC
Figure imgf000324_0001
APD62429PC
Figure imgf000324_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H4 No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H 4 no. Mw.
1567 C22H21F2N302 397,16 3981567 C22H21F2N302 397.16 398
£ fAθ*$£ fAθ * $
1568 C23H22F3N303 445,16 4461568 C23H22F3N303 445.16 446
Figure imgf000325_0001
Figure imgf000325_0001
1569 C23H24FN302 393,18 3941569 C23H24FN302 393.18 394
Fx^ lFx ^ l
€AO*®€ AO * ®
1570 C20H21 N5O2 363,17 3641570 C20H21 N5O2 363.17 364
1571 C21 H21 FN402 380,17 3811571 C21 H21 FN402 380.17 381
1572 C23H30FN3O2 399,23 4001572 C23H30FN3O2 399.23 400
1573 C22H22N403S 422,14 4231573 C22H22N403S 422.14 423
1574 C23H25N302S 407,17 4081574 C23H25N302S 407.17 408
Figure imgf000325_0002
Figure imgf000325_0002
1575 C23H25N302S 407,17 4081575 C23H25N302S 407.17 408
1576 C23H25N3OS2 423,14 4241576 C23H25N3OS2 423.14 424
Figure imgf000325_0003
APD62429PC
Figure imgf000325_0003
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1577 C24H27N302S 421 ,18 4221577 C24H27N302S 421, 18 422
1578 C24H27N302S 421 ,18 4221578 C24H27N302S 421, 18 422
1579 C23H22N40S 402,15 4031579 C23H22N40S 402.15 403
1580 C24H27N303S 437,18 4381580 C24H27N303S 437.18 438
1581 C24H25N302S 419,17 4201581 C24H25N302S 419.17 420
1582 C24H25N302S 419,17 4201582 C24H25N302S 419.17 420
1583 C23H23N303S 421 ,15 4221583 C23H23N303S 421, 15 422
1584 C23H25N30S2 423,14 4241584 C23H25N30S2 423.14 424
Figure imgf000326_0001
APD62429PC
Figure imgf000326_0001
APD62429PC
Figure imgf000327_0001
APD62429PC
Figure imgf000327_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1593 C23H22F3N302S 461 ,14 4621593 C23H22F3N302S 461, 14 462
1594 C24H26N402S 434,18 4351594 C24H26N402S 434.18 435
1595 C21 H24N402S 396,16 3971595 C21 H24N402S 396.16 397
1596 C21 H21 FN40S 396,14 3971596 C21 H21 FN40S 396.14 397
1597 C25H27N303S 449,18 4501597 C25H27N303S 449.18 450
1598 C28H33N30S 459,23 4601598 C28H33N30S 459.23 460
1599 C24H26N402S 434,18 4351599 C24H26N402S 434.18 435
1600 C25H28N402S 448,19 4491600 C25H28N402S 448.19 449
Figure imgf000328_0001
APD62429PC
Figure imgf000328_0001
APD62429PC
Bsp. Struktur Summenformel Monoisotop. M+H+ No. Molekulargew.Ex. Structure Molecular Formula Monoisotope. M + H + No. Mw.
1601 C25H28N402S 448,19 4491601 C25H28N402S 448.19 449
1602 C24H28N40S 420,20 4211602 C24H28N40S 420,20 421
1603 C24H26N402S 434,18 4351603 C24H26N402S 434.18 435
1604 C24H25N302S 419,17 4201604 C24H25N302S 419.17 420
1605 C20H21 N30S2 383,11 3841605 C20H21 N30S2 383.11 384
1606 C26H28FN302 433,22 4341606 C26H28FN302 433.22 434
1607 C26H27CIFN302 467,18 4681607 C26H27CIFN302 467.18 468
Figure imgf000329_0001
Figure imgf000329_0001
1608 C21 H21FN4OS 396,14 397 APD62429PC1608 C21 H21FN4OS 396.14 397 APD62429PC
Figure imgf000330_0001
Figure imgf000330_0001
Synthesen von als Zwischenstufen benötigten Pyrrolidinylanilinen APD62429PCSyntheses of required as intermediates Pyrrolidinylanilinen APD62429PC
[1-(4-Amino-2-chlor-phenyl)-pyrrolidin-3-yl]-dimethyl-amin Methode C-a[1- (4-Amino-2-chloro-phenyl) -pyrrolidin-3-yl] -dimethyl-amine Method C-a
Eine Lösung von 2-Chlor-1-fluor-4-nitro-benzol (0,52 g) in DMF (5 mL) wurde langsam mit 3-Dimethylamino-pyrrolidin (0,34 g) versetzt. Nach 1 Stunde wurde die Reaktionsmischung mit Ethylacetat (30 mL) versetzt und mit Salzsäure 10 % (2 x 20 mL) extrahiert. Die wassrige Phase wurde mit Ethylacetat (2 x 20 mL) gewaschen, mit Ammoniak 10 % auf pH >10 eingestellt und dann mit Ethylacetat extrahiert. Die gelbe Lösung wurde mit Natriumsulfat getrocknet, filtriert und am Rotationsverdampfer konzentriert. Der Rückstand wurde dann in Dichlormethan (50 mL) gelöst, Zink (10 g) hinzugegeben und langsam unter Eiskühlung Eisessig (5 mL) zugetropft. Die Suspension wurde 15 Minuten gerührt, filtriert, mit Ammoniak 10 % (2 x 20 mL) gewaschen und konzentriert. Man erhielt so das Produkt mit dem Molekulargewicht 239,75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240 (M+H+),A solution of 2-chloro-1-fluoro-4-nitro-benzene (0.52 g) in DMF (5 mL) was added slowly with 3-dimethylamino-pyrrolidine (0.34 g). After 1 hour, the reaction mixture was added with ethyl acetate (30 mL) and extracted with hydrochloric acid 10% (2 x 20 mL). The aqueous phase was washed with ethyl acetate (2 x 20 mL), adjusted to pH> 10 with ammonia 10% and then extracted with ethyl acetate. The yellow solution was dried with sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was then dissolved in dichloromethane (50 mL), zinc (10 g) added, and glacial acetic acid (5 mL) added slowly dropwise with ice cooling. The suspension was stirred for 15 minutes, filtered, washed with ammonia 10% (2 x 20 mL) and concentrated. This gave the product with the molecular weight 239.75 (C12H18CIN3); MS (ESI): 239 (M + H +), 240 (M + H +),
5-Amino-2-(3-dimethylamino-pyrrolidin-1-yl)-benzonitril5-amino-2- (3-dimethylamino-pyrrolidin-1-yl) -benzonitrile
Nach Methode C-a wurde Dimethylamino-pyrrolidin mit 2-Fluor-5-nitro-benzonitril behandelt und anschließend reduziert. Man erhielt so das Produkt mit dem Molekulargewicht 230,32 (C13H18N4); MS (ESI): 231 (M+H+),According to method C-a dimethylamino-pyrrolidine was treated with 2-fluoro-5-nitro-benzonitrile and then reduced. This gave the product of molecular weight 230.32 (C13H18N4); MS (ESI): 231 (M + H +),
[1-(4-Amino-3-chlor-phenyl)-pyrrolidin-3-yl]-dimethylamin Nach Methode C-a wurde Dimethylamino-pyrrolidin mit 3-Chlor-1-fluor-4-nitro- benzen behandelt und anschließend reduziert. Man erhielt so das Produkt mit dem Molekulargewicht 239,75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240 (M+H+),[1- (4-Amino-3-chlorophenyl) -pyrrolidin-3-yl] -dimethylamine According to Method C-a, dimethylamino-pyrrolidine was treated with 3-chloro-1-fluoro-4-nitrobenzene and then reduced. This gave the product with the molecular weight 239.75 (C12H18CIN3); MS (ESI): 239 (M + H +), 240 (M + H +),
[1-(4-Amino-3-methyl-phenyl)-pyrrolidin-3-yl]-dimethylamin Nach Methode C-a wurde Dimethylamino-pyrrolidin mit 4-Fluor-2-methyl-1-nit.ro- benzen behandelt und anschließend reduziert. Man erhielt so das Produkt mit dem Molekulargewicht 219,33 (C13H21 N3); MS (ESI): 220 (M+H+). APD62429PC[1- (4-Amino-3-methyl-phenyl) -pyrrolidin-3-yl] -dimethylamine According to method Ca, dimethylamino-pyrrolidine was treated with 4-fluoro-2-methyl-1-nitro-trenzenene and then reduced , This gave the product with the molecular weight 219.33 (C13H21 N3); MS (ESI): 220 (M + H +). APD62429PC
(R)-[1-(4-Amino-2-fluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester Methode C-b(R) - [1- (4-Amino-2-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester Method C-b
Eine Suspension von 3,4-Difluor-nitrobenzen (1 ,59 g) und Kaliumcarbonat (2,8 g) in DMF (10 mL) wurde langsam mit (R)-(+)-Pyrrolidin-3-yl-carbaminsäure tert- butylester (1 ,86 g) versetzt. Nach 10 Minuten wurde Ethylacetat (50 mL) hinzugefügt, im Scheidetrichter mit Wasser (3 x 50 mL) gewaschen, mit Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde in DMF (10 mL) gelöst und mit Natriumhydrid (0,48 g) versetzt. Nach 15 Minuten wurde dann Methyljodid (1 ,41 g) unter Eiskühlung zugegeben. Nach 30 Minuten wurde mit Ethylacetat (50 mL) versetzt, im Scheidetrichter mit Wasser (3 x 50 mL) gewaschen, mit Natriumsulfat getrocknet, filtriert und eingeengt. Dann wurde die Substanz wie unter Methode B beschrieben behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 309,39 (C16H24FN302); MS (ESI): 310 (M+H+).A suspension of 3,4-difluoro-nitrobenzene (1.59 g) and potassium carbonate (2.8 g) in DMF (10 mL) was slowly added with (R) - (+) - pyrrolidin-3-yl-carbamic acid tert. butyl ester (1.86 g). After 10 minutes, ethyl acetate (50 mL) was added, washed with water (3 x 50 mL) in a separatory funnel, dried with sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (10 mL) and sodium hydride (0.48 g) added. After 15 minutes, methyl iodide (1.41 g) was added with ice-cooling. After 30 minutes, ethyl acetate (50 mL) was added, washed with water (3 x 50 mL) in a separatory funnel, dried with sodium sulfate, filtered and concentrated. Then the substance was treated as described under Method B. This gave the product of molecular weight 309.39 (C16H24FN302); MS (ESI): 310 (M + H +).
Analog wurde (S)-[1 -(4-Amino-2-fluor-phenyl)-pyrrolidin-3-yl]-methyl- carbaminsäure tert-butylester erhalten.Analogously, (S) - [1- (4-amino-2-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester was obtained.
(R)-[1 -(2-Fluor-4-isopropylamino-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert- butyl ester(R) - [1- (2-Fluoro-4-isopropylamino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
(R)-[1-(4-Amino-2-fluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester wurde nach Methode N unter Verwendung von Triacetoxyborhydrid als Reduktionmittel mit Aceton alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 351 ,47 (C19H30FN3O2); MS (ESI): 352 (M+H+).(R) - [1- (4-Amino-2-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester was alkylated by Method N using triacetoxyborohydride as the reducing agent with acetone. This gave the product with the molecular weight 351, 47 (C19H30FN3O2); MS (ESI): 352 (M + H +).
(R)-[1-(2-Fluor-4-cyclobutylamino-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester(R) - [1- (2-Fluoro-4-cyclobutylamino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
(R)-[1-(4-Amino-2-fluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester wurde nach Methode N unter Verwendung von Triacetoxyborhydrid als Reduktionmittel mit Cyclobutanon alkyliert. Man erhielt so das Produkt mit dem Molekulargewicht 363,48 (C20H30FN3O2); MS (ESI): 364 (M+H+). APD62429PC(R) - [1- (4-Amino-2-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester was alkylated by Method N using triacetoxyborohydride as reducing agent with cyclobutanone. This gave the product with a molecular weight of 363.48 (C20H30FN3O2); MS (ESI): 364 (M + H +). APD62429PC
(R)-[1-(2-Fluor-4-methylamino-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester(R) - [1- (2-Fluoro-4-methylamino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
(R)-{1 -[4-(Benzyloxycarbonyl-methyl-amino)-2-fluor-phenyl]-pyrrolidin-3-yl}-methyl- carbamic acid tert-butylester wurde wie unter Methode B beschrieben behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 323,41 (C17H26FN302); MS (ESI): 324 (M+H+).(R) - {1- [4- (Benzyloxycarbonyl-methyl-amino) -2-fluoro-phenyl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester was treated as described under Method B. This gave the product with the molecular weight 323.41 (C17H26FN302); MS (ESI): 324 (M + H +).
(R)-{1-[4-(Benzyloxycarbonyl-methyl-amino)-2-fluor-phenyl]-pyrrolidin-3-yl}-methyl- carbamic acid tert-butylester Eine Lösung von N-(Benzyloxycarbonyloxy)-succinimid (2,49 g) in Dichlormethan (30 mL) wurde mit (R)-(+)-[1-(4-Amino-2-fluor-phenyl)-pyrrolidin-3-yl]-methyl- carbaminsäure tert-butylester (0,93 g) versetzt. Nach 12 Stunden wurde mit Wasser gewaschen (2 x 30 mL), Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde aus Acetonitril umkristallisiert. Das so erhaltene Produkt wurde in DMF (10 mL) gelöst und mit Natriumhydrid (0,24 g) versetzt. Nach 15 Minuten wurde unter Eiskühlung mit Methyljodid (0,71 g) versetzt. Es wurde nach 15 Minuten Ethylacetat (50 mL) hinzugegeben, mit Wasser gewaschen (3 x 30 mL), Natriumsulfat getrocknet, filtriert und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 457,55 (C25H32FN304); MS (ESI): 458 (M+H+).(R) - {1- [4- (Benzyloxycarbonyl-methyl-amino) -2-fluoro-phenyl] -pyrrolidin-3-yl} -methyl-carbamic acid tert -butyl ester A solution of N- (benzyloxycarbonyloxy) -succinimide ( 2.49 g) in dichloromethane (30 ml) was treated with (R) - (+) - [1- (4-amino-2-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester ( 0.93 g). After 12 hours, it was washed with water (2 × 30 ml), dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile. The resulting product was dissolved in DMF (10 mL) and sodium hydride (0.24 g) added. After 15 minutes, methyl iodide (0.71 g) was added under ice-cooling. It was added after 15 minutes ethyl acetate (50 mL), washed with water (3 x 30 mL), dried over sodium sulfate, filtered and concentrated. This gave the product of molecular weight 457.55 (C25H32FN304); MS (ESI): 458 (M + H +).
(R)-[1-(2-Fluor-4-methylamino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin (R)-{1-[4-(Benzyloxycarbonyl-methyl-amino)-2-fluor-phenyl]-pyrrolidin-3-yl}-methyl- carbamic acid tert-butylester wurde nach Methode G behandelt und das erhaltene Amin nach Methode M methyliert. Abschliessend wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 237,32 (C13H20FN3); MS (ESI): 238 (M+H+).(R) - [1- (2-Fluoro-4-methylamino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine (R) - {1- [4- (benzyloxycarbonyl-methyl-amino) -2-fluoro -phenyl] -pyrrolidin-3-yl} -methyl- carbamic acid tert-butyl ester was treated by Method G and methylated the resulting amine by Method M. Finally, it was hydrogenated by Method B. This gave the product with the molecular weight 237.32 (C13H20FN3); MS (ESI): 238 (M + H +).
Analog kann Dimethyl-[1-(4-methylamino-phenyl)-pyrrolidin-3-yl]-amin hergestellt werden.Analogously, dimethyl [1- (4-methylamino-phenyl) -pyrrolidin-3-yl] -amine can be prepared.
2-Dimethylamino-N-[1-(2-fluor-4-methylamino-phenyl)-pyrrolidin-3-yl]-N-methyl- acetamid APD62429PC2-Dimethylamino-N- [1- (2-fluoro-4-methylamino-phenyl) -pyrrolidin-3-yl] -N-methyl-acetamide APD62429PC
(R)-{1-[4-(Benzyloxycarbonyl-methyl-amino)-2-fluor-phenyl]-pyrrolidin-3-yl}- methyl-carbamic acid tert-butylester wurde nach Methode G behandelt und das erhaltene Amin nach Methode E mit N,N-Dimethylglycin umgesetzt. Abschliessend wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 308,40 (C16H25FN40); MS (ESI): 309 (M+H+).(R) - {1- [4- (Benzyloxycarbonyl-methyl-amino) -2-fluoro-phenyl] -pyrrolidin-3-yl} -methyl-carbamic acid tert-butyl ester was treated by Method G and the amine obtained by Method E reacted with N, N-dimethylglycine. Finally, it was hydrogenated by Method B. This gave the product with the molecular weight 308.40 (C16H25FN40); MS (ESI): 309 (M + H +).
(R)-[1 -(4-Amino-3-fluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester(R) - [1- (4-Amino-3-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-b wurde 2,4-Difluor-nitrobenzen mit (R)-(+)-Pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt, methyliert und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 309,39 (C16H24FN302); MS (ESI): 310 (M+H+).According to method C-b, 2,4-difluoro-nitrobenzene was treated with (R) - (+) - pyrrolidin-3-yl-carbamic acid tert-butyl ester, methylated and then hydrogenated. This gave the product of molecular weight 309.39 (C16H24FN302); MS (ESI): 310 (M + H +).
[1 -(4-Amino-naphthalen-1 -yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Methode C-c[1- (4-Amino-naphthalen-1-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester Method C-c
Eine Suspension von 4-Fluor-1-nitro-naphtalen (1 ,91 g) und Kaliumcarbonat (2,8 g) in DMF (10 mL) wurde langsam mit Methyl-pyrrolidin-3-yl-carbaminsäure tert- butylester (1 ,86 g) versetzt. Nach 10 Minuten wurde Ethylacetat (50 mL) hinzugefügt, im Scheidetrichter mit Wasser (3 x 50 mL) gewaschen, mit Natriumsulfat getrocknet, filtriert und eingeengt. Dann wurde die Substanz wie unter Methode B beschrieben behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 341 ,46 (C20H27N3O2); MS (ESI): 342 (M+H+).A suspension of 4-fluoro-1-nitro-naphthalene (1.91 g) and potassium carbonate (2.8 g) in DMF (10 mL) was slowly treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1, 86 g). After 10 minutes, ethyl acetate (50 mL) was added, washed with water (3 x 50 mL) in a separatory funnel, dried with sodium sulfate, filtered and concentrated. Then the substance was treated as described under Method B. This gave the product with the molecular weight 341, 46 (C20H27N3O2); MS (ESI): 342 (M + H +).
[1-(4-Amino-3-brom-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-a wurde 2-Brom-4-fluor-1 -nitro-benzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend reduziert. Man erhielt so das Produkt mit dem Molekulargewicht 370,29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+).[1- (4-Amino-3-bromo-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to method Ca, 2-bromo-4-fluoro-1-nitrobenzene was treated with methylpyrrolidine. 3-yl-carbamic acid treated tert-butyl ester and then reduced. This gave the product with the molecular weight 370.29 (C16H24BrN302); MS (ESI): 370 (M + H +), 372 (M + H +).
[1 -(4-Amino-3-cyano-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-a wurde 2-Cyano-4-f luor-1 -nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend reduziert. Man erhielt APD62429PC[1- (4-Amino-3-cyano-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to method Ca, 2-cyano-4-fluoro-1-nitrobenzene with methylpyrrolidine-3 -yl-carbamic acid treated tert-butyl ester and then reduced. One received APD62429PC
so das Produkt mit dem Molekulargewicht 316,41 (C17H24N402); MS (ESI): 317 (M+H+).so the product with the molecular weight 316.41 (C17H24N402); MS (ESI): 317 (M + H +).
[1-(5-Amino-6-chlor-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (5-Amino-6-chloro-pyridin-2-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2-Chlor-6-fluor-3-nitro-pyridin mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 326,83 (C15H23CIN402); MS (ESI): 326 (M+H+), 327 (M+H+).According to method C-c, 2-chloro-6-fluoro-3-nitro-pyridine was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 326.83 (C15H23CIN402); MS (ESI): 326 (M + H +), 327 (M + H +).
[1-(4-Amino-2,3-difluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-2,3-difluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2,3,4-Trifluor-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 327,38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).By method C-c, 2,3,4-trifluoro-nitrobenzene was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 327.38 (C16H23F2N3O2); MS (ESI): 328 (M + H +).
[1 -(4-Amino-2-brom-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-a wurde 3-Brom-4-fluor-1 -nitro-benzen mit Methyl-pyrrolidin-3-yl- carbaminsaure tert-butylester behandelt und anschließend reduziert. Man erhielt so das Produkt mit dem Molekulargewicht 370,29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+).[1- (4-Amino-2-bromo-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to method Ca, 3-bromo-4-fluoro-1-nitrobenzene was treated with methylpyrrolidine. Treated 3-yl-carbamic acid tert-butyl ester and then reduced. This gave the product with the molecular weight 370.29 (C16H24BrN302); MS (ESI): 370 (M + H +), 372 (M + H +).
[1 -(4-Amino-2,6-difluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-2,6-difluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 3,4,5-Trifluor-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 327,38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).According to method C-c, 3,4,5-trifluoro-nitrobenzene was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 327.38 (C16H23F2N3O2); MS (ESI): 328 (M + H +).
(R)-[1-(4-Amino-2-hydroxymethyl-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert- butylester APD62429PC(R) - [1- (4-amino-2-hydroxymethyl-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester APD62429PC
Nach Methode C-c wurde (2-Fluor-5-nitro-phenyl)-methanol mit (R)-(+)-Pyrrolidin- 3-yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 307,40 (C16H25N3O3); MS (ESI): 308 (M+H+).According to method C-c, (2-fluoro-5-nitro-phenyl) -methanol was treated with (R) - (+) - pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 307.40 (C16H25N3O3); MS (ESI): 308 (M + H +).
[1-(4-Amino-2-chlor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-c wurde 2-Chlor-1 -fluor-4-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 311 ,81 (C15H22CIN3O2); MS (ESI): 311 (M+H+), 312 (M+H+).[1- (4-Amino-2-chloro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to Method Cc, 2-chloro-1-fluoro-4-nitrobenzene was treated with methylpyrrolidine-3- yl-carbamic acid treated tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 311, 81 (C15H22CIN3O2); MS (ESI): 311 (M + H +), 312 (M + H +).
[1-(4-Amino-2,5-difluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-2,5-difluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 3,4,6-Trifluor-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsaure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 327,38 (C16H23F2N302); MS (ESI): 328 (M+H+).According to method C-c, 3,4,6-trifluoro-nitrobenzene was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 327.38 (C16H23F2N302); MS (ESI): 328 (M + H +).
[1 -(4-Amino-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-c wurde 4-Fluor-3-methyl-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 291 ,40 (C16H25N302); MS (ESI): 292 (M+H+).[1- (4-Amino-2-methyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to Method Cc, 4-fluoro-3-methyl-nitrobenzene with methyl-pyrrolidin-3-yl treated carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 291, 40 (C16H25N302); MS (ESI): 292 (M + H +).
[1 -(4-Amino-3-trifluorrmethyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-3-trifluoromethyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 4-Fluor-2-trifluormethyl-nitrobenzen mit Methyl- pyrrolidin-3-yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 345,37 (C16H22F3N302); MS (ESI): 346 (M+H+). APD62429PCAccording to method Cc, 4-fluoro-2-trifluoromethyl-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and then hydrogenated. This gave the product of molecular weight 345.37 (C16H22F3N302); MS (ESI): 346 (M + H +). APD62429PC
[1-(4-Amino-2-chlor-3-fluor-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-2-chloro-3-fluoro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2,4-Difluor-3-chlor-nitrobenzen mit Methyl-pyrrolidin-3- yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 329,80 (C15H21CIN302); MS (ESI): 329 (M+H+), 330 (M+H+).According to method C-c, 2,4-difluoro-3-chloro-nitrobenzene was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 329.80 (C15H21CIN302); MS (ESI): 329 (M + H +), 330 (M + H +).
[1-(4-Amino-2-cyano-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-c wurde 3-Cyano-4-fluor-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsaure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 302,38 (C16H22N402); MS (ESI): 303 (M+H+).Methyl tert-butyl [1- (4-amino-2-cyano-phenyl) -pyrrolidin-3-yl] -methyl-carbamate treated carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 302.38 (C16H22N402); MS (ESI): 303 (M + H +).
[1-(4-Amino-5-chlor-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-5-chloro-2-methyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 1-Chlor-5-fluor-4-methyl-2-nitro-benzen mit Methyl- pyrrolidin-3-yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 325,84 (C16H24CIN3O2); MS (ESI): 325 (M+H+), 326 (M+H+).According to method C-c, 1-chloro-5-fluoro-4-methyl-2-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and then hydrogenated. This gave the product of molecular weight 325.84 (C16H24CIN3O2); MS (ESI): 325 (M + H +), 326 (M + H +).
(R)-[1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-b wurde 2-Chlor-5-nitro-pyridin mit (R)-(+)-Pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 322,37 (C16H24FN3O2); MS (ESI): 323 (M+H+).(R) - [1- (5-Amino-pyridin-2-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to method Cb, 2-chloro-5-nitro-pyridine with (R) - (+) - treated pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 322.37 (C16H24FN3O2); MS (ESI): 323 (M + H +).
[1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-c wurde 2-Chlor-5-nitro-pyridin mit Methyl-pyrrolidin-3-yi- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 322,37 (C16H24FN3O2); MS (ESI): 323 (M+H+). APD62429PC[1- (5-Amino-pyridin-2-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to Method Cc, 2-chloro-5-nitropyridine was reacted with methylpyrrolidin-3-yl treated carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 322.37 (C16H24FN3O2); MS (ESI): 323 (M + H +). APD62429PC
(R)-[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-b wurde 4-Fluor-nitrobenzen mit (R)-(+)-Pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 291 ,40 (C16H25N302); MS (ESI): 292 (M+H+).(R) - [1- (4-Amino-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to method Cb, 4-fluoro-nitrobenzene was treated with (R) - (+) - pyrrolidine-3 yl-carbamic acid treated tert-butyl ester and then hydrogenated. This gave the product of molecular weight 291, 40 (C16H25N302); MS (ESI): 292 (M + H +).
[1-(4-Amino-2-trifluorrmethyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-2-trifluoromethyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 4-Fluor-3-trifluormethyl-nitrobenzen mit Methyl- pyrrolidin-3-yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 345,37 (C16H22F3N302); MS (ESI): 346 (M+H+).According to method C-c, 4-fluoro-3-trifluoromethyl-nitrobenzene was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 345.37 (C16H22F3N302); MS (ESI): 346 (M + H +).
[1-(5-Amino-4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (5-Amino-4-methyl-pyridin-2-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2-Chlor-4-methyl-5-nitro-pyridin mit Methyl-pyrrolidin-3- yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 306,419 (C16H26N402); MS (ESI): 306 (M+H+), 307 (M+H+).According to method C-c, 2-chloro-4-methyl-5-nitro-pyridine was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 306.419 (C16H26N402); MS (ESI): 306 (M + H +), 307 (M + H +).
[1 -(5-Amino-3-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (5-Amino-3-methylpyridin-2-yl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2-Chlor-3-methyl-5-nitro-pyridin mit Methyl-pyrrolidin-3- yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 306,419 (C16H26N402); MS (ESI): 306 (M+H+), 307 (M+H+).According to method C-c, 2-chloro-3-methyl-5-nitro-pyridine was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 306.419 (C16H26N402); MS (ESI): 306 (M + H +), 307 (M + H +).
[1-(4-Amino-2-hydroxymethyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester Nach Methode C-c wurde (2-Fluor-5-nitro-phenyl)-methanol mit Methyl-pyrrolidin- 3-yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man APD62429PC[1- (4-Amino-2-hydroxymethyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to Method Cc, (2-fluoro-5-nitrophenyl) -methanol was treated with methylpyrrolidine. 3-yl-carbamic acid tert-butyl ester and then hydrogenated. you APD62429PC
erhielt so das Produkt mit dem Molekulargewicht 321 ,42 (C17H27N3O3); MS (ESI): 322 (M+H+).thus obtained the product with the molecular weight 321, 42 (C17H27N3O3); MS (ESI): 322 (M + H +).
[1-(4-Amino-3-chlor-2-cyano-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert- butylester[1- (4-Amino-3-chloro-2-cyano-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester
Nach Methode C-c wurde 2-Chlor-6-fluor-3-nitro-benzonitril mit Methyl-pyrrolidin-3- yl-carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 350,85 (C17H23CIN402); MS (ESI): 350 (M+H+), 351 (M+H+).According to method C-c, 2-chloro-6-fluoro-3-nitro-benzonitrile was treated with methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product with a molecular weight of 350.85 (C17H23CIN402); MS (ESI): 350 (M + H +), 351 (M + H +).
[1-(4-Amino-3-methyl-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester Nach Methode C-c wurde 4-Fluor-2-methyl-nitrobenzen mit Methyl-pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 291,40 (C16H25N302); MS (ESI): 292 (M+H+).[1- (4-Amino-3-methyl-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester According to Method Cc, 4-fluoro-2-methyl-nitrobenzene with methylpyrrolidin-3-yl treated carbamic acid tert-butyl ester and then hydrogenated. This gave the product with the molecular weight 291.40 (C16H25N302); MS (ESI): 292 (M + H +).
[1 - (5-Ami no-pyridi n-2-y I) -pyrrol idi n-3-y I] -carbami nsäure tert-butylester Nach Methode C-c wurde 2-Chlor-5-nitro-pyridin mit (R)-(+)-Pyrrolidin-3-yl- carbaminsäure tert-butylester behandelt und anschließend hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 278,36 (C14H22N402); MS (ESI): 279 (M+H+).[1- (5-Amino-pyridine-n-2-yl) -pyrrole-idi-n-3-yl] -carbamic acid tert-butyl ester According to Method Cc, 2-chloro-5-nitro-pyridine was labeled with (R) - (+) - treated pyrrolidin-3-yl-carbamic acid tert-butyl ester and then hydrogenated. This gave the product of molecular weight 278.36 (C14H22N402); MS (ESI): 279 (M + H +).
5-(3-Dimethylamino-pyrrolidin-1-yl)-pyridin-2-ylamin5- (3-dimethylamino-pyrrolidin-1-yl) -pyridin-2-ylamine
Eine Suspension aus 5-Brom-2-nitropyridin (2 g), 3-(Dimethylamino)-pyrrolidin (1 ,14 g), (R)-(+)2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (0,5 g),A suspension of 5-bromo-2-nitropyridine (2 g), 3- (dimethylamino) -pyrrolidine (1, 14 g), (R) - (+) 2,2'-bis (diphenylphosphino) -1, 1 ' -binaphthyl (0.5 g),
Palladium(ll)acetat (0,09 g), Cäsiumcarbonat (4,5 g) in Toluen (20 mL) wurden 3 Stunden auf 1009C erwärmt. Nach dem Abkühlen auf Raumtemperatur wurde mit Salzsäure 1 N (2 x 100 mL) extrahiert. Die wäßrige Phase wurde mit Ammoniak auf pH > 10 eingestellt, mit Ethylacetat (2 x 100 mL) extrahiert, mit Natriumsulfat getrocknet, filtriert und eingeengt. Dann wurde die Substanz wie unter Methode B beschrieben behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 206,29 (C11H18FN4); MS (ESI): 207 (M+H+). APD62429PCPalladium (II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 mL) was added 3 hours at 100 9 C heated. After cooling to room temperature, 1N (2 x 100 mL) was extracted with hydrochloric acid. The aqueous phase was adjusted to pH> 10 with ammonia, extracted with ethyl acetate (2 × 100 ml), dried with sodium sulfate, filtered and concentrated. Then the substance was treated as described under Method B. This gave the product of molecular weight 206.29 (C11H18FN4); MS (ESI): 207 (M + H +). APD62429PC
N-[1-(4-Amino-phenyl)-4-hydroxy-pyrrolidin-3-yl]-N-methyl-acetamid Trans-N-(4-Hydroxy-pyrrolidin-3-yl)-N-methyl-acetamid wurde nach Methode C mit 4-Fluornitrobenzol umgesetzt und das Produkt anschließend nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 249,32 (C13H19N3O2); MS (ESI): 250 (M+H+).N- [1- (4-Amino-phenyl) -4-hydroxy-pyrrolidin-3-yl] -N-methyl-acetamide Trans-N- (4-hydroxy-pyrrolidin-3-yl) -N-methyl-acetamide was reacted with 4-fluoronitrobenzene according to method C and the product was subsequently hydrogenated by method B. This gave the product with the molecular weight 249.32 (C13H19N3O2); MS (ESI): 250 (M + H +).
Trans-N-(4-Hydroxy-pyrrolidin-3-yl)-N-methyl-acetamid Trans-3-Hydroxy-4-methylamino-pyrrolidin-1 -carbonsäure tert-butylester (1.0 g, Tetrahedron: Asymmetry 2001 , 12, 2989) wurde mit Pyridin (1 ,5 g) undTrans-N- (4-Hydroxy-pyrrolidin-3-yl) -N-methyl-acetamide tert -butyl trans-3-hydroxy-4-methylamino-pyrrolidine-1-carboxylate (1.0 g, Tetrahedron: Asymmetry 2001, 12, 2989) was treated with pyridine (1, 5 g) and
Acetanhydrid (0.567 g) versetzt. Nach 3 Stunden wurden flüchtige Anteile im Hochvakuum entfernt. Der Rückstand wurde nach Methode G behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 158,20 (C7H14N202); MS (ESI): 159 (M+H+).Acetic anhydride (0.567 g). After 3 hours, volatiles were removed under high vacuum. The residue was treated by Method G. This gave the product with the molecular weight 158.20 (C7H14N202); MS (ESI): 159 (M + H +).
Trans-1-(4-Amino-phenyl)-4-dimethylamino-pyrrolidin-3-ol 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carbonsäure tert-butylester (2.0 g, Tetrahedron: Asymmetry 2001, 12, 2989) wurde 12 Stunden mit Dimethylamin (40% aq., 10 mL) gerührt. Die Mischung wurde eingeengt und zwischen Wasser und Ethylacetat verteilt. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde nach Methode G behandelt. Das erhaltene Amin wurde nach Methode C mit 4-Fluornitrobenzol umgesetzt. Die erhaltene Nitroverbindung wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 221 (C12H19N30); MS (ESI): 222 (M+H+).Trans-1- (4-Amino-phenyl) -4-dimethylamino-pyrrolidin-3-ol 6-oxa-3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (2.0 g, Tetrahedron: Asymmetry 2001, 12, 2989) was stirred for 12 hours with dimethylamine (40% aq., 10 mL). The mixture was concentrated and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was treated by Method G. The resulting amine was reacted by method C with 4-fluoronitrobenzene. The resulting nitro compound was hydrogenated by Method B. This gave the product of molecular weight 221 (C12H19N30); MS (ESI): 222 (M + H +).
[1-(4-Amino-phenyl)-4-methoxy-pyrrolidin-3-yl]-dimethyl-amin Alternativ kann die in der vorhergehenden Vorschrift hergestellte Nitroverbindung nach Methode F mit Methyliodid alkyliert und dann nach Mehode B hydriert werden. Man erhielt so das Produkt mit dem Molekulargewicht 235 (C13H21 N30); MS (ESI): 236 (M+H+).[1- (4-Amino-phenyl) -4-methoxy-pyrrolidin-3-yl] -dimethyl-amine Alternatively, the nitro compound prepared in the previous procedure can be alkylated by Method F with methyl iodide and then hydrogenated to Mehode B. This gave the product of molecular weight 235 (C13H21 N30); MS (ESI): 236 (M + H +).
[1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin APD62429PC[1- (4-Amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine APD62429PC
Dimethyl-pyrrolidin-3-yl-amin wurde nach Methode C mit 4-Fluornitrobenzol umgesetzt und das Produkt anschließend nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 205,31 (C12H19N3); MS (ESI): 206 (M+H+).Dimethyl-pyrrolidin-3-yl-amine was reacted with 4-fluoronitrobenzene according to method C and the product was then hydrogenated by method B. This gave the product of molecular weight 205.31 (C12H19N3); MS (ESI): 206 (M + H +).
1 -(4-Amino-phenyl)-3-dimethylamino-pyrrolidin-2-on Eine Lösung von 4-Nitroanilin (5.0 g) in Acetonitril (30 mL) wurde mit Trinatriumphosphat (3.56 g) versetzt und bei 0°C 2-Brom-4-chlorbutyrylbromid (11 g) zugesetzt. Nach einer Stunde wurde eine Lösung von Natriumhydroxid (3.2 g) in Wasser (10 mL) zugesetzt und die Mischung bei Raumtemperatur heftig gerührt. Nach 6 Stunden wurde nochmal die gleiche Menge Natronlauge zugesetzt und über Nacht stehen gelassen. Die Reaktionslösung wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt (0.5 g) wurde mit Dimethylamin (160 mg) für 3 Stunden in Toluol (20 mL) auf 80°C erwärmt. Die Reaktionslösung wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 219,29 (C12H17N30); MS (ESI): 220 (M+H+). Auf analoge Weise wurde 1 -(4-Amino-phenyl)-3-(7-aza-bicyclo[2.2.1]hept-7-yl)- pyrrolidin-2-on erhalten.1- (4-Amino-phenyl) -3-dimethylamino-pyrrolidin-2-one To a solution of 4-nitroaniline (5.0 g) in acetonitrile (30 mL) was added trisodium phosphate (3.56 g) and stirred at 0 ° C. Bromo-4-chlorobutyryl bromide (11 g) was added. After one hour, a solution of sodium hydroxide (3.2 g) in water (10 mL) was added and the mixture stirred vigorously at room temperature. After 6 hours, the same amount of sodium hydroxide solution was again added and allowed to stand overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product (0.5 g) was heated to 80 ° C. with dimethylamine (160 mg) in toluene (20 mL) for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was hydrogenated by Method B. This gave the product with the molecular weight 219.29 (C12H17N30); MS (ESI): 220 (M + H +). In an analogous manner, 1- (4-amino-phenyl) -3- (7-aza-bicyclo [2.2.1] hept-7-yl) -pyrrolidin-2-one was obtained.
4-[3-(7-Aza-bicyclo[2.2.1]hept-7-yl)-pyrrolidin-1-yl]-phenylamin 1-(4-Nitro-phenyl)-3-(7-aza-bicyclo[2.2.1]hept-7-yl)-pyrrolidin-2-on (0.25 g) in THF (10 mL) wurde mit Boran-THF-Komplex (1 M in THF, 0,83 mL) versetzt und 3 Stunden am Ruckfluss gekocht. Nach beendeter Reaktion wurde mit Wasser verdünnt und mit Salzsäure (4 N) auf pH 9-10 gestellt. Extraktion in Ethylacetat, Trocknen und Einengen der organischen Phase ergab ein Rohprodukt, dass nach Methode B hydriert wurde. Man erhielt so das Produkt mit dem Molekulargewicht 257,38 (C16H23N3); MS (ESI): 258 (M+H+).4- [3- (7-Azabicyclo [2.2.1] hept-7-yl) -pyrrolidin-1-yl] -phenylamine 1- (4-nitro-phenyl) -3- (7-aza-bicyclo) 2.2.1] hept-7-yl) -pyrrolidin-2-one (0.25 g) in THF (10 mL) was treated with borane-THF complex (1 M in THF, 0.83 mL) and refluxed for 3 hours cooked. After completion of the reaction was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4 N). Extraction in ethyl acetate, drying and concentration of the organic phase gave a crude product which was hydrogenated by Method B. This gave the product with the molecular weight 257.38 (C16H23N3); MS (ESI): 258 (M + H +).
(R)-1 '-(4-Amino-phenyl)-[1 ,3']bipyrrolidinyl-2-on APD62429PC(R) -1 '- (4-Amino-phenyl) - [1, 3'] bipyrrolidinyl-2-one APD62429PC
[1-(4-Nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure tert-butylester wurde nach Methode G behandelt. Das Rohprodukt (1 ,4 g) gelöst in Acetonitril (20 mL) wurde mit Trinatriumphosphat (0.67 g) und 4-Chlorbuttersäurechlorid (1.1 g) versetzt. Nach 2 Stunden wurde Natriumhydroxid (0.6 g) in Wasser (10 mL) zugesetzt und die Mischung heftig gerührt. Nach 12 Stunden wurde nochmal die gleiche Menge Natronlauge zugesetzt und weitere 24 Stunden gerührt. Die eingeengte Reaktionslösung wurde zwischen Wasser und Ethylacetat verteilt und die organische Phase getrocknet und eingeengt. Der Rückstand wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 245,33 (C14H19N30); MS (ESI): 246 (M+H+).[1- (4-Nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester was treated according to Method G. The crude product (1.4 g) dissolved in acetonitrile (20 mL) was treated with trisodium phosphate (0.67 g) and 4-chlorobutyric acid chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 mL) was added and the mixture stirred vigorously. After 12 hours, the same amount of sodium hydroxide solution was added again and stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and ethyl acetate and the organic phase was dried and concentrated. The residue was hydrogenated by Method B. This gave the product with a molecular weight of 245.33 (C14H19N30); MS (ESI): 246 (M + H +).
1 -Methyl-piperidin-3-carbonsäure [(R)-1 -(4-amino-phenyl)-pyrrolidin-3-yl]-methyl- amid1-Methyl-piperidine-3-carboxylic acid [(R) -1- (4-amino-phenyl) -pyrrolidin-3-yl] -methyl-amide
(R)-[1 -(4-Nitro-phenyl)-pyrrolidin-3-yl]-methyl-carbaminsäure tert-butylester wurde nach Methode G behandet und nach Methode E mit 1-Methyl-piperidin-3- carbonsäure umgesetzt. Abschliessend wurde noch nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 316,45 (C18H28N4O); MS (ESI):(R) - [1- (4-nitro-phenyl) -pyrrolidin-3-yl] -methyl-carbamic acid tert-butyl ester was treated according to method G and reacted according to method E with 1-methyl-piperidine-3-carboxylic acid. Finally, it was hydrogenated by Method B. This gave the product of molecular weight 316.45 (C18H28N4O); MS (ESI):
317 (M+H+).317 (M + H +).
Auf analoge Weise wurde unter Verwendung von N,N-Diemthylglycin (R)-N-[1-(4- Amino-phenyl)-pyrrolidin-3-yl]-2-dimethylamino-N-methyl-acetamid erhalten.In an analogous manner, using N, N-dimethylglycine (R) -N- [1- (4-amino-phenyl) -pyrrolidin-3-yl] -2-dimethylamino-N-methyl-acetamide was obtained.
N-[(R)-1-(4-Amino-phenyl)-pyrrolidin-3-yl]-N-(2-diethylamino-ethyl)-acetamid Nach Methode B wurde N-(2-Diethylamino-ethyl)-N-[(R)-1-(4-nitro-phenyl)- pyrrolidin-3-yl]-acetamid hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 318,47 (C18H30N4O); MS (ESI): 319 (M+H+).N - [(R) -1- (4-Amino-phenyl) -pyrrolidin-3-yl] -N- (2-diethylamino-ethyl) -acetamide. By Method B, N- (2-diethylamino-ethyl) -N - [(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide hydrogenated. This gave the product with the molecular weight 318.47 (C18H30N4O); MS (ESI): 319 (M + H +).
N-(2-Diethylamino-ethyl)-N-[(R)-1-(4-nitro-phenyl)-pyrrolidin-3-yl]-acetamid Acetylchlorid ((2,9 g) wurde in 50 mL trockenem Dichlormethan gelöst, mit 5,3 mL Trieethylamin versetzt, N,N-Diethyl-N'-[(R)-1 -(4-nitro-phenyl)-pyrrolidin-3-yl]-ethan- 1 ,2-diamin (5,8 g) zugegeben und 30 Minuten bei Raumtemperatur gerührt.N- (2-Diethylamino-ethyl) -N - [(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -acetamide Acetyl chloride (2.9 g) was dissolved in 50 mL of dry dichloromethane , treated with 5.3 ml of triethylamine, N, N-diethyl-N '- [(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -ethane-1,2-diamine (5, 8 g) was added and stirred for 30 minutes at room temperature.
Anschließend (LCMS - Kontrolle) wurde die Reaktion mit Wasser (10 mL) versetzt und mit Dichlormethan (2 x 10 mL) extrahiert. Die vereinigten organischen Phasen APD62429PCSubsequently (LCMS control) the reaction was mixed with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic phases APD62429PC
wurden über Magnesiumsulfat getrocknet, das Lösungsmittel entfernt und das Rohprodukt über Kieselgel (Dichlormethan/Methanol 10:1) chromatografisch getrennt. Man erhielt so das Produkt mit dem Molekulargewicht 348,45 (C18H28N403); MS (ESI): 349 (M+H+).were dried over magnesium sulfate, the solvent was removed and the crude product was chromatographically separated over silica gel (dichloromethane / methanol 10: 1). This gave the product with the molecular weight 348.45 (C18H28N403); MS (ESI): 349 (M + H +).
N,N-Diethyl-N'-[(R)-1-(4-nitro-phenyl)-pyrrolidin-3-yl]-ethan-1 ,2-diamin (2-Diethylamino-ethyl)-[(R)-1-(4-nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure-tert- butylester (7,9 g) wurde nach Methode G mit Trifluoressigsaure umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 306,41 (C16H26N402); MS (ESI): 307 (M+H+).N, N-diethyl-N '- [(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -ethane-1,2-diamine (2-diethylamino-ethyl) - [(R) 1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (7.9 g) was reacted by method G with trifluoroacetic acid. This gave the product with the molecular weight 306.41 (C16H26N402); MS (ESI): 307 (M + H +).
(2-Diethylamino-ethyl)-[(R)-1-(4-nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure-tert- butylester(2-Diethylamino-ethyl) - [(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester
[(R)-1 -(4-Nitro-phenyl)-pyrrolidin-3-yl]-carbaminsäure-tert-butylester (6,0 g) wurde in 50 mL N,N-Dimethylformamid gelöst, mit Natriumhydrid (1 ,1 g) versetzt, 30 Minuten bei Raumtemperatur gerührt und anschließend mit Chlorethyl- diethylamin-Hydrochlorid (4,1 g) versetzt. Anschließend wurde 4 Stunden bei Raumtemperatur unter Feuchtigkeitsausschluß gerührt . Durch Zugabe von Wasser (50 mL) wurde die Reaktion abgebrochen, anschließend wurde mit Ethylacetat (3x50 mL) extrahiert und die vereinigten organischen Phasen über Magnesiumsulfat getrocknet und das Lösungsmittel entfernt. Man erhielt so das Produkt mit dem Molekulargewicht 406,53 (C21 H34N404); MS (ESI): 407 (M+H+).[(R) -1- (4-nitro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert -butyl ester (6.0 g) was dissolved in 50 mL N, N-dimethylformamide, washed with sodium hydride (1, 1 g), stirred for 30 minutes at room temperature and then treated with chloroethyl diethylamine hydrochloride (4.1 g). The mixture was then stirred for 4 hours at room temperature with exclusion of moisture. The reaction was quenched by addition of water (50 mL), then extracted with ethyl acetate (3x50 mL) and the combined organic phases dried over magnesium sulfate and the solvent removed. This gave the product of molecular weight 406.53 (C21 H34N404); MS (ESI): 407 (M + H +).
Piperidin-4-carbonsäure [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amid Nach Methode E wurde Piperidin-1 ,4-dicarbonsäure mono-tert-butylester mit [1 -(4- amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt und das Produkt dann nach Methode G behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 316,45 (C18H28N40); MS (ESI): 317 (M+H+).Piperidine-4-carboxylic acid [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -amide According to Method E, piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was treated with [1- (4-amino-phenyl ) -pyrrolidin-3-yl] -dimethyl-amine reacted and the product then by method G. This gave the product of molecular weight 316.45 (C18H28N40); MS (ESI): 317 (M + H +).
Synthese von als Zwischenstufen benötigten Aminen APD62429PCSynthesis of required as intermediates amines APD62429PC
Spiro[1 ,3-benzodioxol-2,1 '-cyclopentan]-5-aminSpiro [1,3-benzodioxole-2,1'-cyclopentane] -5-amine
Eine Lösung von Spiro[5-nitro-1 ,3-benzodioxol-2,1'-cyclopentan] (8,8 g) in Methanol (90 mL) wurde in Gegenwart von Palladium auf Kohle (10%ig, 0,1 g) bei 6 bar hydriert. Nach 30 Minuten bei Raumtemperatur wurde der Ansatz filtriert und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 191 ,23 (C11H13N02); MS(ESI): 192 (M+H+).A solution of spiro [5-nitro-1,3-benzodioxole-2,1'-cyclopentane] (8.8 g) in methanol (90 mL) was added in the presence of palladium on carbon (10%, 0.1 g ) hydrogenated at 6 bar. After 30 minutes at room temperature, the reaction was filtered and concentrated. This gave the product of molecular weight 191, 23 (C11H13NO 2); MS (ESI): 192 (M + H +).
Spiro[5-nitro-1 ,3-benzodioxol-2,1 '-cyclopentan]Spiro [5-nitro-1,3-benzodioxole-2,1'-cyclopentane]
Eine Lösung von Spiro[1 ,3-benzodioxol-2,1'-cyclopentan] (8,5 g) in 20 mL Dichlormethan wurde bei 10°C zu 65 %iger Salpetersäure (65 mL) getropft. NachA solution of spiro [1,3-benzodioxole-2,1'-cyclopentane] (8.5 g) in 20 mL dichloromethane was added dropwise at 10 ° C to 65% nitric acid (65 mL). After
2 Stunden bei 5-10 °C wurde der Ansatz mit Wasser verdünnt, die organische2 hours at 5-10 ° C, the approach was diluted with water, the organic
Pahse abgetrennt und die wäßrige Phase zweimal mit Dichlormethan extrahiert.Pahse separated and the aqueous phase extracted twice with dichloromethane.
Die vereinigten organischen Phasen wurden mit Wasser neutral gewaschen, überThe combined organic phases were washed neutral with water, over
Natriumsulfat getrocknet, eingeengt und aus Heptan kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 221 ,21 (C11 H11 NO4); MS(ESI): 222Dried sodium sulfate, concentrated and crystallized from heptane. This gave the product with the molecular weight 221, 21 (C11 H11 NO4); MS (ESI): 222
(M+H+).(M + H +).
Spiro[1 ,3-benzodioxol-2,1 '-cyclopentan]Spiro [1,3-benzodioxole-2,1'-cyclopentane]
Brenzcatechin (11g) und Cyclopentanon (9 mL) wurden in Toluol (150 mL) mit p- Toluolsulfonsäure (0,18 g) am Wasserabscheider zum Rückfluß erhitzt. Nach 18 Stunden wurde der Ansatz eingeengt und durch Chromatographie (Kieselgel, Heptan/Ethylacetat 4:1) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 176,22 (C11 H12O2); MS(ESI): 177 (M+H+).Catechol (11 g) and cyclopentanone (9 mL) were heated to reflux in toluene (150 mL) with p-toluenesulfonic acid (0.18 g) on a water condenser. After 18 hours, the reaction was concentrated and purified by chromatography (silica gel, heptane / ethyl acetate 4: 1). This gave the product with the molecular weight 176.22 (C11 H12O2); MS (ESI): 177 (M + H +).
5-Chlor-2,,3,,5',6,-tetrahydro-1 Η-[2,4']bipyridinyl-4'-ol5-Chloro-2 , 3 , 5, 5, 6 , -tetrahydro-1 Η- [2,4 '] bipyridinyl-4'-ol
Eine Lösung von 2-Brom-5-chlorpyridin (2,0 g) in Diethylether (50 mL) wurde bei - 78°C tropfenweise mit Butyllithium (15% in Hexan; 7,6 mL) versetzt und nach einer Stunde eine Lösung von N-tert.-Butoxycarbonyl-4-piperidinon (2,1 g) in Diethylether (10 mL) zugetropft. Nach 30 Minuten wurde vorsichtig Wasser zugesetzt und die Mischung mit Ethylacetat extrahiert. Die organische Phase wurde über Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde APD62429PCA solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 mL) was added dropwise at -78 ° C with butyllithium (15% in hexane, 7.6 mL) and after one hour a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 mL) was added dropwise. After 30 minutes, water was added cautiously and the mixture extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue became APD62429PC
nach Methode G behandelt. Man erhielt so das Produkt mit dem Molekulargewicht 212,68 (C10H13CIN2O); MS(ESI): 213 (M+H+). Analog wurden erhalten:treated according to method G. This gave the product with the molecular weight 212.68 (C10H13CIN2O); MS (ESI): 213 (M + H +). Analog were obtained:
S-Fluor-^.S'.δ'.δ'-tetrahydro-I Η-p^'jbipyridinyl-^-ol β-Chlor-^^'.δ'.e'-tetrahydro-l ,H-[3,4']bipyridinyl-4,-ol.S-fluoro - ^. S'.δ'.δ'-tetrahydro-1 Η-p ^ 'jbipyridinyl-α-ol β-chloro-^^'. Δ'.e'-tetrahydro-l , H- [3 , 4 '] bipyridinyl-4 , -ol.
6-Cyclopentyloxy-pyridin-3-ylamin6-cyclopentyloxy-pyridin-3-ylamine
Eine Mischung von 2-Hydroxy-5-nitropyridin (1 ,4 g), Cyclopentylbromid (1 ,5 g) undA mixture of 2-hydroxy-5-nitropyridine (1, 4 g), cyclopentyl bromide (1, 5 g) and
Kaliumcarbonat (3 g) wurde in DMF (20 mL) für 6 Stunden auf 80°C erhitzt. Die Mischung wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel (Laufmittel Ethylacetat / Heptan 1 :2) gereinigt. Die so erhaltene Nitroverbindung wurde nach Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 178,24 (C10H14N2O2); MS(ESI): 179 (M+H+).Potassium carbonate (3 g) was heated in DMF (20 mL) at 80 ° C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent ethyl acetate / heptane 1: 2). The resulting nitro compound was hydrogenated by Method B. This gave the product with the molecular weight 178.24 (C10H14N2O2); MS (ESI): 179 (M + H +).
6-(4-Fluor-phenyl)-3-aza-bicyclo[4.1.0]heptan6- (4-fluoro-phenyl) -3-aza-bicyclo [4.1.0] heptane
Diethylzink (1 M in Hexan, 19 mL) in Dichlormethan (100 mL) wurde mitDiethylzinc (1 M in hexane, 19 mL) in dichloromethane (100 mL) was washed with
Trifluoressigsaure (3 mL) bei 0°C versetzt. Nach 20 Minuten wurde Diiodmethan (3 mL) in Dichlormethan (10 mL) zugesetzt. Dann wurde 4-(4-Fluor-phenyl)-1 ,2,3,6- tetrahydro-pyridin (3.0 g) in Dichlormethan (10 mL) zugesetzt und die Mischung über Nacht bei Raumtemperatur gerührt. Nach Zusatz von Salzsäure (1 N) wurden die Phasen getrennt und die organische Phase mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 191 ,25 (C12H14FN); MS(ESI): 192 (M+H+).Trifluoroacetic acid (3 mL) was added at 0 ° C. After 20 minutes, diiodomethane (3 mL) in dichloromethane (10 mL) was added. Then, 4- (4-fluoro-phenyl) -1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 mL) was added and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1 N), the phases were separated and the organic phase washed with water, dried over magnesium sulfate and concentrated. This gave the product with the molecular weight 191, 25 (C12H14FN); MS (ESI): 192 (M + H +).
Synthese von als Zwischenstufen benötigten CarbonsäurenSynthesis of required as intermediates carboxylic acids
4-(4-Methylpiperidin-1 -yl)-benzoesäure4- (4-methylpiperidin-1-yl) benzoic acid
4-(4-Methylpiperidin1 -yl)-benzonitril (1 ,2 g) wurde mit Kaliumhydroxid (0,7 g) in Wasser (2 mL) und Ethylenglykol (8 mL) für 3 Stunden zum Rückfluß erhitzt. Der APD62429PC4- (4-Methylpiperidin1-yl) benzonitrile (1.2 g) was refluxed with potassium hydroxide (0.7 g) in water (2 mL) and ethylene glycol (8 mL) for 3 hours. Of the APD62429PC
Ansatz wurde mit Wasser verdünnt, mit Ethylacetat gewaschen und mit 2 N Salzsäure angesäuert. Das ausgefallene Produkt wurde abgesaugt, in Dichlormethan gelöst, über Natriumsulfat getrocknet, eingeengt und aus Diethylether kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 219,29 (C13H17N02); MS(ESI): 220 (M+H+).The reaction was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitated product was filtered off, dissolved in dichloromethane, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This gave the product with the molecular weight 219.29 (C13H17NO2); MS (ESI): 220 (M + H +).
4-(4-Methylpiperidin1-yl)-benzonitril4- (4-Methylpiperidin1-yl) -benzonitrile
4-Fluorbenzonitril (1 ,21 g) wurde mit 4-Methylpiperidin (1 ,00 g) für 1 Stunde auf 180°C erhitzt. Anschließend wurde der Ansatz in Ethylacetat aufgenommen, mit Wasser, 2N Natronlauge und ges. Natriumhydrogencarbonatlosung gewaschen, über Natriumsulfat getrocknet, eingeengt und aus n-Pentan kristallisiert. Man erhielt so das Produkt mit dem Molekulargewicht 200,29 (C13H16N2); MS(ESI): 201 (M+H+).4-Fluorobenzonitrile (1.21 g) was heated at 180 ° C with 1-methylpiperidine (1.00 g) for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and sat. Washed sodium bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This gave the product with a molecular weight of 200.29 (C13H16N2); MS (ESI): 201 (M + H +).
4-Butoxy-cyclohexancarbonsäure4-Butoxy-cyclohexanecarboxylic acid
Eine Lösung von 4-Hydroxy-cyclocarbonsäure-ethylester (10 g) und Butyljodid (10,6 g) in DMF wurde unter Eiskühlung und Argon mit Natriumhydrid (2,78 g) versetzt. Nach 12 Stunden wurde die Mischung auf Eis (200 g) gegossen, mit Ethylacetat (100 mL) extrahiert und anschließend mit Wasser (3 x 50 mL) gewaschen. Die organische Phase wurde konzentriert und mit Ethanol (50 mL) und Natriumhydroxid 5N (30 mL) versetzt. Die Lösung wurde 4 Stunden auf 60 qC erwärmt. Nach dem Abkühlen auf Raumtemperatur wurde mit Salzsäure 2N auf pH < 2 eingestellt, mit Ethylacetat extrahiert (3 x 50 mL), Magnesiumsulfat getrocknet, filtriert und konzentriert. Man erhielt so das Produkt mit dem Molekulargewicht 200,28 (C11 H20O3); MS (ESI): 201 (M+H+).A solution of ethyl 4-hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF was added under ice-cooling and argon with sodium hydride (2.78 g). After 12 hours, the mixture was poured onto ice (200 g), extracted with ethyl acetate (100 mL) and then washed with water (3 x 50 mL). The organic phase was concentrated and combined with ethanol (50 mL) and 5N sodium hydroxide (30 mL). The solution was heated to 60 ° C for 4 hours. After cooling to room temperature, 2N was adjusted to pH <2 with hydrochloric acid, extracted with ethyl acetate (3 x 50 mL), dried over magnesium sulfate, filtered and concentrated. This gave the product with a molecular weight of 200.28 (C11 H20O3); MS (ESI): 201 (M + H +).
1 -Benzyl-1 H-[1 ,2,3]triazol-4-carbonsäure1-Benzyl-1 H- [1,2,3] triazole-4-carboxylic acid
1-Benzyl-1H-[1,2,3]triazol-4-carbonsäure-methylester (217 mg) wurde in 4 mL Methanol gelöst und mit 2 mL 2N Natronlauge verseift. Nach Ansäuern mit 4 mL 2N Salzsäure wurde der entstehende Niederschlag abfiltriert, in 5 mL Ethylacetat aufgenommen und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 203,2 (C10H9N3O2); MS (ESI): 204 (M+H+). APD62429PC1-Benzyl-1H- [1,2,3] triazole-4-carboxylic acid methyl ester (217 mg) was dissolved in 4 mL of methanol and saponified with 2 mL of 2N sodium hydroxide solution. After acidification with 4 mL 2N hydrochloric acid, the resulting precipitate was filtered off, taken up in 5 mL ethyl acetate and purified by preparative HPLC. This gave the product with the molecular weight 203.2 (C10H9N3O2); MS (ESI): 204 (M + H +). APD62429PC
1 -Benzyl-1 H-[1 ,2,3]triazol-4-carbonsäure-methylester Benzylazid (266 mg) wurde zusammen mit Natriumascorbat (20 mg) und Kupfersulfat (5 mg) in 8 mL des Lösungsmittelgemisches (ferf.Butanol/Wasser 3:1) gelöst und Propionsäuremethylester (336 mg) zugegeben. Die Lösung wurde bei 2 Stunden bei Raumtemperatur gerührt. Es fiel ein weißer Niederschlag aus, der über eine Fritte abgesaugt und anschließend getrocknet wurde. Man erhielt so das Produkt mit dem Molekulargewicht 217,23 (C11 H11 N302); MS (ESI): 218 (M+H+). Analog wurde 1 -Biphenyl-4-yl-1 H-[1 ,2,3]triazol-4-carbonsäure aus 4- Ethinylbiphenyl und Azidoessigsäureethylester hergestellt.1-Benzyl-1 H- [1,2,3] triazole-4-carboxylic acid methyl ester Benzyl azide (266 mg) was combined with sodium ascorbate (20 mg) and copper sulfate (5 mg) in 8 mL of the solvent mixture (fer. Water 3: 1) and added methyl propionate (336 mg). The solution was stirred at room temperature for 2 hours. It precipitated a white precipitate, which was filtered through a frit and then dried. This gave the product with the molecular weight 217.23 (C11 H11 N302); MS (ESI): 218 (M + H +). Similarly, 1-biphenyl-4-yl-1 H- [1,2,3] triazole-4-carboxylic acid was prepared from 4-ethynyl-biphenyl and ethyl azidoacetate.
1 -Butyl-1 H-indole-5-carbonsäure1-butyl-1H-indole-5-carboxylic acid
1H-lndole-5-carbonsäure methyl ester (5.0 g) in DMF (100 mL) wurde mit Natriumhydrid (50% in Öl, 1 ,4 g) versetzt und nach beendeter Gasentwicklung Brombutan (3,9 g) zugesetzt. Nach 12 Stunden wurde die Reaktionslösung mit Ethylacetat verdünnt und dreimal mit Wasser gewaschen. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel (Laufmittel Ethylacetat / Heptan 1 :6) gereinigt. Der erhaltene Ester wurde in Methanol (10 mL) gelöst und mitSodium hydride (50% in oil, 1.4 g) was added to 1H-indole-5-carboxylic acid methyl ester (5.0 g) in DMF (100 mL) and bromobutane (3.9 g) was added when gas evolution ceased. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent ethyl acetate / heptane 1: 6). The resulting ester was dissolved in methanol (10 mL) and washed with
Natriumhydroxid (0,6 g ) in Wasser (10 mL) für 12 Stunden am Ruckfluss gekocht. Die Mischung wurde mit Wasser verdünnt und mit Salzsäure sauer gestellt, gefolgt von einer Extraktion mit Ethylacetat. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 217,27 (C13H15N02); MS (ESI): 218 (M+H+).Sodium hydroxide (0.6 g) boiled in water (10 mL) for 12 h. The mixture was diluted with water and made acidic with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This gave the product of molecular weight 217.27 (C13H15NO 2); MS (ESI): 218 (M + H +).
3'-Acetylamino-biphenyl-4-carbonsäure3'-Acetylamino-biphenyl-4-carboxylic acid
3'-Amino-biphenyl-4-carbonsäure (0,2 g) wurde mit Pyridin (0,7 g) und Acetanhydrid (180 mg) versetzt und nach 14 Stunden flüchtige Anteile entfernt. Der Rückstand wurde in Natronlauge (2N) aufgenommen und mit Diethylether gewaschen. Die wassrige Phase wurde mit Salzsäure sauer gestellt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat APD62429PC3'-Amino-biphenyl-4-carboxylic acid (0.2 g) was added with pyridine (0.7 g) and acetic anhydride (180 mg) and volatiles removed after 14 hours. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was over magnesium sulfate APD62429PC
getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 255,28 (C15H13N03); MS (ESI): 256 (M+H+).dried and concentrated. This gave the product with a molecular weight of 255.28 (C15H13NO3); MS (ESI): 256 (M + H +).
3'-lsobutyrylamino-biphenyl-4-carbonsäure 3'-Amino-biphenyl-4-carbonsäure (0,2 g) in Dichlormethan wurde mit3'-Isobutyrylamino-biphenyl-4-carboxylic acid 3'-Amino-biphenyl-4-carboxylic acid (0.2 g) in dichloromethane was washed with
Kaliumcarbonat (121 mg) und Isobutyrylchlorid (94 mg) versetzt. Nach 12 Stunden wurde die Mischung mit Natronlauge verdünnt und mit Diethylether gewaschen. Die wassrige Phase wurde mit Salzsäure sauer gestellt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 283,33 (C17H17N03); MS (ESI): 284 (M+H+).Potassium carbonate (121 mg) and isobutyryl chloride (94 mg) were added. After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This gave the product of molecular weight 283.33 (C17H17NO3); MS (ESI): 284 (M + H +).
5-Butoxy-pyridin-2-carbonsäure5-butoxy-pyridine-2-carboxylic acid
5-Hydroxy-pyridin-2-carbonsäure benzhydryl ester (2.0 g) gelöst in DMF (20 mL) wurde mit Natriumhydrid (50% in Öl, 250 mg) versetzt und nach beendeter Gasentwicklung 1 -Brombutan (0,72 g) zugesetzt. Die Mischung wurde für 6 Stunden auf 90 °C erwärmt. Es wurde mit Wasser verdünnt und mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde analog der Methode B hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 195,22 (C10H13NO3); MS (ESI): 196 (M+H+).Benzhydryl ester 5-hydroxy-pyridine-2-carboxylic acid (2.0 g) dissolved in DMF (20 mL) was treated with sodium hydride (50% in oil, 250 mg) and, after completion of gas evolution, 1-bromobutane (0.72 g). The mixture was heated to 90 ° C for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated analogously to Method B. This gave the product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M + H +).
4-Methyl-3,4,5,6-tetrahydro-2H-[1 ,3']bipyridinyl-6'-carbonsäure 5-Trifluormethanesulfonyloxy-pyridin-2-carbonsäure benzhydryl ester (3,0 g) wurde mit 4-Methylpiperidin (1 ,4 g) für eine Stunde auf 80 °C erwärmt. Das Reaktionsgemisch wurde direkt durch präparative HPLC gereinigt und anschließend analog der Methode hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 220,27 (C12H16N202); MS (ESI): 221 (M+H+).4-Methyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-carboxylic acid 5-trifluoromethanesulfonyloxy-pyridine-2-carboxylic acid benzhydryl ester (3.0 g) was treated with 4-methylpiperidine (1, 4 g) for one hour at 80 ° C heated. The reaction mixture was purified directly by preparative HPLC and then hydrogenated analogously to the method. This gave the product with the molecular weight 220.27 (C12H16N202); MS (ESI): 221 (M + H +).
N-[4-(3-Dimethylamino-pyrrolidin-1 -yl)-phenyl]-terephthalamic acid Methode P-a APD62429PCN- [4- (3-dimethylamino-pyrrolidin-1-yl) -phenyl] -terephthalamic acid Method Pa APD62429PC
N-[4-(3-Dimethylamino-pyrrolidi,n-1-yl)-phenyl]-terephthalamic acid methyl ester (1 ,7 g) gelöst in Methanol (20 mL) wurde mit Natronlauge (2N, 15 mL) für 24 Stunden bei Raumtemperatur gerührt. Bei unvollständigem Umsatz kann auch zum Ruckfluss erwärmt werden. Das organische Lösungsmittel wurde abdestilliert und die Mischung mit Salzsäure sauer gestellt. Der ausgefallene Niederschlag wurde abgesaugt und getrocknet. Man erhielt so das Produkt mit dem Molekulargewicht 353,42 (C20H23N3O3); MS (ESI): 354 (M+H+).N- [4- (3-Dimethylamino-pyrrolidin, n-1-yl) -phenyl] -terephthalamic acid methyl ester (1.7 g) dissolved in methanol (20 mL) was washed with sodium hydroxide solution (2N, 15 mL) for 24 Stirred hours at room temperature. With incomplete turnover can also be heated to reflux. The organic solvent was distilled off and the mixture was made acidic with hydrochloric acid. The precipitate was filtered off with suction and dried. This gave the product with the molecular weight 353.42 (C20H23N3O3); MS (ESI): 354 (M + H +).
N-[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-terephthalamic acid methyl ester [1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amin wurde nach Methode E mit Terephthalsäuremonomethylester umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 367,45 (C21 H25N303); MS (ESI): 368 (M+H+).N- [4- (3-Dimethylamino-pyrrolidin-1-yl) -phenyl] -terephthalamic acid methyl ester [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine was obtained by Method E with Terephthalic acid monomethyl ester reacted. This gave the product with the molecular weight 367.45 (C21 H25N303); MS (ESI): 368 (M + H +).
4-(Cyclopentanecarbonyl-methyl-amino)-benzoesäure 4-Methylamino-benzoesäuremethylester wurde nach Methode E mit4- (cyclopentanecarbonyl-methyl-amino) -benzoic acid 4-methylamino-benzoic acid methyl ester was according to method E with
Cyclopentancarbonsäure umgesetzt und dann nach Methode P-a verseift. Man erhielt so das Produkt mit dem Molekulargewicht 247,30 (C14H17NO3); MS (ESI):Cyclopentanecarboxylic reacted and then saponified by method P-a. This gave the product with the molecular weight 247.30 (C14H17NO3); MS (ESI):
248 (M+H+).248 (M + H +).
Analog wurden folgende Verbindungen erhalten: 4-(Cyclopentanecarbonyl-amino)-3-methoxy-benzoesäureThe following compounds were obtained analogously: 4- (cyclopentanecarbonylamino) -3-methoxybenzoic acid
2-Chlor-4-(cyclopentanecarbonyl-amino)-benzoesäure2-chloro-4- (cyclopentanecarbonyl-amino) -benzoic acid
2-Fluor-4-(cyclopentanecarbonyl-amino)-benzoesäure2-fluoro-4- (cyclopentanecarbonyl-amino) -benzoic acid
4-(Cyclopentanecarbonyl-amino)-3-methyl-benzoesäure4- (Cyclopentanecarbonyl-amino) -3-methyl-benzoic acid
4-(Cyclopentanecarbonyl-amino)-benzoesäure 4-(Cyclopentanecarbonyl-amino)-3-trifluormethoxy-benzoesäure4- (Cyclopentanecarbonylamino) benzoic acid 4- (cyclopentanecarbonylamino) -3-trifluoromethoxybenzoic acid
3-Chlor-4-(cyclopentanecarbonyl-amino)-benzoesäure3-chloro-4- (cyclopentanecarbonyl-amino) -benzoic acid
5-Chlor-4-(cyclopentanecarbonyl-amino)-2-methoxy-benzoesäure5-chloro-4- (cyclopentanecarbonyl-amino) -2-methoxy-benzoic acid
4-[(Cyclohex-1 -enecarbonyl)-amino]-benzoesäure4 - [(cyclohex-1-enecarbonyl) amino] benzoic acid
4-[(Cyclopent-1-enecarbonyl)-amino]-benzoesäure4 - [(cyclopent-1-enecarbonyl) -amino] -benzoic acid
3-Fluor-4-(1-methyl-butoxy)-benzoesäure APD62429PC3-fluoro-4- (1-methyl-butoxy) -benzoic acid APD62429PC
Zu einer Lösung aus 1 ,36 g NaOH, 1 ,6 g Brom in 6,8 mL Wasser wurde tropfenweise eine Lösung aus 0,449 g 1-[3-Fluor-4-(1-methyl-butoxy)-phenyl]- ethanon in 6,8 mL Dioxan getropft. Die Mischung wurde 30 Minuten bei Raumtemperatur gerührt und anschließend 1 h auf 50 °C erhitzt. Der Bromüberschuß wurde durch Zugabe eine Natriumdisulf itlosung zerstört und anschließend die Lösung in 25%ige Salzsäure gegossen und 20 Minuten gerührt. Die Lösung wurde mit Ethylacetat extrahiert. Die vereinigten organischen Phasen über Natriumsulfat getrocknet, im Vakuum eingeengt und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 226,1 (C12H15F03); MS (ESI): 227 (M+H+).To a solution of 1.36 g of NaOH, 1.6 g of bromine in 6.8 mL of water was added dropwise a solution of 0.449 g of 1- [3-fluoro-4- (1-methyl-butoxy) -phenyl] -ethanone 6.8 mL of dioxane was added dropwise. The mixture was stirred for 30 minutes at room temperature and then heated at 50 ° C for 1 h. The excess bromine was destroyed by adding a Natriumdisulf itlosung and then the solution poured into 25% hydrochloric acid and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic phases dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This gave the product with the molecular weight 226.1 (C12H15F03); MS (ESI): 227 (M + H +).
1 -[3-Fluor-4-(1 -methyl-butoxy)-phenyl]-ethanon1 - [3-fluoro-4- (1-methyl-butoxy) -phenyl] -ethanone
Zu einer Lösung aus 0,176 g 2-Pentanol in 2 mL DMF wurden 0,058 g NaH gegeben und die Lösung 1 Stunde bei Raumtemperatur gerührt. Anschließend wurden 0,312 g 3,4-Difluoracetophenon zugegen und über Nacht beiTo a solution of 0.176 g of 2-pentanol in 2 mL of DMF was added 0.058 g of NaH and the solution was stirred for 1 hour at room temperature. Subsequently, 0.312 g of 3,4-difluoroacetophenone were added and overnight
Raumtemperatur gerührt. Die Reaktionslösung wurde in Ethylacetat aufgenommen und zweimal mit Wasser gewaschen. Die organische Phase wurde über Natriumsulfat getrocknet und im Vakuum eingeengt. Die erhalteneRoom temperature stirred. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The obtained
Verbindung wurde ohne weitere Aufreinigung weiter umgesetzt. Analog wurden folgende Verbindungen erhalten:Compound was further reacted without further purification. The following compounds were obtained analogously:
4-Cyclobutoxy-3-fluor-benzoesäure4-cyclobutoxy-3-fluoro-benzoic acid
3-Fluor-4-(2-methyl-cyclopropylmethoxy)-benzoesäure3-fluoro-4- (2-methyl-cyclopropylmethoxy) benzoic acid
4-(2-Cyclopropyl-ethoxy)-3-fluor-benzoesäure4- (2-cyclopropyl-ethoxy) -3-fluoro-benzoic acid
3-Fluor-4-(1-methyl-piperidin-3-yloxy)-benzoesäure 4-(1 -Acetyl-piperidin-3-yloxy)-3-fluor-benzoesäure3-Fluoro-4- (1-methyl-piperidin-3-yloxy) -benzoic acid 4- (1-acetyl-piperidin-3-yloxy) -3-fluoro-benzoic acid
3-Fluor-4-(1-methyl-pyrrolidin-3-yloxy)-benzoesäure3-fluoro-4- (1-methyl-pyrrolidin-3-yloxy) benzoic acid
4-(1-Acetyl-pyrrolidin-3-yloxy)-3-fluor-benzoesäure4- (1-acetyl-pyrrolidin-3-yloxy) -3-fluoro-benzoic acid
3-Fluor-4-(1-methyl-piperidin-3-ylmethoxy)-benzoesäure3-fluoro-4- (1-methyl-piperidin-3-ylmethoxy) -benzoic acid
4-(2,4-Difluorphenoxy)-benzoesäure APD62429PC4- (2,4-difluorophenoxy) benzoic acid APD62429PC
Zu einer Lösung aus 0,428 g 4-(2,4-Difluorphenoxy)-benzoesäureethylester in 2 mL THF /Wasser (1 :1) wurden 0,518 g Kaliumhydroxid gegeben. Die Lösung wurde 6 Stunden auf 110 °C erwärmt. Anschließend wurde das THF im Vakuum entfernt, die Wasserphase gefriergetrocknet und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 250,04 (C13H8F203); MS (ESI): 251 (M+H+).To a solution of 0.428 g of ethyl 4- (2,4-difluorophenoxy) benzoate in 2 mL of THF / water (1: 1) was added 0.518 g of potassium hydroxide. The solution was heated to 110 ° C for 6 hours. Subsequently, the THF was removed in vacuo, the water phase was freeze-dried and purified by preparative HPLC. This gave the product with a molecular weight of 250.04 (C13H8F203); MS (ESI): 251 (M + H +).
4-(2,4-Difluorphenoxy)-benzoesäureethylester4- (2,4-difluorophenoxy) benzoate
Zu einer Lösung aus 0,1 g 2,4-Difluorphenol in 0,5 mL DMF wurden mit 0,018 g NaH versetzt. Die Reaktion wurde 45 Minuten bei Raumtemperatur gerührt.To a solution of 0.1 g of 2,4-difluorophenol in 0.5 mL of DMF was added 0.018 g of NaH. The reaction was stirred at room temperature for 45 minutes.
Anschließend wurden 0,129 g 4-Fluorbenzoesäureethylester in 0,5 mL DMF zugetropft. Die Reaktion wurde über Nacht auf 110 °C erhitzt. Nach dem Abkühlen im Vakuum eingeengt und der Rückstand in Ethylacetat /Wasser aufgenommen.Subsequently, 0.129 g of ethyl 4-fluorobenzoate in 0.5 ml of DMF were added dropwise. The reaction was heated at 110 ° C overnight. After cooling, concentrated in vacuo and the residue taken up in ethyl acetate / water.
Die Ethylacetatphase wurde dreimal mit Wasser gewaschen, über Natriumsulfat getrocknet, im Vakuum eingeengt und durch päparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 278,08 (C15H12F2O3); MSThe ethyl acetate phase was washed three times with water, dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This gave the product of molecular weight 278.08 (C15H12F2O3); MS
(ESI): 279 (M+H+)(ESI): 279 (M + H +)
Nach Methode E-b wurde 4-(2,4-Difluorphenoxy)-benzoesäure mit [1-(4-Amino- phenyl)-pyrrolidin-3-yl]-dimethyl-amin umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 437,19 (C25H25F2N302); MS (ESI): 438 (M+H+) alsAccording to method E-b, 4- (2,4-difluorophenoxy) benzoic acid was reacted with [1- (4-amino-phenyl) -pyrrolidin-3-yl] -dimethyl-amine. This gave the product with the molecular weight 437.19 (C25H25F2N302); MS (ESI): 438 (M + H +) as
Hydrotrifluoracetat.Hydrotrifluoroacetate.
4-Butoxy-3-methoxy-benzoesäure4-butoxy-3-methoxy-benzoic acid
4-Hydroxy-3-methoxy-benzoesäure methyl ester wurde nach Methode H mit Brombutan alkyliert und nach Methode P-a verseift. Man erhielt so das Produkt mit dem Molekulargewicht 224,26 (C12H1604); MS (ESI): 225 (M+H+).4-Hydroxy-3-methoxy-benzoic acid methyl ester was alkylated by method H with bromobutane and saponified by method P-a. This gave the product with the molecular weight 224.26 (C12H1604); MS (ESI): 225 (M + H +).
Analog wurden folgende Verbindungen hergestellt:The following compounds were prepared analogously:
4-Butoxy-3,5-dichlor-benzoesäure4-Butoxy-3,5-dichloro-benzoic acid
4-Butoxy-3-nitro-benzoesäure 4-Butoxy-3-chlor-benzoesäure4-butoxy-3-nitro-benzoic acid 4-butoxy-3-chloro-benzoic acid
4-Butoxy-3,5-dimethyl-benzoesäure4-Butoxy-3,5-dimethyl-benzoic acid
4-Butoxy-2,3-dichlor-5-methoxy-benzoesäure APD62429PC4-Butoxy-2,3-dichloro-5-methoxy-benzoic acid APD62429PC
4-Butoxy-2,3,5,6-tetrafluor-benzoesäure 4-Butoxy-3-fluor-benzoesäure 3-Acetyl-4-butoxy-benzoesäure 2,4-Dibutoxy-benzoesäure 4-Butoxy-2-chlor-benzoesäure4-Butoxy-2,3,5,6-tetrafluoro-benzoic acid 4-Butoxy-3-fluoro-benzoic acid 3-Acetyl-4-butoxy-benzoic acid 2,4-Dibutoxy-benzoic acid 4-Butoxy-2-chloro-benzoic acid
4-Propoxymethyl-benzoesäure4-propoxymethyl-benzoic acid
Eine Lösung von Propanol (0,6 g) in DMF (8 mL) wurde vorsichtig mitA solution of propanol (0.6 g) in DMF (8 mL) was carefully added
Natriumhydrid (50% in Öl; 0,42g) versetzt. Nach beenderter Gasentwicklung wurde 4-Brommethyl-benzoesäure methyl ester (1 ,0 g) zugesetzt. Nach 4 Stunden wurde die Mischung zwischen Wasser und Ethylacetat verteilt. Die organischeSodium hydride (50% in oil, 0.42 g). After completion of gas evolution 4-bromomethyl-benzoic acid methyl ester (1, 0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic
Phase wurde über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde nach Methode P-a verseift. Man erhielt so das Produkt mit demPhase was dried over magnesium sulfate and concentrated. The residue was saponified by Method P-a. One received thus the product with the
Molekulargewicht 194,23 (C11 H1403); MS (ESI): 195 (M+H+). Analog wurden folgende Verbindungen hergestellt:Molecular weight 194.23 (C11 H1403); MS (ESI): 195 (M + H +). The following compounds were prepared analogously:
4-Ethoxymethyl-benzoesäure4-ethoxymethyl-benzoic acid
4-Butoxymethyl-benzoesäure4-butoxymethyl-benzoic acid
4-lsobutoxymethyl-benzoesäure4-isobutoxymethyl-benzoic acid
4-Phenoxymethyl-benzoesäure 4-(Pyridin-3-yloxymethyl)-benzoesäure4-phenoxymethylbenzoic acid 4- (pyridin-3-yloxymethyl) benzoic acid
4-(Pyridin-2-yloxymethyl)-benzoesäure4- (pyridin-2-yloxymethyl) -benzoic acid
4-Benzoimidazol-1-ylmethyl-benzoesäure4-benzoimidazol-1-ylmethyl-benzoic acid
4-lndol-1 -ylmethyl-benzoesäure4-indole-1-ylmethyl-benzoic acid
4-Phenylsulfanylmethyl-benzoesäure 4-(Pyrimidin-2-ylsulfanylmethyl)-benzoesäure4-Phenylsulfanylmethylbenzoic acid 4- (pyrimidin-2-ylsulfanylmethyl) benzoic acid
4- (Pyridi n-2-ylsu If anylmethyl) -benzoesäu re4- (pyridinyl-2-ylsulfonylmethyl) benzoic acid
4-(2-Cyano-phenoxymethyl)-benzoesäure4- (2-cyano-phenoxymethyl) -benzoic acid
4-(2-Chlor-phenoxymethyl)-benzoesäure4- (2-chloro-phenoxymethyl) -benzoic acid
4-Cyclobutoxymethyl-benzoesäure 4-Cyclopentyloxymethyl-benzoesäure4-cyclobutoxymethylbenzoic acid 4-cyclopentyloxymethylbenzoic acid
4-Cyclohexyloxymethyl-benzoesäure4-Cyclohexyloxymethyl-benzoic acid
4-sec-Butoxymethyl-benzoesäure APD62429PC4-sec-butoxymethyl-benzoic acid APD62429PC
4-Pentoxymethyl-benzoesäure4-pentoxymethyl-benzoic acid
4-(3-Oxo-3a,4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl)-benzoesäure Eine Lösung von 4-Hydrazinobenzoesäure (0,3 g), Ethyl-2- oxocyclopentancarboxylat (0,31 g) und p-Toluolsulfonsäure (340 mg) in Ethanol (1 mL) wurde für 12 Stunden am Ruckfluss gekocht . Die eingeengte Reaktionslösung wurde durch präparative HPLC gereingt. Das isolierte Reaktionsprodukt (als Ethylester) wurde nach Methode P-a verseift. Man erhielt so das Produkt mit dem Molekulargewicht 244,25 (C13H12N203); MS (ESI): 245 (M+H+).4- (3-Oxo-3a, 4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl) -benzoic acid A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl 2-oxocyclopentanecarboxylate (0.31 g ) and p-toluenesulfonic acid (340 mg) in ethanol (1 mL) was refluxed for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was saponified by method P-a. This gave the product with the molecular weight 244.25 (C13H12N203); MS (ESI): 245 (M + H +).
4-Butoxy-2-methoxy-benzoesäure 4-Hydroxy-2-methoxy-benzaldehyd wurde nach Methode H mit 1 -Brombutan alkyliert. Der erhaltene Aldehyd (6,4 g) in Dioxan (100 mL) wurde mit Natriumdihydrogenphosphat (14,4 g) und Schwefelsäure (2,4 mL) versetzt und die Lösung auf 10°C gekühlt. Es wurde eine Lösung von Natriumchlorit (3,61 g) in Wasser (100 mL) zugegeben, so dass die Temperatur nicht über 10°C stieg. 15 Minuten nach beendeter Zugabe wurde Natriumsulfit (4,6 g) zugesetzt. Nach weiteren 15 Minuten wurde mit Salzsäure auf einen pH-Wert von 2 gestellt und das Dioxan am Rotationsverdampfer entfernt. Die wassrige Phase wurde mit Ethylacetat extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 224,26 (C12H1604); MS (ESI): 225 (M+H+). Als Nebenprodukt fiel 4-Butoxy-5-chlor-2-methoxy-benzoesäure an.4-Butoxy-2-methoxy-benzoic acid 4-hydroxy-2-methoxybenzaldehyde was alkylated by method H with 1-bromobutane. To the resulting aldehyde (6.4 g) in dioxane (100 mL) was added sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 mL) and the solution was cooled to 10 ° C. A solution of sodium chlorite (3.61 g) in water (100 mL) was added so that the temperature did not rise above 10 ° C. Fifteen minutes after the completion of the addition, sodium sulfite (4.6 g) was added. After a further 15 minutes, the pH was adjusted to 2 with hydrochloric acid and the dioxane was removed on a rotary evaporator. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 224.26 (C12H1604); MS (ESI): 225 (M + H +). By-product was 4-butoxy-5-chloro-2-methoxy-benzoic acid.
4-(1 -Propoxy-ethyl)-benzoesäure 4-(1-Hydroxy-ethyl)-benzoesäuremethylester (2,0 g) gelöst in DMF (30 mL) wurde mit Propyliodid (3,8 g) versetzt und dann Natriumhydrid (50%ig in Öl, 0,53 g) zugegeben. Nach dem Ende der exothermen Reaktion wurde noch 1 Stunde APD62429PC4- (1-Propoxy-ethyl) -benzoic acid 4- (1-Hydroxy-ethyl) -benzoic acid methyl ester (2.0 g) dissolved in DMF (30 mL) was added with propyl iodide (3.8 g) and then sodium hydride (50 % in oil, 0.53 g). After the end of the exothermic reaction was still 1 hour APD62429PC
gerührt und dann vorsichtig Wasser zur Mischung gegeben. Es wurde mit Ethylacetat extrahiert, die organische Phase über Natriumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde nach Methode P-a verseift. Man erhielt so das Produkt mit dem Molekulargewicht 208,26 (C12H1603); MS (ESI): 209 (M+H+). stirred and then carefully added water to the mixture. It was extracted with ethyl acetate, the organic phase dried over sodium sulfate, filtered and concentrated. The residue was saponified by Method P-a. This gave the product of molecular weight 208.26 (C12H1603); MS (ESI): 209 (M + H +).

Claims

APD62429PCAPD62429PC
Patentansprücheclaims
1. Verbindungen der Formel I,1. Compounds of the formula I,
Figure imgf000355_0001
Figure imgf000355_0001
worin bedeutenin which mean
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CR78R79)0-R12, (CrC4)-Alkoxy-(Cι-C4)-alkyl, Aryloxy-(C C4)-alkyl, (C3-C8)-R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR 78 R 79) 0 -R 12, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, aryloxy- (CC 4 ) -alkyl, (C 3 -C 8 ) -
Alkenyl, (C3-C8)-Alkinyl, CO-(C C8)-Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(C C4)-alkyl, CO-(C2-C8)-Alkenyl, CO-(C2-C8)- Alkinyl, COCH=CH(R13), COCC(R14), CO-(C C4)-alkyl- S(0)p-(C C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 4 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8)-Alkyl, (C C4)-Alkoxy-(C C4) -alkyl, Hydroxy-(C1-C4)-Alkyl, (C0-C8)- Alkylen-aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(C C6)-Alkyl, N(R31)(R32) oderAlkenyl, (C3-C8) -alkynyl, CO- (CC 8) -alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (CC 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 (0) p - (CC 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 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 of oxygen and nitrogen and sulfur, where the heterocyclic ring system can additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (CC 6 ) -alkyl, 0- (CC 8 ) -alkyl, (CC 4 ) -alkoxy- ( CC 4 ) -alkyl, hydroxy (C 1 -C 4 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, COO (R29 ), N (R30) CO (CC 6) -alkyl, N (R31) (R32), or
S02CH3; APD62429PCS0 2 CH 3 ; APD62429PC
o 0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
P 0, 1 , 2;P 0, 1, 2;
q, r, s unabhängig voneinander 0, 1 , 2, 3, 4;q, r, s are independently 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann;R13, R14 independently of one another a 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, N0 2, CN, (CC 6) alkyl 0- (CC 8 ) -alkyl may be substituted;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (C-i-Cβ) -Alkyl;R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another are H, (C-i-Cβ) -alkyl;
R18 H, (C C6)-Alkyl, CO(C C6)-Alkyl, CO(R33); oderR18 H, (CC 6) -alkyl, CO (CC 6) -alkyl, CO (R33); or
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit demR17 and R18, R21 and R22, R27 and R28, R31 and R32 independently optionally together with the
Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;Nitrogen atom to which they are attached, a 5-6 membered ring, which in addition to the nitrogen atom may contain 0-1 further heteroatoms from the group N- (-C-C 6 ) alkyl, oxygen and sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR33 is a 5-10 membered aromatic ring system containing 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6)- Alkyl, 0-(Cι-C8)-Alkyl substituiert sein kann;Contain heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , N0 2 , CN, (CC 6 ) - alkyl, 0- (-CC 8 ) alkyl may be substituted;
R12 OH, 0-(C C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(CrC6)-R 12 is OH, O- (CC 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, CN, S- (CrC 6 ) -
Alkyl, COO(R80), CON(R81)(R93), N(R82)(R83), 3-12 APD62429PCAlkyl, COO (R80), CON (R81) (R93), N (R82) (R83), 3-12 APD62429PC
gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, J, OH, CF3, N02, CN, OCF3, Oxo, 0-(C C6)-Alkyl, (C C4)-Alkoxy-(C C4)-alkyl, S-(C C6)-Alkyl, (C C6)-Alkyl, (C2-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- (CC 6 ) -alkyl, (CC 4 ) -alkoxy- (CC 4 ) -alkyl, S- (CC 6 ) -alkyl, (CC 6 ) -alkyl, (C 2 -
C6)-Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C3-C8)- Cycloalkenyl, 0-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, O-(C0- C8)-Alkylen-aryl, (C0-C8)-Alkylen-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C C6)-Alkyl, COCOO(C C6)-Alkyl, COO(R40),C 6) alkenyl, (C 3 -C 8) -cycloalkyl, 0- (C 3 -C 8) cycloalkyl, (C 3 -C 8) - cycloalkenyl, 0- (C 3 -C 8) cycloalkenyl, (C 2 -C 6 ) alkynyl, O- (C 0 -C 8 ) -alkylene-aryl, (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35), COCH = CH (R 36) , (C (R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (CC 6) -alkyl, COCOO (CC 6) -alkyl, COO (R40) .
S(0)u (R41) und COOH enthalten kann;S (0) may contain u (R41) and COOH;
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2; oderu 0, 1, 2; or
R34, R35, R37, R38 unabhängig voneinander H, (CrC8) -Alkyl;R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl;
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(CrC6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;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, also contains 0-1 further heteroatoms from the group consisting of N- (C 1 -C 6 ) -alkyl, oxygen and sulfur and optionally may be substituted with 1 -2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6) -Alkyl, 0-(d-C8)-Alkyl substituiert sein kann; APD62429PCR36, R39 are independently (C 3 -C 8 ) -cycloalkyl, 5-10 membered aromatic ring system containing 0-2 other heteroatoms from the group consisting of nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , N0 2 , CN, (CC 6 ) -alkyl, 0- (dC 8 ) -alkyl may be substituted; APD62429PC
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R40 H, (CC 8) -alkyl, (C 2 -C 6) alkenyl, (C 0 -C 8) -alkylene-aryl;
R41 (d-CβJ-Alkyl, 5-10 gliedriges aromatisches Ringsystem, dasR41 (d-CβJ-alkyl, 5-10 membered aromatic ring system, the
0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann;0-2 further heteroatoms from the group nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF 3 , N0 2 , CN, (CC 6 ) alkyl, 0- (CC 8 ) alkyl substituted;
R78, R79 unabhängig voneinander H, (C C8) -Alkyl, Hydroxy-(d-C4)- Alkyl, OH, (CrC4)-Alkoxy-(CrC4)-Alkyl;R78, R79 independently of one another H, (CC 8) alkyl, hydroxy (dC 4) - alkyl, OH, (CrC 4) alkoxy (CrC 4) alkyl;
R80, R81 ,R80, R81,
R93 unabhängig voneinander H, (C-ι-C8) -Alkyl, (C2-C6)-Alkenly,R93 independently of one another are H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl,
(Co-Cs)-Alkylen-Aryl;(Co-Cs) alkylene-aryl;
R82, R83 unabhängig voneinander H, (C C6) -Alkyl; oderR82, R83 are independently H, (CC 6 ) -alkyl; or
R82 undR82 and
R83 optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer demR83 optionally together with the nitrogen atom to which they are attached, a 5-6 membered ring which except the
Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;Nitrogen atom still contain 0-1 further heteroatoms from the group N- (-CC 6 ) alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups;
R3 H, (C C6)-Alkyl;R 3 is H, (CC 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (CrC6)-Alkyl, OH, 0-(C C6)-R 4, R 5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (CC 6 ) -
Alkyl, 0-CO(C C6)-Alkyl, S-(C C6)-Alkyl;Alkyl, O-CO (CC 6 ) -alkyl, S- (CC 6 ) -alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (CrC8)-Alkyl, oder APD62429PCR 6, R 7, R 8, R 9 independently of one another are H, (C 1 -C 8 ) -alkyl, or APD62429PC
R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;R6 and R7, R8 and R9 independently of one another optionally oxo;
n, m unabhängig voneinander 0, 1 , 2;n, m are independently 0, 1, 2;
A, B, D, G unabhängig voneinander N, C(R42); oder die Gruppen A und B oder die Gruppen D und G sind jeweils C(R42) und bilden gemeinsam einen 5- oder 6-gliedrigen carbocyclischen oder heterocyclischen Rest, so dass sich insgesamt ein bicyclisches System ergibt;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;
R42 H, F, Cl, Br, J, OH, CF3, N02, CN, OCF3, 0-(CrC6)-Alkyl, O-R42 H, F, Cl, Br, I, OH, CF 3, N0 2, CN, OCF 3, 0- (C r C6) alkyl, O-
(Cι-C4)-Alkoxy-(C C4)-alkyl, S-(C C6)-Alkyl, (Cι-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C3- (Cι-C4) alkoxy (CC 4) alkyl, S- (CC 6) alkyl, (Cι-C6) alkyl, (C 2 -C 6) alkenyl, (C 3 -C 8 ) -Cycloalkyl, 0- (C 3 -C 8 ) -cycloalkyl, (C 3 -
C8)-Cycloalkenyl, 0-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0- C8)-Alkylen-Aryl, O-(C0-C8) -Alkylen-Aryl, S-Aryl, N(R43)(R44), S02-CH3, COOH, COO-(C C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51), -(CR84R85)X- 0(R86);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-aryl, S-aryl, N (R43) (R44) S0 2 -CH 3, COOH, COO- (CC 6) -alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51), - (CR84R85) X - 0 (R86);
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (CrC8) -Alkyl; oder R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl; atom or R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen to which they are attached form a 5-6 membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatoms from the group of N- (Cι-C 6 ) -Alkyl, oxygen and sulfur may include;
R48, R50, R51 APD62429PCR48, R50, R51 APD62429PC
unabhängig voneinander H, (Ci-CβJ-Alkyl, Aryl;independently of one another H, (Ci-CβJ-alkyl, aryl;
R84, R85 unabhängig voneinander H, (C-ι-C8) -Alkyl;R 84, R 85 independently of one another are H, (C 1 -C 8 ) -alkyl;
R86 H, (C C6)-Alkyl, Aryl;R86 H, (CC 6) -alkyl, aryl;
x 1 , 2, 3, 4, 5, 6;x 1, 2, 3, 4, 5, 6;
R10 H, (C C8)-Alkyl, (C3-C6)-Alkenyl, (C3-C6)-Alkinyl;R 10 is H, (CC 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)0,X N (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O,
CO, C≡C, eine Gruppe der Formel -(CR87R88)γ-, worin eine oder mehrere Gruppen -(CR87R88)- durch Y ersetzt sein können, wobei sich ein chemisch sinnvoller Rest ergibt;CO, C≡C, a group of the formula - (CR87R88) γ- in which one or more groups - (CR87R88) - may be replaced by Y to give a chemically reasonable residue;
Y O, S, N(R89);Y O, S, N (R89);
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8) -AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
R87, R88 unabhängig voneinander H, (d-C4)-Alkyl, wobei R87 und R88 in den y Gruppen jeweils die gleichen oder verschiedene Bedeutungen aufweisen können;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;
y 2, 3, 4, 5, 6;y 2, 3, 4, 5, 6;
R89 H, (C C8)-Alkyl;R89 H, (CC 8) alkyl;
E 3-14 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O undE 3-14 membered bivalent carbo- or heterocyclic ring structure containing 0-4 heteroatoms from the group N, O and
S, die optional Substituenten aus der Gruppe H, F, Cl, Br, J, OH, CF3, N02, CN, OCF3, Oxo, 0-(CrC6)-Alkyl, 0-(d-C4)- APD62429PCS, which optionally have substituents from the group H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O- (C 1 -C 6 ) -alkyl, O- (C 1 -C 4 ) - APD62429PC
Alkoxy-(C C4)-alkyl, S-(C C6) -Alkyl, (C C6)-Alkyl, (C2-C6)- Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C3-C8)- Cycloalkenyl, 0-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)- Alkylen-aryl, O-(C0-C8)-Alkylen-aryl, S-Aryl, N(R57)(R58), S02- CH3, COOH, COO-(C C6)-Alkyl, CON(R59)(R60),Alkoxy (CC 4 ) alkyl, S (CC 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, 0- (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) S0 2 - CH 3, COOH, COO- (CC 6) -alkyl, CON (R59) (R60 )
N(R61)CO(R62), N(R63)S02(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;N (R61) CO (R62), N (R63) S0 2 (R64), CO (R65) bear and can be mono- or bicyclic;
R57, R58, R59, R60, R61 , R63 unabhängig voneinander H, (CrC8) -Alkyl; oder R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitereR 57, R 58, R 59, R 60, R 61, R 63 independently of one another are H, (C 1 -C 8 ) -alkyl; or R57 and R58, R59 and R60 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, is still 0-1 further
Heteroatome aus der Gruppe N-fd-Cβ) -Alkyl, Sauerstoff und Schwefel beinhalten kann;Heteroatoms from the group N-fd-Cβ) -alkyl, oxygen and sulfur may include;
R62, R64, R65 unabhängig voneinander H, (C-ι-C8) -Alkyl, Aryl;R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
K eine Bindung, O, OCH2, CH20, S, SO, S02, N(R66),K is a bond, O, OCH 2 , CH 2 O, S, SO, S0 2 , N (R66),
N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C≡C, C=C, eine Gruppe der Formel -(CR90R91)Z-, worin eine oder mehrere Gruppen -(CR90R91)- durch Z ersetzt sein können, wobei sich ein chemisch sinnvoller Rest ergibt;N (R67) CO, CON (R68), (C (R69) (R70)) V , CO, C≡C, C = C, a group of the formula - (CR90R91) Z -, in which one or more groups - ( CR90R91) - may be replaced by Z, resulting in a chemically meaningful residue;
v 1 , 2, 3, 4;v 1, 2, 3, 4;
R66, R67, R68, R69, R70 unabhängig voneinander H, (CrC8)-Alkyl; APD62429PCR66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
Z O, S, N(R92), CO, SO, S02;ZO, S, N (R92), CO, SO, S0 2 ;
R90, R91 unabhängig voneinander H, (d-C8)-Alkyl, Hydroxy- (C C4)- Alkyl, Hydroxy, (CrC4)-Alkoxy-(Cι-C4)-Alkyl, wobei R90 und R91 in den z Gruppen jeweils die gleichen oder verschiedeneR90, R91 independently of one another are H, (C 1 -C 8 ) -alkyl, hydroxy- (CC 4 ) -alkyl, hydroxy, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, where R 90 and R 91 in the z groups in each case the same or different
Bedeutungen aufweisen können;May have meanings;
z 2, 3, 4, 5, 6;z 2, 3, 4, 5, 6;
R92 H, (d-Cs)-Alkyl;R92 is H, (C 1 -C 5) -alkyl;
R11 H, (CrC8)-Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl,R11 H, (C r C 8) alkyl, (dC 4) alkoxy- (Cι-C4) alkyl, (C 3 -C 8) alkenyl,
(C3-C8)-Alkinyl, ein 3 bis 10-gliedriger mono-, bi-, tri oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und(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 consisting of oxygen, nitrogen and
Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, N02, CN, (d-C6)-Alkyl, 0-(C C8)- Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, (C0-C8)-Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, Hydroxy-(C C4)-alkyl, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oderSulfur, where the ring system can additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 ) -alkyl, O- (CC 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkoxy- dC 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
S02CH3, SCF3 ;S0 2 CH 3 , SCF 3 ;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (d-C8)-Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff undR72 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 , Oxygen and
Schwefel beinhalten kann; oder APD62429PCMay include sulfur; or APD62429PC
E, K und R11 zusammen einen Tricyclus bilden, wobei die Ringe unabhängig voneinander gesättigt, teilgesättigt oder ungesättigt und jeweils 3 - 8 Ringatome enthalten können;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;
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
2. Verbindungen der Formel I nach Anspruch 1 ,2. Compounds of formula I according to claim 1,
worin bedeutenin which mean
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CH2)0 -R12, (d-R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CH 2 ) 0 -R 12, (d-
C4)-Alkoxy-(Cι-C4)-alkyl, Aryloxy-(CrC4)-alkyl, (C3-C8)- Alkenyl, (C3-C8)-Alkinyl, CO-(C C8) -Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(Cι-C4)-alkyl, CO-(C2-C8)-Alkenyl, CO-(C2-C8)- Alkinyl, COCH=CH(R13), COCC(R14), CO-(C C4)-alkyl-Alkyl C 4) alkoxy- (Cι-C alkyl 4), aryloxy (CrC 4), (C 3 -C 8) - alkenyl, (C 3 -C 8) -alkynyl, CO- (CC 8) alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (Cι-C4) alkyl, CO- (C 2 -C 8) -alkenyl, CO- (C 2 -C 8) - alkynyl , COCH = CH (R13), COCC (R14), CO- (CC 4) -alkyl-
S(0)p-(d-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom(0) p S - (dC 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, together with the nitrogen atom to which they are attached, form a 4 to 10 membered mono-, bi- or spiro-cyclic ring other than the nitrogen atom
0 bis 4 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8) -Alkyl, (C C4)-Alkoxy-(d-C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R26),0 to 4 may contain additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, it being possible for the heterocyclic ring system additionally to be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (CC 6 ) -alkyl, 0- (CC 8 ) -alkyl, (CC 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R 26),
CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(C C6)- Alkyl, N(R31)(R32) oder S02CH3;CON (R27) (R28), hydroxy, COO (R29), N (R30) CO (CC 6) - alkyl, N (R31) (R32), or S0 2 CH 3;
0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
0, 1 , 2; APD62429PC0, 1, 2; APD62429PC
q, r, s unabhängig voneinander 0, 1 , 2, 3, 4;q, r, s are independently 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br,R 13, R 14 independently of one another contain a 5-10 membered aromatic ring system which contains 0-2 further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and with F, Cl, Br,
CF3, N02, CN, (d-Ce)-Alkyl, 0-(C C8) -Alkyl substituiert sein kann;CF 3 , NO 2 , CN, (d-Ce) alkyl, 0- (CC 8 ) alkyl may be substituted;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (d-C6)-Alkyl;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, (C C6)-Alkyl, CO(Cι-C6)-Alkyl, CO(R33);R18 H, (CC 6) -alkyl, CO (Cι-C 6) -alkyl, CO (R33);
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;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 ) alkyl, may include oxygen and sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitereR33 is a 5-10 membered aromatic ring system containing 0-2 others
Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6)- Alkyl, 0-(Cι-C8)-Alkyl substituiert sein kann;Contain heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , N0 2 , CN, (CC 6 ) - alkyl, 0- (-CC 8 ) alkyl may be substituted;
R12 OH, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, J, OH, CF3, N02, CN, OCF3, Oxo,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,
0-(C C6)-Alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, S-(d-C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)- APD62429PC0- (CC 6) alkyl, (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 ) - APD62429PC
Cycloalkyl, (C3-C8)-Cycloalkenyl, 0-(C3-C8) -Cycloalkenyl, (C2- C6)-Alkinyl, O-(C0-C8)-Alkylen-Aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(d-C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40), S(0)u (R41) und COOH enthalten kann;Cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, O- (C 3 -C 8 ) -cycloalkenyl, (C 2 -C 6 ) -alkynyl, O- (C 0 -C 8 ) -alkylene-aryl, N ( R34) (R35), COCH = CH (R36), (C (R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (dC 6) alkyl, COCOO (dC 6 ) alkyl, COO (R 40), S (0) u (R 41) and COOH may contain;
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (CrC8) -Alkyl;R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl;
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer demR34 and R35 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring other than the
Stickstoffatom noch 0-1 weitere Heteroatome aus der GruppeNitrogen atom still 0-1 further heteroatoms from the group
N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;N- (C 1 -C 6 ) -alkyl, oxygen and sulfur and may optionally be substituted with 1-2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8) -Alkyl substituiert sein kann;R36, R39 are independently (C 3 -C 8 ) -cycloalkyl, 5-10 membered aromatic ring system containing 0-2 other heteroatoms from the group consisting of nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , N0 2 , CN, (CC 6 ) -alkyl, 0- (CC 8 ) -alkyl may be substituted;
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R40 H, (CC 8) -alkyl, (C 2 -C 6) alkenyl, (C 0 -C 8) -alkylene-aryl;
R41 (d-C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, Br, CF3, N02, CN, (d- C6)-Alkyl, 0-(d-C8)-Alkyl substituiert sein kann; APD62429PCR41 (dC 6 ) alkyl, 5-10 membered aromatic ring system containing 0-2 other heteroatoms from the group nitrogen, oxygen and sulfur and with F, Cl, Br, CF 3 , N0 2 , CN, (d- C 6 ) -alkyl, 0- (dC 8 ) -alkyl may be substituted; APD62429PC
R3 H, (d-C6)-Alkyl;R 3 is H, (C 1 -C 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (C C6)-Alkyl, OH, 0-(C C6)- Alkyl, 0-CO(C C6)-Alkyl, S-(d-C6)-Alkyl;R4, R5 are independently H, (CC 6 ) alkyl, OH, O- (CC 6 ) alkyl, O-CO (CC 6 ) alkyl, S (dC 6 ) alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (C C8) -Alkyl;R6, R7, R8, R9 independently of one another are H, (CC 8 ) -alkyl;
R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;R6 and R7, R8 and R9 independently of one another optionally oxo;
n, m unabhängig voneinander 0, 1 , 2;n, m are independently 0, 1, 2;
A, B, D, G unabhängig voneinander N, C(R42);A, B, D, G are independently N, C (R42);
R42 H, F, Cl, Br, J, OH, CF3, N02, CN, OCF3, 0-(d-C6)-Alkyl, O-R 42 is H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , 0- (dC 6 ) -alkyl, O-
(d-C4)-Alkoxy-(Cι-C4)-alkyl, S-(C C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C3- C8)-Cycloalkenyl, 0-(C3-C8) -Cycloalkenyl, (C2-C6)-Alkinyl, (C0-(dC 4) alkoxy- (Cι-C4) alkyl, S- (CC 6) alkyl, (dC 6) alkyl, (C 2 -C 6) -alkenyl, (C 3 -C 8) - cycloalkyl, 0- (C 3 -C 8) cycloalkyl, (C 3 - C 8) cycloalkenyl, 0- (C 3 -C 8) -cycloalkenyl, (C 2 -C 6) -alkynyl, (C 0 -
C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, S-Aryl, N(R43)(R44), S02-CH3, COOH, COO-(C C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl, S-aryl, N (R 43) (R 44), SO 2 -CH 3 , COOH, COO- (CC 6 ) -alkyl , CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51)
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (CrC8) -Alkyl;R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl;
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigenR43 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 one
Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere APD62429PCRing, which in addition to the nitrogen atom still 0-1 more APD62429PC
Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;Heteroatoms from the group N- (dC 6 ) alkyl, may include oxygen and sulfur;
R48, R50, R51 unabhängig voneinander H, (d-C8) -Alkyl, Aryl;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
R10 H, (C C8)-Alkyl, (C3-C6)-Alkenyl, (C3-C6)-Alkinyl;R 10 is H, (CC 8 ) -alkyl, (C 3 -C 6 ) -alkenyl, (C 3 -C 6 ) -alkynyl;
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)0;X N (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O;
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O undE 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group N, O and
S, die optional Substituenten aus der Gruppe H, F, Cl, Br, J, OH, CF3, N02, CN, OCF3, 0-(C C6) -Alkyl, 0-(C C4)-Alkoxy- (d-C4)-alkyl, S-(C C6)-Alkyl, (C C6) -Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, 0-(C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl,S, which are optionally substituents from the group H, F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , 0- (CC 6 ) -alkyl, O- (CC 4 ) -alkoxy- ( dC 4 ) -alkyl, S- (CC 6 ) -alkyl, (CC 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 3 -C 8 ) -cycloalkyl, 0- (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-(C0-C8)-Alkylen-Aryl, S-Aryl, N(R57)(R58), S02-CH3, COOH, COO-(d-C6)-Alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;O- (C 0 -C 8 ) -alkylene-aryl, S-aryl, N (R 57) (R 58), SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CON (R 59) (R 60) , N (R61) CO (R62), N (R63) S0 2 (R64), CO (R65) bear and can be mono- or bicyclic;
R57, R58, R59, R60, R61 , R63 unabhängig voneinander H, (CrC8) -Alkyl;R 57, R 58, R 59, R 60, R 61, R 63 independently of one another are H, (C 1 -C 8 ) -alkyl;
R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit demR57 and R58, R59 and R60 independently of each other optionally together with the
Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere APD62429PCNitrogen atom to which they are attached, a 5-6 membered ring, which in addition to the nitrogen atom still 0-1 more APD62429PC
Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;Heteroatoms from the group N- (-C-C 6 ) alkyl, may include oxygen and sulfur;
R62, R64, R65 unabhängig voneinander H, (Cι-C8) -Alkyl, Aryl;R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
K eine Bindung, O, OCH2, CH20, S, SO, S02, N(R66),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;N (R67) CO, CON (R68), (C (R69) (R70)) V , CO, C≡C;
v 1 , 2, 3, 4v 1, 2, 3, 4
R66, R67, R68, R69, R70 unabhängig voneinander H, (CrC8) -Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (d-C8)-Alkyl, (C C4)-Alkoxy-(d-C4)-alkyl, (C3-C8)-Alkenyl,R11 H, (DC 8) alkyl, (CC 4) alkoxy- (dC 4) alkyl, (C 3 -C 8) alkenyl,
(C3-C8)-Alkinyl, ein 3 bis 10-gliedriger mono-, bi- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, N02, CN, (C C6)-Alkyl, 0-(C C8)-(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, which ring system may additionally be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (CC 6 ) -alkyl, O- (CC 8 ) -
Alkyl, (Cι-C4)-Alkoxy-(Cι-C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(C C6)-Alkyl, N(R76)(R77) oder S02CH3;Alkyl, (-CC 4 ) alkoxy (-CC 4 ) alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (CC 6) -alkyl, N (R76) (R77), or S0 2 CH 3;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (CrC8) -Alkyl;R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl;
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigenR72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are attached form a 5-6 membered one
Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere APD62429PCRing, which in addition to the nitrogen atom still 0-1 more APD62429PC
Heteroatome aus der Gruppe N-(Cι-Cβ) -Alkyl, Sauerstoff und Schwefel beinhalten kann; oderHeteroatoms from the group N- (-C-Cβ) alkyl, may include oxygen and sulfur; or
E, K und R11 zusammen einen Tricyclus bilden, wobei die Ringe unabhängig voneinander gesättigt, teilgesättigt oder ungesättigt und jeweils 3 - 8 Ringatome enthalten können;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;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
3. Verbindungen der Formel I gemäß Anspruch 1 oder 2,3. Compounds of formula I according to claim 1 or 2,
worin bedeuten:in which mean:
R1 , R2 unabhängig voneinander H, (d-C8) -Alkyl, -(CH2)0 -R12, (d- C4)-Alkoxy-(d-C4)-alkyl, CO-(C C8) -Alkyl, -CO-(CH2)0 -R12,R 1, R 2 independently of one another are H, (C 1 -C 8 ) -alkyl, - (CH 2 ) O -R 12, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, CO- (CC 8 ) -alkyl, -CO - (CH 2 ) 0 -R 12,
COCH=CH(R13), COCC(R14), CO-(Cι-C4)-alkyl-S(0)p-(Cι- C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterozyklische Ringsystem zusätzlich substituiert sein kann mit F, (Cι-C6)-Alkyl, 0-(C C8) -Alkyl, (C0-C8)-Alkylen-Aryl, Oxo,COCH = CH (R13), COCC (R14), CO- (C 1 -C 4 ) -alkyl-S (O) p - (C 1 -C 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, in addition to the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group consisting of oxygen and nitrogen and sulfur, where the heterocyclic ring system can additionally be substituted by F, (-CC 6 ) -alkyl, O- (CC 8 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, oxo,
CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(C C6)-Alkyl, N(R31)(R32) oder S02CH3;CO (R26), CON (R27) (R28), hydroxy, COO (R29), N (R30) CO (CC 6) -alkyl, N (R31) (R32), or S0 2 CH 3;
0, 1 , 2, 3, 4;0, 1, 2, 3, 4;
0, 1 , 2; APD62429PC0, 1, 2; APD62429PC
q, r, s unabhängig voneinander 0, 1 , 2, 3;q, r, s are independently 0, 1, 2, 3;
R13, R14 unabhängig voneinander ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl,R 13, R 14, independently of one another, contain a 5-10-membered aromatic ring system which contains a further heteroatoms from the group consisting of nitrogen, oxygen and sulfur, and with F, Cl,
(d-C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann;(C 1 -C 6 ) -alkyl, O- (CC 8 ) -alkyl may be substituted;
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (d-C6) -Alkyl;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, (d-C6)-Alkyl, CO(d-C6)-Alkyl, CO(R33);R18 H, (dC 6) -alkyl, CO (dC 6) -alkyl, CO (R33);
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit demR17 and R18, R21 and R22, R27 and R28, R31 and R32 independently optionally together with the
Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-Cβ) -Alkyl, Sauerstoff und Schwefel beinhalten kann;Nitrogen atom to which they are attached, a 5-6 membered ring, which in addition to the nitrogen atom may contain 0-1 further heteroatoms from the group N- (-C-Cβ) alkyl, oxygen and sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteresR33 is a 5-10 membered aromatic ring system, which is another
Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, 0-(C C8)- Alkyl substituiert sein kann;Containing heteroatom from the group nitrogen, oxygen and sulfur and may be substituted by F, Cl, (dC 6 ) alkyl, 0- (CC 8 ) alkyl;
R12 OH, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, CF3, CN, Oxo, 0-(C C6)-Alkyl, (d- C6)-Alkyl, O-(C0-C8)-Alkylen-Aryl, N(R34)(R35),R 12 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, CF 3 , CN, Oxo, O- (CC 6 ) -alkyl, (C 1 -C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35),
COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t APD62429PCCOCH = CH (R36), (C (R37) (R38)) t (R39), CO (C (R37) (R38)) t APD62429PC
(R39), CO(C C6)-Alkyl, COCOO(d-C6)-Alkyl, COO(R40) und S(0)u (R41) enthalten kann;(R39), (0) u (R41) may contain CO (CC 6) -alkyl, COCOO (dC 6) -alkyl, COO (R40) and S;
0, 1 , 2, 3, 4;0, 1, 2, 3, 4;
0, 1 , 2;0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (CrC8)-Alkyl;R34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl;
R34 und R35 optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;R34 and R35 optionally together with the nitrogen atom to which they are attached, a 5-6 membered ring, which in addition to the nitrogen atom 0-1 further heteroatoms from the group N- (dC 6 ) alkyl, oxygen and sulfur include and optionally substituted with 1 to 2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das ein weiteres Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (C C6)-Alkyl, 0-(d-C8)-Alkyl substituiert sein kann;R36, R39 are independently (C 3 -C 8 ) -cycloalkyl, 5-10 membered aromatic ring system containing another heteroatom from the group consisting of nitrogen, oxygen and sulfur, and with F, Cl, (CC 6 ) -alkyl, 0- (C 1 -C 8 ) -alkyl may be substituted;
R40 H, (C C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-Aryl;R40 H, (CC 8) -alkyl, (C 2 -C 6) alkenyl, (C 0 -C 8) -alkylene-aryl;
R41 (CrC6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, dasR41 (C 1 -C 6 ) alkyl, 5-10 membered aromatic ring system,
0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, 0-(Cι-C8)- Alkyl substituiert sein kann;0-2 contain further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl;
R3 H, (Cι-C6)-Alkyl; APD62429PCR 3 is H, (C 1 -C 6 ) -alkyl; APD62429PC
R4, R5 unabhängig voneinander H, (C C6)-Alkyl, OH, 0-(C C6)-R4, R5 independently of one another are H, (CC 6 ) -alkyl, OH, O- (CC 6 ) -
Alkyl, 0-CO(C C6)-Alkyl;Alkyl, O-CO (CC 6 ) -alkyl;
R6, R7, R8, R9 unabhängig voneinander H, (d-C8)-Alkyl;R6, R7, R8, R9 independently of one another are H, (C 1 -C 8 ) -alkyl;
R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;R6 and R7, R8 and R9 independently of one another optionally oxo;
n, m unabhängig voneinander 0, 1 , 2;n, m are independently 0, 1, 2;
A, B, D, G unabhängig voneinander N, C(R42);A, B, D, G are independently N, C (R42);
R42 H, F, Cl, Br, CF3, CN, 0-(C C6)-Alkyl, (d-C6)-Alkyl, (C3-C8)- Cycloalkyl, (C0-C2) -Alkylen-Aryl, O-(C0-C2)-Alkylen-Aryl,R 42 is H, F, Cl, Br, CF 3 , CN, O- (CC 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 0 -C 2 ) -alkylene Aryl, O- (C 0 -C 2 ) -alkylene-aryl,
N(R43)(R44), S02-CH3, COO-(d-C6)-Alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)N (R43) (R44) S0 2 CH 3, COO- (dC 6) -alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2 (R50), CO (R51)
R43, R44, R45, R46, R47, R49 unabhängig voneinander H, (d-C8)-Alkyl;R43, R44, R45, R46, R47, R49 independently of one another are H, (C 1 -C 8 ) -alkyl;
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitereR43 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, is 0-1 further
Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;Heteroatoms from the group N- (dC 6 ) alkyl, may include oxygen and sulfur;
R48, R50, R51 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
R10 H, (C C8)-Alkyl; APD62429PCR 10 is H, (CC 8 ) -alkyl; APD62429PC
X N(R52), O, eine Bindung, C=C, C(R53)(R54), C(R55)(R56)0;X N (R52), O, a bond, C = C, C (R53) (R54), C (R55) (R56) O;
R52, R53, R54, R55, R56 unabhängig voneinander H, (Cι-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclischeE 3-8-membered bivalent carbo- or heterocyclic
Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, CF3, N02, OH, CN, 0-(C C6)-Alkyl, (d-C6)-Alkyl, (C0-C8)-Alkylen-Ring structure with 0-4 heteroatoms from the group N, O and S, which optionally have substituents from the group H, F, Cl, CF 3 , NO 2 , OH, CN, O- (CC 6 ) -alkyl, (dC 6 ) Alkyl, (C 0 -C 8 ) -alkylene
Aryl, O-(C0-C8)-Alkylen-Aryl, N(R57)(R58), S02-CH3, COO- (d-C6)-Alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;Aryl, O- (C 0 -C 8 ) -alkylene-aryl, N (R 57) (R 58), SO 2 -CH 3 , COO- (dC 6 ) -alkyl, CON (R59) (R60), N (R61 ) CO (R62), N (R63) S0 2 (R64), CO (R65) bear and can be mono- or bicyclic;
R57, R58, R59, R60, R61 , R63 unabhängig voneinander H, (C C8)-Alkyl;R57, R58, R59, R60, R61, R63 independently of one another are H, (CC 8 ) -alkyl;
R57 und R58, R59 und R60 unabhängig voneinander optional zusammen mit demR57 and R58, R59 and R60 independently of each other optionally together with the
Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;Nitrogen atom to which they are attached, a 5-6 membered ring, which in addition to the nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) alkyl, oxygen and sulfur;
R62, R64, R65 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
K eine Bindung, O, CH20, N(R66), (C(R69)(R70))V, C≡C;K is a bond, O, CH 2 O, N (R66), (C (R69) (R70)) V , C≡C;
v 1 , 2; APD62429PCv 1, 2; APD62429PC
R66, R68, R69, R70 unabhängig voneinander H, (Cι-C8)-Alkyl;R66, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (d-C8)-Alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C3-C8)-Alkenyl, ein 3 bis 10-gliedriger mono-, bi- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, N02, CN, (d-C6)-Alkyl, 0-(d-C8)-Alkyl, (d-C4)-Alkoxy-(d- C4)-alkyl, (C0-C8)-Alkylen-Aryl, Oxo, CO(R71),R11 H, (DC 8) alkyl, (dC 4) alkoxy- (dC 4) alkyl, (C 3 -C 8) alkenyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which May contain from 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, which ring system may additionally be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 ) alkyl, O- (dC 8) -alkyl, (dC 4) alkoxy- (dC 4) alkyl, (C 0 -C 8) -alkylene-aryl, oxo, CO (R71),
CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(C C6)- Alkyl, N(R76)(R77) oder S02CH3;CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (CC 6) - alkyl, N (R76) (R77), or S0 2 CH 3;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (d-C8)-Alkyl;R71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl;
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitereR72 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, is 0-1 further
Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann.Heteroatoms from the group N- (dC 6 ) alkyl, oxygen and sulfur may include.
4. Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass4. Compounds of the formula I according to one of claims 1 to 3, characterized in that
A, B, D, G unabhängig voneinander N oder C(R42) bedeuten und die Gesamtzahl der Stickstoffatome in diesem Ring 0-2 beträgt.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.
5. Verbindungen der Formel I, gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass APD62429PC5. Compounds of formula I, according to one of claims 1 to 4, characterized in that APD62429PC
n 1 und m 1 oder 2 bedeuten.n is 1 and m is 1 or 2.
6. Verbindungen der Formel I nach Anspruch 1 ,6. Compounds of formula I according to claim 1,
worin bedeuten:in which mean:
R1 , R2 unabhängig voneinander H, (C C8)-Alkyl, -(CR78R79)0 -R12,R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR78R79) 0 -R 12,
(d-C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl, CO-(C C8)- Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(C C4) -alkyl,(dC 4) alkoxy- (Cι-C4) alkyl, (C 3 -C 8) -alkenyl, CO- (CC 8) - alkyl, -CO- (CH 2) 0 -R12, CO-aryloxy- (CC 4 ) -alkyl,
COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18),COCH = CH (R13), COCC (R14), CO (C (R15) (R16)) q N (R17) (R18),
CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (CrC6)-Alkyl, 0-(C C4)-Alkyl, (C C4)-Alkoxy-CO (C ( R 19) ( R 20)) r CON ( R 21) ( R 22), CO (C ( R 23) ( R 24)) s O (R 25); 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, in addition to the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3, (C r C6) alkyl, 0- (CC 4) alkyl, (CC 4) alkoxy
(d-C4)-alkyl, Hydroxy-(C C4)-alkyl, (C0-C2)-Alkylen-aryl, Oxo, CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(d-C6)-Alkyl, N(R31)(R32) oder S02CH3;(C 1 -C 4 ) -alkyl, hydroxy- (CC 4 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28), hydroxy, COO (R 29), N (R30) CO (dC 6) -alkyl, N (R31) (R32), or S0 2 CH 3;
o 0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
q, r unabhängig voneinander 1 , 2, 3;q, r are independently 1, 2, 3;
s 0, 1 , 2, 3, 4;s 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander einen Phenylring, der 0-1 Stickstoffatome enthalten kann; APD62429PCR 13, R 14 are each independently a phenyl ring which may contain 0-1 nitrogen atoms; APD62429PC
R15, R16, R17, R19, R20, R21 , R22, R23, R24, R25 , R26, R27, R28, R29, R30, R31 , R32 unabhängig voneinander H, (CrCβJ-Alkyl;R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another are H, (CrCβJ-alkyl;
R18 H, (C C6)-Alkyl, CO(d-C6)-Alkyl, CO(R33); oderR18 H, (CC 6) -alkyl, CO (dC 6) -alkyl, CO (R33); or
R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigenR17 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 one
Ring, welcher ausser dem Stickstoffatom noch 0-1 weitereRing, which in addition to the nitrogen atom still 0-1 more
Heteroatome aus der Gruppe N-(Cι-C6) -Alkyl, Sauerstoff undHeteroatoms from the group N- (-CC 6 ) alkyl, oxygen and
Schwefel beinhalten kann;May include sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteresR33 is a 5-10 membered aromatic ring system, which is another
Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten kann und mit F, Cl, (d-C6) -Alkyl, 0-(C C8)-Alkyl substituiert sein kann;Heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (dC 6 ) alkyl, 0- (CC 8 ) alkyl;
R12 OH, 0-(d-C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(C C6)-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 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3, CN, Oxo, 0-(d-C6)-Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, (CAlkyl, 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, 0- (dC 6) alkyl, (Cι-C4) alkoxy (dC 4) alkyl, (C
C6)-Alkyl, O-(C0-C8)-Alkylen-Aryl, (C0-C8)-Alkylen-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C C6)-Alkyl, COCOO(C C6)- Alkyl, COO(R40), S(0)U (R41) enthalten kann;C 6 ) -alkyl, O- (C 0 -C 8 ) -alkylene-aryl, (C 0 -C 8 ) -alkylene-aryl, N (R 34) (R 35), COCH = CH (R 36), (C ( R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (CC 6) -alkyl, COCOO (CC 6) - alkyl, COO (R40), S (0 ) U (R41);
0, 1 , 2, 3, 4, 5, 6; APD62429PC0, 1, 2, 3, 4, 5, 6; APD62429PC
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (Cι-C8)-Alkyl; oderR34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R34 und R35 optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer demR34 and R35 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring other than the
Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1-2 Oxo-Gruppen substituiert sein kann;Nitrogen atom may contain 0-1 further heteroatoms from the group N- (dC 6 ) alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (Cι-C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann;R36, R39 independently of one another contain (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, (Cι-C6) - Alkyl, O- (CC 8 ) -alkyl may be substituted;
R40 H, (d-C8) -Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-aryl;R 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl;
R41 (Cι-C6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, dasR41 (-CC 6 ) alkyl, 5-10 membered aromatic ring system, the
0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-C6)-Alkyl, 0-(Cι-C8)- Alkyl substituiert sein kann;0-2 contain further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C 1 -C 6 ) -alkyl, O- (C 1 -C 8 ) -alkyl;
R78, R79 unabhängig voneinander H, (C C8) -Alkyl, Hydroxy- (d-C4)-R78, R79 independently of one another are H, (CC 8 ) -alkyl, hydroxy (dC 4 ) -
Alkyl, OH, (d-C4)-Alkoxy-(CrC4)-alkyl;Alkyl, OH, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl;
R80, R81 unabhängig voneinander H, (d-C8) -Alkyl;R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl;
R3 H, (C C6)-Alkyl;R 3 is H, (CC 6 ) -alkyl;
R4, R5 unabhängig voneinander H, (d-C6)-Alkyl, OH, 0-(C C6)-R4, R5 independently of one another are H, (C 1 -C 6 ) -alkyl, OH, O- (CC 6 ) -
Alkyl, 0-CO(Cι-C6)-Alkyl, S-(C C6)-Alkyl; APD62429PCAlkyl, O-CO (C 1 -C 6 ) -alkyl, S- (CC 6 ) -alkyl; APD62429PC
R6, R7, R8, R9R6, R7, R8, R9
H; oder R6 und R7, R8 und R9 unabhängig voneinander optional Oxo;H; or R6 and R7, R8 and R9 independently of one another optionally oxo;
11
m 1 oder 2;m is 1 or 2;
A, B, D, G unabhängig voneinander N, C(R42); oder die Gruppen A und B oder D und G sind jeweils C(R42) und bilden gemeinsam eine ortho-Phenyleneinheit, so dass sich insgesamt ein 1 ,4-bisubstituiertes Naphthalinsystem ergibt;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;
R42 H, F, Cl, Br, CF3, CN, 0-(d-C6)-Alkyl, 0-(d-C4)-Alkoxy-(d-R 42 is H, F, Cl, Br, CF 3 , CN, O- (dC 6 ) -alkyl, 0- (dC 4 ) -alkoxy- (d-)
C4)-alkyl, S-(C C6) -Alkyl, (d-C6) -Alkyl, (C0-C8)-Alkylen-Aryl, O-(C0-C8)-Alkylen-Aryl, N(R43)(R44), S02-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)X-C 4 ) -alkyl, S- (CC 6 ) -alkyl, (dC 6 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl, O- (C 0 -C 8 ) -alkylene-aryl, N ( R43) (R44) S0 2 -CH 3, CON (R45) (R46), N (R47) CO (R48), CO (R51), - (CR84R85) X -
0(R86);0 (R86);
R43, R44, R45, R46, R47 unabhängig voneinander H, (Cι-C8)-Alkyl; oderR43, R44, R45, R46, R47 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R43 und R44, R45 und R46 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoff atom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6) -Alkyl, Sauerstoff undR43 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, in addition to the nitrogen atom, contains 0-1 further heteroatoms from the group N- (dC 6 ) - Alkyl, oxygen and
Schwefel beinhalten kann; APD62429PCMay include sulfur; APD62429PC
R48, R50, R51 unabhängig voneinander H, (d-C8)-Alkyl, Aryl; R84, R85 H;R48, R50, R51 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl; R84, R85 H;
R86 H, (d-Ce)-Alkyl;R86 is H, (d-Ce) -alkyl;
x 0, 1 , 2;x 0, 1, 2;
R10 H, (d-Cs)-Alkyl;R 10 is H, (C 1 -C 5) -alkyl;
X N(R52), eine Bindung, C=C, C(R53)(R54), C(R55)(R56)0,X N (R52), a bond, C = C, C (R53) (R54), C (R55) (R56) O,
C≡C, CH2-CH2, YCH2;C≡C, CH 2 -CH 2 , YCH 2 ;
Y O, S, N(R89);Y O, S, N (R89);
R89 H, (Cι-C8)-Alkyl;R89 is H, (C 1 -C 8 ) -alkyl;
R52, R53, R54, R55, R56 unabhängig voneinander H, (d-C8)-AlkylR52, R53, R54, R55, R56 independently of one another are H, (C 1 -C 8 ) -alkyl
E 3-8 gliedrige bivalente carbo- oder heterocyclischeE 3-8-membered bivalent carbo- or heterocyclic
Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(C C6)-Alkyl, 0-(d-C4)-Alkoxy-(C C4)-alkyl, S-(d-C6)-Alkyl, (d-C6)-Alkyl, (C2-C6)-Alkenyl, O-Ring structure with 0-4 heteroatoms from the group N, O and S, which optionally substituents from the group H, F, Cl, Br, OH, CF 3 , N0 2 , CN, OCF 3 , 0- (CC 6 ) alkyl , 0- (dC 4) alkoxy- (CC 4) alkyl, S- (dC 6) alkyl, (dC 6) alkyl, (C 2 -C 6) -alkenyl, O-
(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0- C8)-Alkylen-aryl, O-(C0-C8)-Alkylen-aryl, S-Aryl, N(R57)(R58), S02-CH3, N(R61)CO(R62), N(R63)S02(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;(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) S0 2 CH 3, N (R61) CO (R62), N (R63) S0 2 (R64), CO (R65) and, mono - or may be bicyclic;
R57, R58, R61 , R63 unabhängig voneinander H, (d-C8)-Alkyl; APD62429PCR57, R58, R61, R63 independently of one another are H, (C 1 -C 8 ) -alkyl; APD62429PC
R62, R64, R65 unabhängig voneinander H, (d-C8)-Alkyl, Aryl;R62, R64, R65 independently of one another are H, (C 1 -C 8 ) -alkyl, aryl;
K eine Bindung, 0, OCH2, CH20, S, SO, S02, N(R66),K is a bond, O, OCH 2 , CH 2 O, S, SO, S0 2 , N (R66),
N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C≡C, SCH2, S02CH2;N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C = C, C≡C, SCH 2, S0 2 CH 2;
v 1 , 2, 3, 4;v 1, 2, 3, 4;
R66, R67, R68, R69, R70 unabhängig voneinander H, (Cι-C8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (d-C8)-Alkyl, (d-C4)-Alkoxy-(CrC4)-alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkinyl, ein 3 bis 10-gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (C C6)-Alkyl, 0-(d-C8)-Alkyl, (d- C4)-Alkoxy-(Cι-C4)-alkyl, Hydroxy-(d-C4)-alkyl, (C0-C8)-R11 H, (DC 8) alkyl, (dC 4) alkoxy (CrC 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 of oxygen, nitrogen and sulfur, which ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, ( CC 6) alkyl, 0- (dC 8) -alkyl, (dC 4) alkoxy- (Cι-C4) alkyl, hydroxy (dC 4) alkyl, (C 0 -C 8) -
Alkylen-aryl, Oxo, CO(R71), CON(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oder S02CH3;Alkylene-aryl, oxo, CO (R71), CON (R72) (R73), hydroxy, COO (R74), N (R75) CO (dC 6) -alkyl, N (R76) (R77), or S0 2 CH 3 ;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (CrC8)-Alkyl; oder R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigenR71, 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 form a 5-6 membered one
Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere APD62429PCRing, which in addition to the nitrogen atom still 0-1 more APD62429PC
Heteroatome aus der Gruppe N-(Cι-C6) -Alkyl, Sauerstoff und Schwefel beinhalten kann; oderHeteroatoms from the group N- (-C-C 6 ) alkyl, may include oxygen and sulfur; or
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
7. Verbindungen nach Anspruch 1 oder 6, dadurch gekennzeichnet, dass sie die Formel la aufweisen7. Compounds according to claim 1 or 6, characterized in that they have the formula la
Figure imgf000381_0001
worin bedeuten
Figure imgf000381_0001
in which mean
R1 , R2 unabhängig voneinander H, (C C8) -Alkyl, -(CR78R79)0 -R12,R 1, R 2 independently of one another are H, (CC 8 ) -alkyl, - (CR78R79) 0 -R 12,
(Cι-C4)-Alkoxy-(C C4)-alkyl, oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoffatom 0 bis 2 zusätzliche(C 1 -C 4 ) -Alkoxy- (CC 4 ) alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4 to 10-membered mono-, bi- or spiro-cyclic ring which except Nitrogen atom 0 to 2 additional
Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit (d-C6) -Alkyl, 0-(C C4)-Alkyl, (Cι-C4)-Alkoxy-(d-C4)-alkyl, Hydroxy-(C1-C4)- alkyl, (C0-C2)-Alkylen~aryl, Oxo, CO(R26), CON(R27)(R28),Heteroatoms may include, selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may be additionally substituted with (dC 6 ) alkyl, 0- (CC 4 ) alkyl, (-CC 4 ) alkoxy (dC 4 ) -alkyl, hydroxy- (C 1 -C 4 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl, oxo, CO (R 26), CON (R 27) (R 28),
Hydroxy, N(R31)(R32) oder S02CH3) wobei R1 und R2 nicht beide gleichzeitig CO(R26) sind;Hydroxy, N (R31) (R32), or S0 2 CH 3) wherein R 1 and R 2 are not both CO (R26);
0, 1 , 2, 3, 4;0, 1, 2, 3, 4;
1. 2, 3;1. 2, 3;
0, 1, 2; APD62429PC0, 1, 2; APD62429PC
R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31 , R32 unabhängig voneinander H, (CrC6) -Alkyl; oderR 15, R 16, R 17, R 18, R 23, R 24, R 25, R 26, R 27, R 28, R 31, R 32 independently of one another are H, (C 1 -C 6 ) -alkyl; or
R17 und R18, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(Cι-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann;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 ) alkyl, may include oxygen and sulfur;
R12 OH, 0-(d-C6)-Alkyl, O-(C0-C2)-Alkylen-aryl, CN, S-(C C6)-R 12 is OH, O- (C 1 -C 6 ) -alkyl, O- (C 0 -C 2 ) -alkylene-aryl, CN, S- (CC 6 ) -
Alkyl, 3-12 gliedriger mono-, bi- oder spirocyclischer Ring, der 1 bis 3 Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, OH, CF3, CN, Oxo, (Cι-C6)-Alkyl, (C0-C2)-Alkylen-aryl,Alkyl, 3-12 membered mono-, bi- or spiro-cyclic 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 ) -alkylene-aryl,
N(R34)(R35), COO(R40), CO(C C6) -Alkyl enthalten kann;N (R34) (R35), COO (R40), CO (CC 6) may contain alkyl;
R34, R35 unabhängig voneinander H, (d-C4) -Alkyl;R34, R35 independently of one another are H, (C 1 -C 4 ) -alkyl;
R40 H, (d-C6)-Alkyl, (C0-C2)-Alkylen-aryl;R 40 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl;
R78, R79 unabhängig voneinander H, (C C8) -Alkyl, Hydroxy- (d-C4)- Alkyl, OH, (d -C4) -AI koxy-(d-C4) -alkyl;R78, R79 independently of one another H, (CC 8) alkyl, hydroxy (dC 4) - alkyl, OH, (d-C4) alkoxy- -AI (dC 4) alkyl;
R42, R42' unabhängig voneinander H, F, Cl, Br, CF3, CN, (d-C6)-Alkyl;R 42, R 42 'independently of one another are H, F, Cl, Br, CF 3 , CN, (C 1 -C 6 ) -alkyl;
R10 H, (d-Cs)-Alkyl;R 10 is H, (C 1 -C 5) -alkyl;
X N(R52), eine Bindung, C=C, C(R53)(R54), CH2CH2; APD62429PCXN (R52), a bond, C = C, C (R53) (R54), CH 2 CH 2; APD62429PC
R52, R53, R54 unabhängig voneinander H, (Cι-Cs)-AlkylR52, R53, R54 independently of one another are H, (-CCs) -alkyl
E 5-7 gliedrige bivalente carbo- oder heterocyclische Ringstruktur mit 0-3 Heteroatomen aus der Gruppe N, O undE 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group N, O and
S, die optional Substituenten aus der Gruppe H, F, Cl, Br, CF3, OH, CN, OCF3, N02, 0-(d-C6)-Alkyl, (d-C6)-Alkyl, S02-CH3, CO(R65) tragen kann;S, which optionally substituents from the group H, F, Cl, Br, CF 3 , OH, CN, OCF 3 , N0 2 , 0- (dC 6 ) alkyl, (dC 6 ) alkyl, S0 2 -CH 3 , CO (R65) can carry;
R65 H, (Cι-C8) -Alkyl;R65 is H, (C 1 -C 8 ) -alkyl;
K eine Bindung, O, OCH2, CH20, S, S02, N(R66), N(R67)CO,K is a bond, O, OCH 2 , CH 2 O, S, SO 2 , N (R66), N (R67) CO,
CON(R68), (C(R69)(R70))V, CO, C≡C, SCH2, S02CH2;CON (R68), (C (R69) (R70)) v, CO, C≡C, SCH 2, S0 2 CH 2;
v 1 , 2, 3;v 1, 2, 3;
R66, R67, R68, R69, R70 unabhängig voneinander H, (C C8) -Alkyl;R66, R67, R68, R69, R70 are independently H, (CC 8) alkyl;
R11 (C C8)-Alkyl, (Cι-C4)-Alkoxy-(CrC4)-alkyl, ein 3 bis 10- gliedriger mono-, bi-, tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (C C6)-Alkyl, 0-(C C8)-Alkyl, Oxo, CO(R71), Hydroxy,R 11 (CC 8 ) -alkyl, (C 1 -C 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may contain 0 to 4 heteroatoms, 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, 0- (CC 8 ) alkyl, oxo, CO (R71 ), Hydroxy,
N(R75)CO(d-C6)-Alkyl, oder S02CH3;N (R75) CO (dC 6) alkyl, or S0 2 CH 3;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (CrC8)-Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R72 und R73, R76 und R77 APD62429PCR72 and R73, R76 and R77 APD62429PC
unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten kann; oderindependently of one another optionally together with the nitrogen atom to which they are attached, 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 1 -C 6 ) -alkyl, oxygen and sulfur; or
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
8. Verbindungen nach Anspruch 1 oder 6, dadurch gekennzeichnet, dass sie die Formel Ib aufweisen8. Compounds according to claim 1 or 6, characterized in that they have the formula Ib
Figure imgf000384_0001
Figure imgf000384_0001
worin bedeuten:in which mean:
R1 , R2 unabhängig voneinander H, (d-C8)-Alkyl, -(CR78R79)0 -R12,R 1, R 2 independently of one another are H, (C 1 -C 8 ) -alkyl, - (C-R 7 R 7) 0 -R 12,
(Cι-C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl, CO-(C C8)- Alkyl, -CO-(CH2)0 -R12, CO-Aryloxy-(d-C4)-alkyl, COCH=CH(R13), COCC(R14), 0(C(R15)(R16))qN(R17)(R18), (Cι-C4) alkoxy- (Cι-C4) alkyl, (C 3 -C 8) -alkenyl, CO- (CC 8) - alkyl, -CO- (CH 2) 0 -R12, CO- Aryloxy (dC 4 ) alkyl, COCH = CH (R 13), COCC (R 14), O (C (R 15) (R 16)) q N (R 17) (R 18),
CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); oder R1 und R2 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 4 bis 10-gliedrigen mono-, bi- oder spirocyclischen Ring welcher ausser dem Stickstoff atom 0 bis 2 zusätzliche Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das heterocyclische Ringsystem zusätzlich substituiert sein kann mit F, Cl, CF3, (C C6) -Alkyl, 0-(d-C4)-Alkyl, (C C4)-Alkoxy- (d-C4)-alkyl, Hydroxy-(d-C4)-alkyl, (C0-C2)-Alkylen-aryl, Oxo, APD62429PCCO (C ( R 19) ( R 20)) r CON ( R 21) ( R 22), CO (C ( R 23) ( R 24)) s O (R 25); or R 1 and R 2, 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 2 additional heteroatoms selected from the group consisting of oxygen, Nitrogen and sulfur, where the heterocyclic ring system can additionally be substituted by F, Cl, CF 3 , (CC 6 ) -alkyl, O- (C 1 -C 4 ) -alkyl, (CC 4 ) -alkoxy- (C 1 -C 4 ) -alkyl, Hydroxy (C 1 -C 4 ) -alkyl, (C 2 -C 2 ) -alkylene-aryl, oxo, APD62429PC
CO(R26), CON(R27)(R28), Hydroxy, COO(R29), N(R30)CO(C C6)-Alkyl, N(R31)(R32) oder S02CH3, wobei R1 und R2 nicht beide gleichzeitig CO(R26) sind;CO (R26), CON (R27) (R28), hydroxy, COO (R29), N (R30) CO (CC 6) -alkyl, N (R31) (R32), or S0 2 CH 3, wherein R1 and R2 are not both are simultaneously CO (R26);
o 0, 1 , 2, 3, 4, 5, 6;0, 1, 2, 3, 4, 5, 6;
q, r unabhängig voneinander 1 , 2, 3;q, r are independently 1, 2, 3;
s 0, 1 , 2, 3, 4;s 0, 1, 2, 3, 4;
R13, R14 unabhängig voneinander einen Phenylring, der 0-1 Stickstoffatome enthalten kann;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 unabhängig voneinander H, (CrCβ)-Alkyl;R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another are H, (CrCβ) -alkyl;
R18 H, (d-C6) -Alkyl, CO(C C6)-Alkyl, CO(R33); oder R17 und R18, R21 und R22, R27 und R28, R31 und R32 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6) -Alkyl, Sauerstoff und Schwefel beinhalten kann;R 18 is H, (C 1 -C 6 ) alkyl, CO (CC 6 ) alkyl, CO (R 33); 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, a 5-6 membered ring, which in addition to the nitrogen atom still 0-1 further heteroatoms from the Group N- (dC 6 ) alkyl, may include oxygen and sulfur;
R33 ein 5-10 gliedriges aromatisches Ringsystem, das ein weiteresR33 is a 5-10 membered aromatic ring system, which is another
Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten kann und mit F, Cl, (d-C6)-Alkyl, 0-(C C8)-Alkyl substituiert sein kann; APD62429PCHeteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (dC 6 ) alkyl, 0- (CC 8 ) alkyl; APD62429PC
R12 OH, 0-(d-C6)-Alkyl, O-(C0-C8)-Alkylen-aryl, CN, S-(C C6)-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 gliedriger mono-, bi- oder spirocyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, OH, CF3,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, 0-(d-C6)-Alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C C6)-Alkyl, O-(C0-C8)-Alkylen-Aryl, (C0-C8)-Alkylen-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(CrC6)-Alkyl, COCOO(C C6)- Alkyl, COO(R40), S(0)u (R41) enthalten kann;CN, oxo, 0- (dC 6) alkyl, (dC 4) alkoxy- (dC 4) alkyl, (CC 6) -alkyl, O- (C 0 -C 8) -alkylene-aryl, (C 0 -C 8 ) -alkylene-aryl, N (R34) (R35), COCH = CH (R36), (C (R37) (R38)) t (R39), CO (C (R37) (R38)) t (R39), CO (C r C 6 ) alkyl, COCOO (CC 6 ) alkyl, COO (R 40), S (O) u (R 41);
t 0, 1 , 2, 3, 4, 5, 6;t 0, 1, 2, 3, 4, 5, 6;
u 0, 1 , 2;u 0, 1, 2;
R34, R35, R37, R38 unabhängig voneinander H, (CrC8) -Alkyl; oderR34, R35, R37, R38 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R34 und R35 optional zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher außer demR34 and R35 optionally together with the nitrogen atom to which they are attached form a 5-6 membered ring other than the
Stickstoffatom noch 0-1 weitere Heteroatome aus der GruppeNitrogen atom still 0-1 further heteroatoms from the group
N-(d-C6)-Alkyl, Sauerstoff und Schwefel beinhalten und optional mit 1 -2 Oxo-Gruppen substituiert sein kann;N- (dC 6 ) alkyl, oxygen and sulfur may be substituted and optionally substituted with 1 -2 oxo groups;
R36, R39 unabhängig voneinander (C3-C8)-Cycloalkyl, 5-10 gliedriges aromatisches Ringsystem, das 0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (d-Ce)-Alkyl, 0-(d-C8)-Alkyl substituiert sein kann;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, (d-Ce) alkyl , 0- (C 1 -C 8 ) -alkyl may be substituted;
R40 H, (Cι-C8)-Alkyl, (C2-C6)-Alkenyl, (C0-C8)-Alkylen-aryl; APD62429PCR 40 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 0 -C 8 ) -alkylene-aryl; APD62429PC
R41 (CrC6)-Alkyl, 5-10 gliedriges aromatisches Ringsystem, dasR41 (C 1 -C 6 ) alkyl, 5-10 membered aromatic ring system,
0-2 weitere Heteroatome aus der Gruppe Stickstoff, Sauerstoff und Schwefel enthalten und mit F, Cl, (C C6)-Alkyl, 0-(C C8)- Alkyl substituiert sein kann;0-2 contain further heteroatoms from the group consisting of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (CC 6 ) alkyl, 0- (CC 8 ) -alkyl;
R78, R79 unabhängig voneinander H, (Cι-C8) -Alkyl, Hydroxy-(Cι-C4)- Alkyl, OH, (Cι-C4)-Alkoxy-(d-C4)-alkyl;R78, R79 independently of one another H, (Cι-C8) alkyl, hydroxy (Cι-C4) - alkyl, OH, (Cι-C4) alkoxy (dC 4) alkyl;
R80, R81 unabhängig voneinander H, (d-C8)-Alkyl;R80, R81 independently of one another are H, (C 1 -C 8 ) -alkyl;
R10 H, (C1-C8)-Alkyl:R 10 H, (C 1 -C 8) -alkyl:
E 3-8 gliedrige bivalente carbo- oder heterocyclischeE 3-8-membered bivalent carbo- or heterocyclic
Ringstruktur mit 0-4 Heteroatomen aus der Gruppe N, O und S, die optional Substituenten aus der Gruppe H, F, Cl, Br, OH,Ring structure with 0-4 heteroatoms from the group N, O and S, which optionally have substituents from the group H, F, Cl, Br, OH,
CF3, N02, CN, OCF3, 0-(C C6)-Alkyl, 0-(Cι-C4)-Alkoxy-(d- C4)-alkyl, S-(CrC6)-Alkyl, (d-C6) -Alkyl, (C2-C6)-Alkenyl, O- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, (C2-C6)-Alkinyl, (C0- C8)-Alkylen-aryl, O-(C0-C8)-Alkylen-aryl, S-Aryl, N(R57)(R58), S02-CH3, N(R61)CO(R62), N(R63)S02(R64), CO(R65) tragen und mono- oder bicyclisch sein kann;CF 3, N0 2, CN, OCF 3, 0- (CC 6) alkyl, 0- (Cι-C4) alkoxy (d- C4) alkyl, S- (C r C6) alkyl , (C 1 -C 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 (R 57) (R 58), SO 2 -CH 3 , N (R 61) CO ( R62), N (R63) S0 2 (R64), CO (R65) and may be mono- or bicyclic;
R57, R58, R61 , R63 unabhängig voneinander H, (CrC8) -Alkyl;R 57, R 58, R 61, R 63 independently of one another are H, (C 1 -C 8 ) -alkyl;
R62, R64, R65 unabhängig voneinander H, (C C8)-Alkyl, Aryl;R62, R64, R65 independently of one another are H, (CC 8 ) -alkyl, aryl;
K eine Bindung, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C≡C,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,
SCH2, S02CH2; APD62429PCSCH 2 , SO 2 CH 2 ; APD62429PC
v 1 , 2, 3, 4;v 1, 2, 3, 4;
R66, R67, R68, R69, R70 unabhängig voneinander H, (d-C8)-Alkyl;R66, R67, R68, R69, R70 independently of one another are H, (C 1 -C 8 ) -alkyl;
R11 H, (C C8)-Alkyl, (d-C4)-Alkoxy-(Cι-C4)-alkyl, (C3-C8)-Alkenyl,R11 H, (CC 8) -alkyl, (dC 4) alkoxy- (Cι-C4) alkyl, (C 3 -C 8) alkenyl,
(C3-C8)-Alkinyl, ein 3 bis 10-gliedriger mono-, bi-; tri- oder spirocyclischer Ring, welcher 0 bis 4 Heteroatome beinhalten kann, ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel, wobei das Ringsystem zusätzlich substituiert sein kann mit F, Cl, Br, CF3, CN, (Cι-C6)-Alkyl, 0-(Cι-C8)-Alkyl, (d- C4)-Alkoxy-(d-C4)-alkyl, Hydroxy-(d-C4)-alkyl, (C0-C8)- Alkylen-aryl, Oxo, CO(R71), C0N(R72)(R73), Hydroxy, COO(R74), N(R75)CO(d-C6)-Alkyl, N(R76)(R77) oder S02CH3, SCF3;(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, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C 1 -C 6 ) - alkyl, 0- (Cι-C8) alkyl, (dC 4) alkoxy- (dC 4) alkyl, hydroxy (dC 4) alkyl, (C 0 -C 8) - alkylene-aryl, oxo, CO (R71), C0N (R72) (R73), hydroxy, COO (R74), N (R75) CO (dC 6) -alkyl, N (R76) (R77), or S0 2 CH 3, SCF 3;
R71 , R72, R73, R74, R75, R76, R77 unabhängig voneinander H, (d-C8)-Alkyl; oderR71, R72, R73, R74, R75, R76, R77 independently of one another are H, (C 1 -C 8 ) -alkyl; or
R72 und R73, R76 und R77 unabhängig voneinander optional zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, welcher ausser dem Stickstoffatom noch 0-1 weitere Heteroatome aus der Gruppe N-(d-C6) -Alkyl, Sauerstoff undR72 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 , Oxygen and
Schwefel beinhalten kann;May include sulfur;
deren N-Oxide sowie deren physiologisch verträgliche Salze.their N-oxides and their physiologically acceptable salts.
9. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem der Ansprüche 1 bis 8. APD62429PC9. A medicament comprising one or more of the compounds according to any one of claims 1 to 8. APD62429PC
10. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem der Ansprüche 1 bis 8 und einen oder mehrere anorektische Wirkstoffe.10. A medicament containing one or more of the compounds according to any one of claims 1 to 8 and one or more anorectic agents.
11. Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Anwendung als Medikament zur Prophylaxe oder Behandlung der Obesitas.11. Compounds of the formula I according to any one of claims 1 to 8 for use as a medicament for the prophylaxis or treatment of obesity.
12. Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Anwendung als Medikament zur Prophylaxe oder Behandlung des Typ II Diabetes.12. Compounds of the formula I according to any one of claims 1 to 8 for use as a medicament for the prophylaxis or treatment of type II diabetes.
13. Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 in13. Compounds of formula I according to any one of claims 1 to 8 in
Kombination mit mindestens einem weiteren anorektischen Wirkstoff zur Anwendung als Medikament zur Prophylaxe oder Behandlung der Obesitas.Combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of obesity.
14. Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 in14. Compounds of formula I according to any one of claims 1 to 8 in
Kombination mit mindestens einem weiteren anorektischen Wirkstoff zur Anwendung als Medikament zur Prophylaxe oder Behandlung der des Typ II Diabetes.Combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of type II diabetes.
15. Verfahren zur Herstellung eines Arzneimittels enthaltend eine oder mehrere der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass der Wirkstoff mit einem pharmazeutisch geeigneten Träger vermischt wird und diese Mischung in eine für die Verabreichung geeignete Form gebracht wird.15. A process for preparing a pharmaceutical composition comprising one or more of the compounds of the formula I according to any one of claims 1 to 8, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture is brought into a suitable form for administration.
16. Verwendung der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Herstellung eines Medikaments zur Gewichtsreduktion bei Säugetieren.16. Use of the compounds of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for weight loss in mammals.
17. Verwendung der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung der Obesitas. APD62429PC17. Use of the compounds of the formula I according to any one of claims 1 to 8 for the manufacture of a medicament for the prophylaxis or treatment of obesity. APD62429PC
18. Verwendung der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung des Typ II Diabetes.18. Use of the compounds of the formula I according to any one of claims 1 to 8 for the manufacture of a medicament for the prophylaxis or treatment of type II diabetes.
19. Verwendung der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 zur Herstellung eines Medikaments zur Behandlung von Störungen des Empfindens und anderer psychiatrischen Indikationen, sowie zur Behandlung von Störungen assoziiert mit dem zirkadianen Rhythmus und zur Behandlung von Drogenmissbrauch.19. Use of the compounds of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of disorders of sensation and other psychiatric indications, as well as for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.
20. Verwendung der Verbindungen der Formel I gemäß einem der Ansprüche 1 bis 8 als MCH Antagonisten. 20. Use of the compounds of the formula I according to any one of claims 1 to 8 as MCH antagonists.
PCT/EP2004/001342 2003-02-14 2004-02-13 Substituted n-arylheterocycles, method for production and use thereof as medicaments WO2004072025A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP04710808A EP1597228A2 (en) 2003-02-14 2004-02-13 Substituted n-arylheterocycles, method for production and use thereof as medicaments
BRPI0407504-8A BRPI0407504A (en) 2003-02-14 2004-02-13 substituted n-aryl heterocycles, process for their preparation and use as medicaments
JP2006501827A JP2006517563A (en) 2003-02-14 2004-02-13 Substituted N-aryl heterocyclic compounds, methods for their preparation and their use as pharmaceuticals
AU2004212145A AU2004212145B2 (en) 2003-02-14 2004-02-13 Substituted N-arylheterocycles, method for production and use thereof as medicaments
MXPA05008449A MXPA05008449A (en) 2003-02-14 2004-02-13 Substituted n-arylheterocycles, method for production and use thereof as medicaments.
CA002516118A CA2516118A1 (en) 2003-02-14 2004-02-13 Substituted n-arylheterocycles, method for production and use thereof as medicaments
NZ541823A NZ541823A (en) 2003-02-14 2004-02-13 Substituted N-aryl heterocycles, method for production and uses thereof as medicaments
YUP-2005/0666A RS20050666A (en) 2003-02-14 2004-02-13 Substituted n- arylheterocycles, method for production and use thereof as medicaments
TNP2005000194A TNSN05194A1 (en) 2003-02-14 2005-08-12 Substituted n-arylheterocycles, method for production and use thereof as medicaments
HR20050710A HRP20050710A2 (en) 2003-02-14 2005-08-12 Substituted n-arylheterocycles, method for production and use thereof as medicaments
NO20054220A NO20054220L (en) 2003-02-14 2005-09-12 Substituted N-aryl heterocycles, process for their preparation and their use as a drug

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10306250.5 2003-02-14
DE10306250A DE10306250A1 (en) 2003-02-14 2003-02-14 Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals

Publications (2)

Publication Number Publication Date
WO2004072025A2 true WO2004072025A2 (en) 2004-08-26
WO2004072025A3 WO2004072025A3 (en) 2004-12-23

Family

ID=32841665

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/001342 WO2004072025A2 (en) 2003-02-14 2004-02-13 Substituted n-arylheterocycles, method for production and use thereof as medicaments

Country Status (29)

Country Link
EP (1) EP1597228A2 (en)
JP (1) JP2006517563A (en)
KR (1) KR20050101215A (en)
CN (1) CN100506792C (en)
AR (1) AR044496A1 (en)
AU (1) AU2004212145B2 (en)
BR (1) BRPI0407504A (en)
CA (1) CA2516118A1 (en)
CO (1) CO5690548A2 (en)
DE (1) DE10306250A1 (en)
EC (1) ECSP055967A (en)
HR (1) HRP20050710A2 (en)
MA (1) MA27735A1 (en)
MX (1) MXPA05008449A (en)
MY (1) MY139102A (en)
NO (1) NO20054220L (en)
NZ (1) NZ541823A (en)
OA (1) OA13027A (en)
PA (1) PA8595901A1 (en)
PE (1) PE20040952A1 (en)
PL (1) PL378065A1 (en)
RS (1) RS20050666A (en)
RU (1) RU2005128551A (en)
TN (1) TNSN05194A1 (en)
TW (1) TW200510297A (en)
UA (1) UA86760C2 (en)
UY (1) UY28186A1 (en)
WO (1) WO2004072025A2 (en)
ZA (1) ZA200506369B (en)

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009988A1 (en) * 2003-07-24 2005-02-03 Euro-Celtique S.A. Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
WO2005063239A1 (en) * 2003-12-23 2005-07-14 Boehringer Ingelheim International Gmbh 3-(4-piperidine-1ylmethyl-phenyl)-propion acid-phenylamide-derivatives and related compounds used in the form of mch antagonists (melanine concentrating hormone) for treating eating disorders
WO2005070925A1 (en) * 2004-01-25 2005-08-04 Sanofi-Aventis Deutschland Gmbh Aryl substituted heterocycles, method for production and use thereof as medicaments
WO2006010082A1 (en) * 2004-07-08 2006-01-26 Arqule, Inc. 1,4-disubstituted naphtalenes as inhibitors of p38 map kinase
WO2006022442A1 (en) * 2004-08-24 2006-03-02 Santen Pharmaceutical Co., Ltd. Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity
WO2006038680A1 (en) * 2004-10-01 2006-04-13 Banyu Pharmaceutical Co.,Ltd 2-arylcarboxamide-nitrogeneous heterocycle compound
EP1657240A1 (en) * 2003-08-18 2006-05-17 Fujifilm Finechemicals Co., Ltd. Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both
WO2006054793A1 (en) * 2004-11-19 2006-05-26 The New Industry Research Organization Benzofuran compound and pharmaceutical composition containing the same
EP1846388A1 (en) * 2005-01-25 2007-10-24 Synta Pharmaceuticals Corporation Thiophene compounds for inflammation and immune-related uses
WO2007123269A1 (en) * 2006-04-19 2007-11-01 Astellas Pharma Inc. Azolecarboxamide derivative
WO2007095124A3 (en) * 2006-02-10 2007-11-01 Transtech Pharma Inc Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
EP1867644A1 (en) * 2003-07-24 2007-12-19 Euro-Celtique S.A. Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
WO2008024390A2 (en) 2006-08-24 2008-02-28 Novartis Ag 2- (pyrazin-2-yl) -thiazole and 2- (1h-pyraz0l-3-yl) -thiazole derivatives as well as related compounds as stearoyl-coa desaturase (scd) inhibitors for the treatment of metabolic, cardiovascular and other disorders
WO2008031772A1 (en) * 2006-09-11 2008-03-20 Glaxo Group Limited Azabicyclic compounds as inhibitors of monoamines reuptake
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
WO2008039794A1 (en) * 2006-09-25 2008-04-03 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
JP2008516959A (en) * 2004-10-18 2008-05-22 イーライ リリー アンド カンパニー 1- (Hetero) aryl-3-amino-pyrrolidine derivatives for use as mGluR3 receptor antagonists
JP2008516999A (en) * 2004-10-21 2008-05-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Heterocyclic carbonyl compounds
WO2008048991A3 (en) * 2006-10-18 2008-07-10 Novartis Ag Organic compounds
WO2008122787A1 (en) * 2007-04-05 2008-10-16 Evotec Ag Piperazine compounds for the inhibition of haematopoietic prostaglandin d synthase
WO2008148868A1 (en) * 2007-06-08 2008-12-11 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
EP2023933A2 (en) * 2006-05-08 2009-02-18 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
WO2009027746A1 (en) * 2007-08-31 2009-03-05 Astrazeneca Ab Heterocyclic amides useful for the treatment of cancer and psoriasis
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
WO2009077956A2 (en) * 2007-12-14 2009-06-25 Alla Chem, Llc HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
JP2009526794A (en) * 2006-02-15 2009-07-23 サノフィ−アベンティス Novel amino alcohol-substituted arylthienopyrimidinones, methods for their preparation and their use as pharmaceuticals
JP2009526792A (en) * 2006-02-15 2009-07-23 サノフィ−アベンティス Novel azacyclyl-substituted arylthienopyrimidinones, methods for their preparation and their use as pharmaceuticals
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US7598249B2 (en) 2004-12-30 2009-10-06 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2010101247A1 (en) 2009-03-05 2010-09-10 塩野義製薬株式会社 Cyclohexane derivative having npy y5 receptor antagonism
US7803816B2 (en) 2005-09-30 2010-09-28 Hoffmann-La Roche Inc. MCH receptor antagonists
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
US7902192B2 (en) 2003-05-15 2011-03-08 Arqule, Inc. Inhibitors of P38 and methods of using the same
WO2011060026A1 (en) 2009-11-12 2011-05-19 Jansen Pharmaceutica Nv Piperazinecarboxamide derivative useful as a modulator of fatty acid amide hydrolase (faah)
EP2334181A1 (en) * 2008-09-16 2011-06-22 Merck Sharp & Dohme Corp. Phthalimide derivative metabotropic glutamate r4 ligands
US8173689B2 (en) 2006-04-19 2012-05-08 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US8178672B2 (en) 2004-10-19 2012-05-15 Arqule, Inc. Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 MAP kinase
US8178563B2 (en) 2006-05-05 2012-05-15 Irm Llc Compounds and compositions as hedgehog pathway modulators
US8252937B2 (en) 2007-09-14 2012-08-28 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
US8278307B2 (en) 2006-05-08 2012-10-02 Ariad Pharmaceuticals, Inc. Monocyclic Heteroaryl compounds
US8299101B2 (en) 2007-03-07 2012-10-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive mGluR2-receptor modulators
US8304547B2 (en) 2007-10-24 2012-11-06 Astellas Pharma Inc. Azolecarboxamide compound or salt thereof
WO2012170561A1 (en) * 2011-06-06 2012-12-13 The Scripps Research Institute (T.S.R.I.) N-benzylindole modulators of pparg
US8399493B2 (en) 2004-09-17 2013-03-19 Janssen Pharmaceuticals, Inc. Pyridinone derivatives and their use as positive allosteric modulators of mGluR2-receptors
EP1799667B1 (en) * 2004-09-20 2013-03-20 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US8546396B2 (en) 2009-03-02 2013-10-01 Irm Llc N-(hetero)aryl, 2-(hetero)aryl—substituted acetamides for use as Wnt signaling modulators
US8633197B2 (en) 2007-06-08 2014-01-21 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8697689B2 (en) 2008-10-16 2014-04-15 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
US8835437B2 (en) 2007-06-08 2014-09-16 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8846664B2 (en) 2008-11-12 2014-09-30 Ariad Pharmaceuticals, Inc. Pyrazinopyrazines and derivatives as kinase inhibitors
US8940745B2 (en) 2010-05-03 2015-01-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
US8946228B2 (en) 2007-06-08 2015-02-03 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8957093B2 (en) 2011-06-06 2015-02-17 The Scripps Research Institute N-biphenylmethylindole modulators of PPARG
US9102669B2 (en) 2011-12-06 2015-08-11 Janssen Pharmaceutica Nv Substituted piperidinyl-pyridazinyl derivatives useful as SCD 1 inhibitors
US9107946B2 (en) 2008-06-05 2015-08-18 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist
US9181235B2 (en) 2010-06-29 2015-11-10 Novartis Ag Substituted pyridines for modulating the WNT signaling pathway
CN105101959A (en) * 2012-11-05 2015-11-25 南特知识产权控股有限责任公司 Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
US9238658B2 (en) 2011-12-06 2016-01-19 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as SCD 1 inhibitors
WO2016008011A1 (en) * 2014-07-16 2016-01-21 Novogen ltd Functionalised and substituted indoles as anti-cancer agents
WO2016028971A1 (en) * 2014-08-21 2016-02-25 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors
US9309227B2 (en) 2011-11-22 2016-04-12 The Scripps Research Institute N-biphenylmethylbenzimidazole modulators of PPARG
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US10016394B2 (en) 2014-04-16 2018-07-10 The Scripps Research Institute PPARG modulators for treatment of osteoporosis
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI417095B (en) 2006-03-15 2013-12-01 Janssen Pharmaceuticals Inc 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors
US7759344B2 (en) * 2007-01-09 2010-07-20 Amgen Inc. Bis-aryl amide derivatives and methods of use
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TWI452044B (en) * 2007-06-15 2014-09-11 Mitsubishi Tanabe Pharma Corp Morpholine derivative
KR20100080597A (en) 2007-09-14 2010-07-09 오르토-맥닐-얀센 파마슈티칼스 인코포레이티드 1,3-disubstituted-4-phenyl-1h-pyridin-2-ones
WO2009052068A1 (en) * 2007-10-17 2009-04-23 Sanofi-Aventis Substituted n-phenyl-bipyrrolidine ureas and therapeutic use thereof
PT2212283E (en) * 2007-10-17 2011-11-03 Sanofi Sa Substituted n-phenyl-bipyrrolidine carboxamides and therapeutic use thereof
PT2212282E (en) * 2007-10-17 2012-01-09 Sanofi Sa Substituted n-phenyl-bipyrrolidine carboxamides and therapeutic use thereof
NZ584691A (en) * 2007-10-17 2011-09-30 Sanofi Aventis Substituted n-phenyl-pyrrolidinylmethylpyrrolidine amides and therapeutic use thereof as histamine h3 receptor modulators
EP2220083B1 (en) 2007-11-14 2017-07-19 Janssen Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
JP2012006837A (en) * 2008-09-30 2012-01-12 Mochida Pharmaceut Co Ltd 2-indoleacrylamide analogue
BRPI0921333A2 (en) 2008-11-28 2015-12-29 Addex Pharmaceuticals Sa indole and benzoxazine derivatives as metabotropic glutamate receptor modulators
AR074466A1 (en) * 2008-12-05 2011-01-19 Sanofi Aventis PIPERIDINE ESPIRO PIRROLIDINONA AND PIPERIDINONA REPLACED AND ITS THERAPEUTIC USE IN DISEASES MEDIATED BY THE MODULATION OF H3 RECEPTORS.
US8889674B2 (en) 2009-03-05 2014-11-18 Shionogi & Co., Ltd. Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY153912A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 1, 2, 4,-triazolo[4,3-a[pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
US9452980B2 (en) 2009-12-22 2016-09-27 Hoffmann-La Roche Inc. Substituted benzamides
AR081908A1 (en) * 2010-05-11 2012-10-31 Sanofi Aventis N-HETEROARIL-ESPIROLACTAMA-BIPIRROLIDINAS REPLACED, PREPARATION AND THERAPEUTIC USES OF THE SAME
WO2011143162A1 (en) * 2010-05-11 2011-11-17 Sanofi Substituted n-heteroaryl bipyrrolidine carboxamides, preparation and therapeutic use thereof
JP5968307B2 (en) * 2010-05-11 2016-08-10 サノフイ Substituted phenylcycloalkylpyrrolidine (piperidine) spirolactams and amides, their preparation and therapeutic use
CN103298809B (en) 2010-11-08 2016-08-31 杨森制药公司 1,2,4-triazol [4,3-a] pyridine derivate and the purposes of the positive allosteric modulators as MGLUR2 acceptor thereof
AU2011328195B2 (en) 2010-11-08 2015-04-02 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
PT2649069E (en) 2010-11-08 2015-11-20 Janssen Pharmaceuticals Inc 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MX2014013752A (en) * 2012-05-11 2014-12-08 Abbvie Inc Nampt inhibitors.
US10428029B2 (en) * 2014-09-10 2019-10-01 Epizyme, Inc. Isoxazole carboxamide compounds
CA2996017A1 (en) * 2015-08-28 2017-03-09 Glenmark Pharmaceuticals S.A. Novel carbocyclic compounds as ror gamma modulators
RU2731095C2 (en) 2016-03-17 2020-08-28 Ф. Хоффманн-Ля Рош Аг 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having taar agonist activity
CN108815167B (en) * 2017-05-24 2021-04-13 四川晶华生物科技有限公司 Application of compound in preparing medicine for treating tumor
TW202136238A (en) * 2020-01-06 2021-10-01 大陸商廣東東陽光藥業有限公司 ROR[gamma]T inhibitor, preparation method therefor and use thereof
CN115160269A (en) * 2021-04-02 2022-10-11 北京大学 Arylcarboxamide derivatives as positive allosteric modulators of NMDAR

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462884A1 (en) 1990-06-18 1991-12-27 Adir Et Compagnie TRH derivatives, their preparations and pharmaceutical compositions containing them
WO1997026265A1 (en) 1996-01-17 1997-07-24 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
WO1997041097A2 (en) 1996-12-31 1997-11-06 Dr. Reddy's Research Foundation Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
WO1998008871A1 (en) 1996-08-30 1998-03-05 Novo Nordisk A/S Glp-1 derivatives
WO1999003861A1 (en) 1997-07-16 1999-01-28 Novo Nordisk A/S Fused 1,2,4-thiadiazine derivatives, their preparation and use
WO1999015525A1 (en) 1997-09-19 1999-04-01 Sanofi-Synthelabo Carboxamidothiazole derivatives, preparation, pharmaceutical compositions containing them
WO2000035454A1 (en) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000040569A1 (en) 1999-01-08 2000-07-13 Alizyme Therapeutics Limited 2-amino-benzoxazinone derivatives for the treatment of obesity
WO2000063208A1 (en) 1999-04-16 2000-10-26 Novo Nordisk A/S Substituted imidazoles, their preparation and use
WO2000066585A1 (en) 1999-04-30 2000-11-09 Neurogen Corporation 9H-PYRIMIDO[4,5-b]INDOLE DERIVATIVES: CRF1 SPECIFIC LIGANDS
WO2000071529A1 (en) 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
WO2000071549A1 (en) 1999-05-21 2000-11-30 Knoll Gmbh Thiazoloderivatives and pharmaceutical compositions containing them
WO2000078312A1 (en) 1999-06-18 2000-12-28 Merck & Co., Inc. Arylthiazolidinedione and aryloxazolidinedione derivatives
WO2001009111A1 (en) 1999-07-29 2001-02-08 Eli Lilly And Company Benzofurylpiperazines and benzofurylhomopiperazines: serotonin agonists
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
US6221897B1 (en) 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
US6245744B1 (en) 1998-10-02 2001-06-12 Aventis Pharma Deutschland Gmbh Aryl-substituted propanolamine derivatives, their preparation, pharmaceuticals comprising them, and their use
WO2001083451A1 (en) 2000-04-28 2001-11-08 Asahi Kasei Kabushiki Kaisha Novel bicyclic compounds
WO2001085695A1 (en) 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
WO2001091752A1 (en) 2000-05-30 2001-12-06 Merck & Co., Inc. Melanocortin receptor agonists
WO2002006232A1 (en) 2000-07-17 2002-01-24 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists
US6342512B1 (en) 1999-09-01 2002-01-29 Aventis Pharma Deutschland Gmbh Sulfonylcarboxamide derivatives, process for their preparation and their use as pharmaceuticals
WO2002042271A2 (en) 2000-11-21 2002-05-30 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
WO2002098839A1 (en) 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides and process for preparation thereof
DE10142734A1 (en) 2001-08-31 2003-03-27 Aventis Pharma Gmbh New (((oxazolylalkyl)-cycloalkyl)-alkyl)-benzoic acid derivatives, are peroxisome proliferator activated receptor agonists or antagonists used e.g. for treating lipid metabolism disorders, type II diabetes, syndrome X and obesity

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3933198B2 (en) * 1994-10-26 2007-06-20 ファルマシア・アンド・アップジョン・カンパニー Phenyloxazolidinone antibacterial agent
CN1285823A (en) * 1997-11-07 2001-02-28 先灵公司 Phenyl-alkyl-imidazoles as H3 receptor antagonists
CN1230421C (en) * 1999-02-10 2005-12-07 三菱制药株式会社 Amide compounds and medicinal use thereof
RU2254333C2 (en) * 1999-04-09 2005-06-20 Астразенека Аб Derivatives of adamantane, method for their preparing, pharmaceutical composition based on thereof and methods for treatment
JP2004504321A (en) * 2000-07-17 2004-02-12 ランバクシー　ラボラトリーズ　リミテッド Oxazolidinone derivatives as antimicrobial agents
PL365183A1 (en) * 2000-07-31 2004-12-27 Smithkline Beecham P.L.C. Carboxamide compounds and their use as antagonists of a human 11cby receptor
JO2654B1 (en) * 2000-09-04 2012-06-17 شركة جانسين فارماسوتيكا ان. في Polyarylcarboxamides useful as lipid lowering agents
JP2002338537A (en) * 2001-05-16 2002-11-27 Mitsubishi Pharma Corp Amide compound and its medicinal use
WO2002098871A1 (en) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Phenylcarboxamides and process for preparation thereof
AU2002346048A1 (en) * 2001-06-07 2002-12-16 Merck And Co., Inc. Benzodiazepine bradykinin antagonists
US7662826B2 (en) * 2002-04-23 2010-02-16 Shionogi & Co., Ltd. Pyrazolo [1,5-a] pyrimidine derivative and nad (p) h oxidase inhibitor containing the same
JP2004175739A (en) * 2002-11-28 2004-06-24 Tanabe Seiyaku Co Ltd Medicinal composition

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462884A1 (en) 1990-06-18 1991-12-27 Adir Et Compagnie TRH derivatives, their preparations and pharmaceutical compositions containing them
WO1997026265A1 (en) 1996-01-17 1997-07-24 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
WO1998008871A1 (en) 1996-08-30 1998-03-05 Novo Nordisk A/S Glp-1 derivatives
WO1997041097A2 (en) 1996-12-31 1997-11-06 Dr. Reddy's Research Foundation Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
WO1999003861A1 (en) 1997-07-16 1999-01-28 Novo Nordisk A/S Fused 1,2,4-thiadiazine derivatives, their preparation and use
WO1999015525A1 (en) 1997-09-19 1999-04-01 Sanofi-Synthelabo Carboxamidothiazole derivatives, preparation, pharmaceutical compositions containing them
US6221897B1 (en) 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
US6245744B1 (en) 1998-10-02 2001-06-12 Aventis Pharma Deutschland Gmbh Aryl-substituted propanolamine derivatives, their preparation, pharmaceuticals comprising them, and their use
WO2000035454A1 (en) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
WO2000040569A1 (en) 1999-01-08 2000-07-13 Alizyme Therapeutics Limited 2-amino-benzoxazinone derivatives for the treatment of obesity
WO2000063208A1 (en) 1999-04-16 2000-10-26 Novo Nordisk A/S Substituted imidazoles, their preparation and use
WO2000066585A1 (en) 1999-04-30 2000-11-09 Neurogen Corporation 9H-PYRIMIDO[4,5-b]INDOLE DERIVATIVES: CRF1 SPECIFIC LIGANDS
WO2000071549A1 (en) 1999-05-21 2000-11-30 Knoll Gmbh Thiazoloderivatives and pharmaceutical compositions containing them
WO2000071529A1 (en) 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
WO2000078312A1 (en) 1999-06-18 2000-12-28 Merck & Co., Inc. Arylthiazolidinedione and aryloxazolidinedione derivatives
WO2001009111A1 (en) 1999-07-29 2001-02-08 Eli Lilly And Company Benzofurylpiperazines and benzofurylhomopiperazines: serotonin agonists
US6342512B1 (en) 1999-09-01 2002-01-29 Aventis Pharma Deutschland Gmbh Sulfonylcarboxamide derivatives, process for their preparation and their use as pharmaceuticals
WO2001083451A1 (en) 2000-04-28 2001-11-08 Asahi Kasei Kabushiki Kaisha Novel bicyclic compounds
WO2001085695A1 (en) 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
WO2001091752A1 (en) 2000-05-30 2001-12-06 Merck & Co., Inc. Melanocortin receptor agonists
WO2002006232A1 (en) 2000-07-17 2002-01-24 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists
WO2002042271A2 (en) 2000-11-21 2002-05-30 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
WO2002098839A1 (en) 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides and process for preparation thereof
DE10142734A1 (en) 2001-08-31 2003-03-27 Aventis Pharma Gmbh New (((oxazolylalkyl)-cycloalkyl)-alkyl)-benzoic acid derivatives, are peroxisome proliferator activated receptor agonists or antagonists used e.g. for treating lipid metabolism disorders, type II diabetes, syndrome X and obesity

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Roten Liste", 2001
"USP Dictionary of USAN and International Drug Names", 2001, US PHARMACOPEIA
ASAKAWA, A ET AL.: "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice", M.:HORMONE AND METABOLIC RESEARCH, vol. 33, no. 9, 2001, pages 554 - 558, XP002950548, DOI: doi:10.1055/s-2001-17205
AUDINOT ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 13554 - 13562
GENNARO,: "Remington: The Science and Practice of Pharmacy, 19. Auflage,", 1995, MACK PUBLISHING CO.
LEE, DANIEL W.; LEINUNG, MATTHEW C.; ROZHAVSKAYA-ARENA, MARINA; GRASSO, PATRICIA: "Leptin agonists as a potential approach to the treatment of obesity", DRUGS OF THE FUTURE, vol. 26, no. 9, 2001, pages 873 - 881
PAUL R., TETRAHEDRON LETT, vol. 41, no. 19, 2000, pages 3705 - 3708
PHARMACEUTICAL RESEARCH, vol. 2, no. 6, 1986, pages 318
SALVADOR, JAVIER; GOMEZ-AMBROSI, JAVIER; FRUHBECK, GEMA: "Perspectives in the therapeutic use of leptin", EXPERT OPINION ON PHARMACOTHERAPY, vol. 2, no. 10, 2001, pages 1615 - 1622
TETRAHEDRON: ASYMMETRY, vol. 12, 2001, pages 2989
ZUNFT H J ET AL.: "Carob pulp preparation for treatment of hypercholesterolemia", ADVANCES IN THERAPY, vol. 18, no. 5, September 2001 (2001-09-01), pages 230 - 6, XP009029721

Cited By (147)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
US7902192B2 (en) 2003-05-15 2011-03-08 Arqule, Inc. Inhibitors of P38 and methods of using the same
EP1867644A1 (en) * 2003-07-24 2007-12-19 Euro-Celtique S.A. Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
US9301953B2 (en) 2003-07-24 2016-04-05 Purdue Pharma L.P. Therapeutic agents useful for treating pain
WO2005009988A1 (en) * 2003-07-24 2005-02-03 Euro-Celtique S.A. Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
US7776861B2 (en) 2003-07-24 2010-08-17 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8637548B2 (en) 2003-07-24 2014-01-28 Purdue Pharma L.P. Therapeutic agents useful for treating pain
EA009480B1 (en) * 2003-07-24 2008-02-28 Еуро-Селтик С. А. Heteroaryl-tetrahydropiperidyl compounds useful for treating or prevention pain
EP2080757A1 (en) * 2003-07-24 2009-07-22 Euro-Celtique S.A. Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
US8178560B2 (en) 2003-07-24 2012-05-15 Purdue Pharma L.P. Therapeutic agents useful for treating pain
EP1657240A4 (en) * 2003-08-18 2009-04-08 Fujifilm Finechemicals Co Ltd Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both
EP1657240A1 (en) * 2003-08-18 2006-05-17 Fujifilm Finechemicals Co., Ltd. Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both
US8530662B2 (en) 2003-08-18 2013-09-10 Fujifilm Finechemicals Co., Ltd Pyridyltetrahydropyridines and pyridylpiperidines, and method of manufacturing them
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
WO2005063239A1 (en) * 2003-12-23 2005-07-14 Boehringer Ingelheim International Gmbh 3-(4-piperidine-1ylmethyl-phenyl)-propion acid-phenylamide-derivatives and related compounds used in the form of mch antagonists (melanine concentrating hormone) for treating eating disorders
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
WO2005070925A1 (en) * 2004-01-25 2005-08-04 Sanofi-Aventis Deutschland Gmbh Aryl substituted heterocycles, method for production and use thereof as medicaments
US8114873B2 (en) 2004-07-08 2012-02-14 Arqule, Inc. 1,4-disubstituted naphthalenes as inhibitors of p38 map kinase
US7829560B2 (en) 2004-07-08 2010-11-09 Arqule, Inc. 1,4-disubstituted naphthalenes as inhibitors of P38 MAP kinase
WO2006010082A1 (en) * 2004-07-08 2006-01-26 Arqule, Inc. 1,4-disubstituted naphtalenes as inhibitors of p38 map kinase
WO2006022442A1 (en) * 2004-08-24 2006-03-02 Santen Pharmaceutical Co., Ltd. Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity
US8399493B2 (en) 2004-09-17 2013-03-19 Janssen Pharmaceuticals, Inc. Pyridinone derivatives and their use as positive allosteric modulators of mGluR2-receptors
EP1799667B1 (en) * 2004-09-20 2013-03-20 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
JPWO2006038680A1 (en) * 2004-10-01 2008-05-15 萬有製薬株式会社 2-Arylcarboxamide-nitrogen-containing heterocyclic compound
EP1798221A4 (en) * 2004-10-01 2010-04-07 Banyu Pharma Co Ltd 2-arylcarboxamide-nitrogeneous heterocycle compound
EP1798221A1 (en) * 2004-10-01 2007-06-20 Banyu Pharmaceutical Co., Ltd. 2-arylcarboxamide-nitrogeneous heterocycle compound
WO2006038680A1 (en) * 2004-10-01 2006-04-13 Banyu Pharmaceutical Co.,Ltd 2-arylcarboxamide-nitrogeneous heterocycle compound
US7531668B2 (en) 2004-10-01 2009-05-12 Banyu Pharmaceutical Co., Ltd. 2-arylcarboxamide-nitrogenous heterocycle compound
JP2008516959A (en) * 2004-10-18 2008-05-22 イーライ リリー アンド カンパニー 1- (Hetero) aryl-3-amino-pyrrolidine derivatives for use as mGluR3 receptor antagonists
US7868014B2 (en) 2004-10-18 2011-01-11 Eli Lilly And Company 1-(hetero)aryl-3-amino-pyrrolidine derivatives for use as mGluR3 antagonists
US8178672B2 (en) 2004-10-19 2012-05-15 Arqule, Inc. Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 MAP kinase
US8815924B2 (en) 2004-10-21 2014-08-26 Merck Patent Gmbh Heterocyclic carbonyl compounds
JP2008516999A (en) * 2004-10-21 2008-05-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Heterocyclic carbonyl compounds
WO2006054793A1 (en) * 2004-11-19 2006-05-26 The New Industry Research Organization Benzofuran compound and pharmaceutical composition containing the same
US8530476B2 (en) 2004-12-30 2013-09-10 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US9169224B2 (en) 2004-12-30 2015-10-27 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
EP2937341A1 (en) 2004-12-30 2015-10-28 Janssen Pharmaceutica N.V. 4-(benzyl)-piperazine-1-carboxylic acid phenylamide derivatives and related compounds as modulators of fatty acid amide hydrolase (faah) for the treatment of anxiety, pain and other conditions
US7598249B2 (en) 2004-12-30 2009-10-06 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
EP1846388A1 (en) * 2005-01-25 2007-10-24 Synta Pharmaceuticals Corporation Thiophene compounds for inflammation and immune-related uses
EP1846388A4 (en) * 2005-01-25 2011-12-07 Synta Pharmaceuticals Corp Thiophene compounds for inflammation and immune-related uses
US8802721B2 (en) 2005-01-25 2014-08-12 Synta Pharmaceuticals Corp. Thiophene compounds for inflammation and immune-related uses
US7803816B2 (en) 2005-09-30 2010-09-28 Hoffmann-La Roche Inc. MCH receptor antagonists
WO2007095124A3 (en) * 2006-02-10 2007-11-01 Transtech Pharma Inc Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
US7820821B2 (en) 2006-02-10 2010-10-26 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
JP2009526792A (en) * 2006-02-15 2009-07-23 サノフィ−アベンティス Novel azacyclyl-substituted arylthienopyrimidinones, methods for their preparation and their use as pharmaceuticals
JP2009526794A (en) * 2006-02-15 2009-07-23 サノフィ−アベンティス Novel amino alcohol-substituted arylthienopyrimidinones, methods for their preparation and their use as pharmaceuticals
US8710048B2 (en) 2006-04-19 2014-04-29 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US8173689B2 (en) 2006-04-19 2012-05-08 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US8163746B2 (en) 2006-04-19 2012-04-24 Astellas Pharma Inc. Azolecarboxamide derivative
WO2007123269A1 (en) * 2006-04-19 2007-11-01 Astellas Pharma Inc. Azolecarboxamide derivative
US8178563B2 (en) 2006-05-05 2012-05-15 Irm Llc Compounds and compositions as hedgehog pathway modulators
US9090561B2 (en) 2006-05-08 2015-07-28 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
US8278307B2 (en) 2006-05-08 2012-10-02 Ariad Pharmaceuticals, Inc. Monocyclic Heteroaryl compounds
AU2007249924B2 (en) * 2006-05-08 2013-07-04 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
EP2023933A2 (en) * 2006-05-08 2009-02-18 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
EP2023933A4 (en) * 2006-05-08 2011-02-23 Ariad Pharma Inc Acetylenic heteroaryl compounds
US8461167B2 (en) 2006-05-08 2013-06-11 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
JP2009536650A (en) * 2006-05-08 2009-10-15 アリアド・ファーマシューティカルズ・インコーポレイテッド Acetylene heteroaryl compounds
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
WO2008024390A2 (en) 2006-08-24 2008-02-28 Novartis Ag 2- (pyrazin-2-yl) -thiazole and 2- (1h-pyraz0l-3-yl) -thiazole derivatives as well as related compounds as stearoyl-coa desaturase (scd) inhibitors for the treatment of metabolic, cardiovascular and other disorders
US8314138B2 (en) 2006-08-24 2012-11-20 Novartis Ag Pyrazole derivative as SCD1 inhibitors for the treatment of diabetes
JP2010501567A (en) * 2006-08-24 2010-01-21 ノバルティス アクチエンゲゼルシャフト 2- (pyrazin-2-yl) -thiazole and 2- (1H-pyrazole-3-) as stearoyl-CoA desaturase (SCD) inhibitors for the treatment of metabolic, cardiovascular and other disorders Yl) thiazole derivatives and related compounds
WO2008024390A3 (en) * 2006-08-24 2008-04-17 Novartis Ag 2- (pyrazin-2-yl) -thiazole and 2- (1h-pyraz0l-3-yl) -thiazole derivatives as well as related compounds as stearoyl-coa desaturase (scd) inhibitors for the treatment of metabolic, cardiovascular and other disorders
WO2008031772A1 (en) * 2006-09-11 2008-03-20 Glaxo Group Limited Azabicyclic compounds as inhibitors of monoamines reuptake
US7691893B2 (en) 2006-09-11 2010-04-06 Glaxo Group Limited Chemical compounds
WO2008039794A1 (en) * 2006-09-25 2008-04-03 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
WO2008048991A3 (en) * 2006-10-18 2008-07-10 Novartis Ag Organic compounds
JP2010506950A (en) * 2006-10-18 2010-03-04 ノバルティス アーゲー Organic compounds
US8222248B2 (en) 2006-10-18 2012-07-17 Novartis Ag Organic compounds
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8299101B2 (en) 2007-03-07 2012-10-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive mGluR2-receptor modulators
WO2008122787A1 (en) * 2007-04-05 2008-10-16 Evotec Ag Piperazine compounds for the inhibition of haematopoietic prostaglandin d synthase
US9120821B2 (en) 2007-06-08 2015-09-01 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8981094B2 (en) 2007-06-08 2015-03-17 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9688696B2 (en) 2007-06-08 2017-06-27 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9227935B2 (en) 2007-06-08 2016-01-05 Janssen Pharmaceutical N.V. Piperidine/piperazine derivatives
WO2008148868A1 (en) * 2007-06-08 2008-12-11 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8633197B2 (en) 2007-06-08 2014-01-21 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
JP2010529089A (en) * 2007-06-08 2010-08-26 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Piperidine / piperazine derivatives
US8835437B2 (en) 2007-06-08 2014-09-16 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
RU2470017C2 (en) * 2007-06-08 2012-12-20 Янссен Фармацевтика Н.В. Piperidine/piperazine derivatives
US8946228B2 (en) 2007-06-08 2015-02-03 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9499567B2 (en) 2007-06-08 2016-11-22 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
WO2009027746A1 (en) * 2007-08-31 2009-03-05 Astrazeneca Ab Heterocyclic amides useful for the treatment of cancer and psoriasis
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8252937B2 (en) 2007-09-14 2012-08-28 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
US8304547B2 (en) 2007-10-24 2012-11-06 Astellas Pharma Inc. Azolecarboxamide compound or salt thereof
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
WO2009077956A3 (en) * 2007-12-14 2009-10-22 Алла Хем, Ллс HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
US8486945B2 (en) 2007-12-14 2013-07-16 Alexandre Vasilievich Ivachtchenko Heterocyclic inhibitors of an Hh-signal cascade, medicinal compositions based thereon and methods for treating diseases caused by the aberrant activity of an Hh-signal system
WO2009077956A2 (en) * 2007-12-14 2009-06-25 Alla Chem, Llc HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
US9724418B2 (en) 2008-06-05 2017-08-08 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist
US9107946B2 (en) 2008-06-05 2015-08-18 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
EP2334181A4 (en) * 2008-09-16 2012-03-14 Merck Sharp & Dohme Phthalimide derivative metabotropic glutamate r4 ligands
EP2334181A1 (en) * 2008-09-16 2011-06-22 Merck Sharp & Dohme Corp. Phthalimide derivative metabotropic glutamate r4 ligands
US8697689B2 (en) 2008-10-16 2014-04-15 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
US8846664B2 (en) 2008-11-12 2014-09-30 Ariad Pharmaceuticals, Inc. Pyrazinopyrazines and derivatives as kinase inhibitors
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
US10251893B2 (en) 2009-03-02 2019-04-09 Novartis Ag N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as Wnt signaling modulators
US8546396B2 (en) 2009-03-02 2013-10-01 Irm Llc N-(hetero)aryl, 2-(hetero)aryl—substituted acetamides for use as Wnt signaling modulators
US9238646B2 (en) 2009-03-02 2016-01-19 Novartis Ag N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as WNT signaling modulators
WO2010101247A1 (en) 2009-03-05 2010-09-10 塩野義製薬株式会社 Cyclohexane derivative having npy y5 receptor antagonism
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
WO2011060026A1 (en) 2009-11-12 2011-05-19 Jansen Pharmaceutica Nv Piperazinecarboxamide derivative useful as a modulator of fatty acid amide hydrolase (faah)
US8940745B2 (en) 2010-05-03 2015-01-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
US9688664B2 (en) 2010-05-03 2017-06-27 Janssen Pharmaceutica Nv Modulators of fatty acid amide hydrolase
US9181235B2 (en) 2010-06-29 2015-11-10 Novartis Ag Substituted pyridines for modulating the WNT signaling pathway
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
US8957093B2 (en) 2011-06-06 2015-02-17 The Scripps Research Institute N-biphenylmethylindole modulators of PPARG
WO2012170561A1 (en) * 2011-06-06 2012-12-13 The Scripps Research Institute (T.S.R.I.) N-benzylindole modulators of pparg
US9051265B2 (en) 2011-06-06 2015-06-09 The Scripps Research Institute N-benzylindole modulators of PPARG
US9309227B2 (en) 2011-11-22 2016-04-12 The Scripps Research Institute N-biphenylmethylbenzimidazole modulators of PPARG
US9238658B2 (en) 2011-12-06 2016-01-19 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as SCD 1 inhibitors
US9102669B2 (en) 2011-12-06 2015-08-11 Janssen Pharmaceutica Nv Substituted piperidinyl-pyridazinyl derivatives useful as SCD 1 inhibitors
US9499539B2 (en) 2012-11-05 2016-11-22 Nantbioscience, Inc. Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
EP2914253A4 (en) * 2012-11-05 2016-04-27 Nant Holdings Ip Llc Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
AU2013337370B2 (en) * 2012-11-05 2018-03-29 Nantbioscience, Inc. Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
CN105101959B (en) * 2012-11-05 2018-04-17 南特知识产权控股有限责任公司 The derivative containing cyclic sulfonamide as the inhibitor of hedgehog signal transduction pathway
US10183013B2 (en) 2012-11-05 2019-01-22 Nant Holdings Ip, Llc Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
CN105101959A (en) * 2012-11-05 2015-11-25 南特知识产权控股有限责任公司 Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10016394B2 (en) 2014-04-16 2018-07-10 The Scripps Research Institute PPARG modulators for treatment of osteoporosis
WO2016008011A1 (en) * 2014-07-16 2016-01-21 Novogen ltd Functionalised and substituted indoles as anti-cancer agents
US10112939B2 (en) 2014-08-21 2018-10-30 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors
CN107108581A (en) * 2014-08-21 2017-08-29 百时美施贵宝公司 It is used as the tieback heterocyclic carbamate derivatives of potent ROCK inhibitor
WO2016028971A1 (en) * 2014-08-21 2016-02-25 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors

Also Published As

Publication number Publication date
UY28186A1 (en) 2004-09-30
ECSP055967A (en) 2006-01-16
MXPA05008449A (en) 2006-05-25
WO2004072025A3 (en) 2004-12-23
NO20054220L (en) 2005-10-28
PL378065A1 (en) 2006-02-20
TW200510297A (en) 2005-03-16
NZ541823A (en) 2009-01-31
MA27735A1 (en) 2006-02-01
UA86760C2 (en) 2009-05-25
TNSN05194A1 (en) 2007-06-11
HRP20050710A2 (en) 2006-07-31
JP2006517563A (en) 2006-07-27
AR044496A1 (en) 2005-09-14
PE20040952A1 (en) 2005-02-08
NO20054220D0 (en) 2005-09-12
CN1774418A (en) 2006-05-17
CN100506792C (en) 2009-07-01
EP1597228A2 (en) 2005-11-23
BRPI0407504A (en) 2006-02-14
CA2516118A1 (en) 2004-08-26
AU2004212145B2 (en) 2010-06-17
KR20050101215A (en) 2005-10-20
ZA200506369B (en) 2006-07-26
RS20050666A (en) 2007-12-31
CO5690548A2 (en) 2006-10-31
PA8595901A1 (en) 2004-09-16
AU2004212145A1 (en) 2004-08-26
DE10306250A1 (en) 2004-09-09
RU2005128551A (en) 2006-02-10
OA13027A (en) 2006-11-10
MY139102A (en) 2009-08-28

Similar Documents

Publication Publication Date Title
EP1597228A2 (en) Substituted n-arylheterocycles, method for production and use thereof as medicaments
US7968550B2 (en) Substituted N-aryl heterocycles, process for their preparation and their use as medicaments
EP1836180B1 (en) Sulfonyl pyrrolidines, method for producing the same and their use as drugs
EP1711494B1 (en) Aryl substituted heterocycles, method for production and use thereof as medicaments
EP1711473B1 (en) Substituted n-cyclohexylimidazolinones having an mch-modulatory effect
EP1874737B1 (en) Substituted 2-aminoalkylthio-benzimidazoles and use thereof for reducing blood sugar levels
EP1651649B1 (en) Novel cyanopyrrolidides, methods for the production thereof, and use of the same as medication
DE602004010829T2 (en) ADAMANTAN AND AZABICYCLOOCTANESE AND NONANDERIVATES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS DPP IV INHIBITORS
DE102004039789A1 (en) Aryl-substituted polycyclic amines, process for their preparation and their use as pharmaceuticals
EP1713803A1 (en) 7-phenylamino-4-quinolone-3-carboxylic acid derivatives, methods for production and use thereof as medicaments
DE102004038270A1 (en) Substituted bicyclic 8-amino-xanthines, process for their preparation and their use as medicaments
DE102004004972B3 (en) Heterocyclic substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
EP1863817B1 (en) Substituted, bicyclic 8-pyrrolidino-benzimidazoles, method for their production and their use as medicaments
EP1597247B1 (en) Substituted 3-(benzoylureido)-thiophene derivatives, method for the production and use thereof
EP1590322B1 (en) Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof
DE102004004973A1 (en) New 7-phenylamino-quinolone or 1,8-naphthyridone derivatives, useful e.g. for treating type II diabetes or arteriosclerosis, are inhibitors of glycogen phosphorylase
DE102004033405A1 (en) New 7-phenylamino-quinolone or 1,8-naphthyridone derivatives, useful e.g. for treating type II diabetes or arteriosclerosis, are inhibitors of glycogen phosphorylase
DE102004019276A1 (en) New cyanopyrrolizine derivatives, used e.g. for lowering blood sugar, treating type 2 diabetes, treating disorders of lipid and carbohydrate metabolism, treating arteriosclerotic symptoms

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-2005/0666

Country of ref document: YU

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2005/06369

Country of ref document: ZA

Ref document number: PA/a/2005/008449

Country of ref document: MX

Ref document number: 200506369

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 170249

Country of ref document: IL

Ref document number: 05079788

Country of ref document: CO

Ref document number: 1902/CHENP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 378065

Country of ref document: PL

Ref document number: P20050710A

Country of ref document: HR

Ref document number: 1020057014989

Country of ref document: KR

Ref document number: 2004212145

Country of ref document: AU

Ref document number: 2006501827

Country of ref document: JP

Ref document number: KE

WWE Wipo information: entry into national phase

Ref document number: DZP2005000289

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 2516118

Country of ref document: CA

Ref document number: 1-2005-501496

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 541823

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2004212145

Country of ref document: AU

Date of ref document: 20040213

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004212145

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004710808

Country of ref document: EP

Ref document number: 2005128551

Country of ref document: RU

Ref document number: 1200501280

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 20048098606

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020057014989

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2004710808

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0407504

Country of ref document: BR

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)