EP1915352A1 - Verbindungen zur behandlung der alzheimer erkrankung - Google Patents

Verbindungen zur behandlung der alzheimer erkrankung

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Publication number
EP1915352A1
EP1915352A1 EP06778201A EP06778201A EP1915352A1 EP 1915352 A1 EP1915352 A1 EP 1915352A1 EP 06778201 A EP06778201 A EP 06778201A EP 06778201 A EP06778201 A EP 06778201A EP 1915352 A1 EP1915352 A1 EP 1915352A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
heteroaryl
cycloalkyl
heterocyclyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06778201A
Other languages
German (de)
English (en)
French (fr)
Inventor
Klaus Fuchs
Christian Eickmeier
Niklas Heine
Stefan Peters
Cornelia Dorner-Ciossek
Sandra Handschuh
Herbert Nar
Klaus Klinder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Priority to EP06778201A priority Critical patent/EP1915352A1/de
Publication of EP1915352A1 publication Critical patent/EP1915352A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to substituted 1,2-ethylenediamines of the general formula (I)
  • a further subject of this invention relates to medicaments comprising a compound of the formula I according to the invention and the use of a compound according to the invention for the preparation of a medicament for the treatment and / or prevention of Alzheimer's disease (AD) and other diseases associated with an abnormal processing of the amyloid precursor protein (US Pat. APP) or aggregation of Abeta peptide, as well as diseases that can be treated or prevented by inhibition of ß-secretase.
  • AD Alzheimer's disease
  • US Pat. APP amyloid precursor protein
  • aggregation of Abeta peptide as well as diseases that can be treated or prevented by inhibition of ß-secretase.
  • Corresponding diseases include MCI (mild cognitive impairment), trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Alzheimer's dementia with Lewy bodies, trauma, stroke, pancreatitis , Inclusion body myositis (IBM), as well as other peripheral amyloidoses, diabetes and arteriosclerosis.
  • MCI mimild cognitive impairment
  • trisomy 21 Down Syndrome
  • cerebral amyloid angiopathy degenerative dementia
  • HHWA-D hereditary cerebral hemorrhage with Dutch-type amyloidosis
  • IBM Inclusion body myositis
  • the compounds according to the invention also inhibit the aspartyl protease cathepsin D and are therefore suitable for suppressing the metastasis of tumor cells.
  • EP 652 009 A1 describes inhibitors of aspartate protease which inhibit the production of beta-amyloid peptides in cell culture and in vivo.
  • WO 00/69262 discloses a beta-secretase and its use in assays for finding potential active substances for the treatment of AD.
  • WO 01/00663 discloses memapsin 2 (human beta-secretase) as well as a recombinant catalytically active enzyme. In addition, methods for identifying inhibitors of memapsin 2 are described.
  • WO 01/00665 discloses inhibitors of memapsin 2 for the treatment of AD.
  • WO 03/057721 discloses substituted aminocarboxamides for the treatment of AD.
  • WO 05/004802 discloses substituted benzyl-substituted N-alkyl-phenylcarboxamides for the treatment of AD.
  • Object of the present invention is also to provide physiologically acceptable salts of the compounds of the invention with a norganic or organic acids.
  • a further object of the present invention is to provide pharmaceutical compositions comprising at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and / or diluents.
  • a further object of the present invention relates to pharmaceutical compositions comprising one or more, preferably one active ingredient, selected from the compounds according to the invention and / or the corresponding salts, and one or more, preferably one further active ingredient in addition to optionally one or more inert carriers and / or diluents.
  • Another object of this invention relates to the use of at least one of the compounds of the invention for inhibiting ⁇ -secretase.
  • APP amyloid precursor protein
  • AD Alzheimer's disease
  • other diseases associated with abnormal processing of APP or aggregation of the Abeta peptide as well as diseases be treated or prevented by inhibition of ß-secretase, in particular AD, are suitable.
  • AD Alzheimer's disease
  • other diseases associated with abnormal processing of APP or aggregation of the Abeta peptide as well as diseases be treated or prevented by inhibition of ß-secretase, in particular AD, are suitable.
  • Another object of this invention relates to a method of inhibiting ⁇ -secretase activity
  • a first subject of the present invention are substituted 1,2-ethylenediamines of the general formula (I)
  • Heteroaryl where the group A may optionally be substituted by one or more fluorine atoms in addition to the radicals L,
  • Carboxy, formyl, cyano, nitro, F 3 C-, HF 2 C-, FH 2 C-, hydroxy-Ci-e alkyl, C 1 -3 alkyl, Ci -6 alkoxy , (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl, (R 12) 2 N- CO- and HOSO 2 - may be substituted,
  • Ci-rAlkylen bridge wherein the Ci -4 -alkylene bridge optionally substituted with one or more groups selected from the group fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro , F 3 C-, HF 2 C-, FH 2 C-, Ci -4 alkyl, Ci 6- alkyl-S-Ci- 3 -alkyl, C 3-7 -cycloalkyl, Cs-y-cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 -alkyl, aryl, aryl -ci- 3 -alkyl, aryl-C 3- 7 -cycloalkyl, heteroaryl, heteroaryl Ci 3 alkyl, heteroaryl-C 3- 7 cycloalkyl, R 13 -O- (R 12) 2 N-SO 2 -, (R 12) 2 N-, (R 13 -O
  • Radicals formed C 3 -7-cycloalkyl optionally unsubstituted with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C-, Ci -3 alkyl, Ci -3 alkoxy, R 13 -O- Ci-s-alkyl, R 12 -CO (R 12) N-, R 12 -SO 2 (R 12) N -, (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl,
  • R 12 is hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 7 cycloalkyl, C 3-7 - cycloalkyl-Ci-6-alkyl-, C 3- 7 cycloalkyl C 2- 6 alkenyl, C 3- 7 cycloalkyl C 2- 6-alkynyl, C 3-7 cycloalkenyl, C ⁇ cycloalkenyl-Ci-e-alkyl-, 3- C 7 -cycloalkenyl-C 2 - 6 alkenyl, C ⁇ cycloalkenyl-C ⁇ e-alkynyl, heterocyclyl, heterocyclyl Ci 6 alkyl, heterocyclyl-C 2 - 6 alkenyl, heterocyclyl -C 2-6 - alkenyl, heterocyclyl -C 2-6 - alkenyl, heterocyclyl, heterocyclyl Ci 6 alkyl
  • R 12 CO- (R 12) N-, R 12 -SO 2 (R 12) N-, (R 12) 2 N-Ci -3 alkyl, (R 12) 2 N-CO-, R 13 -O- and R 13 -O-Ci -3 alkyl can be substituted, R 3, R 4 are each independently hydrogen, Ci -6 alkyl, fluorine, F 3 C-, HF 2 C- or FH 2 C-,
  • R 5 is hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cs-y-cycloalkyl, C 3-7 - cycloalkyl-Ci ⁇ alkyl, C 3 - 7 cycloalkyl-C 2-4 alkenyl, C 3 - 7 cycloalkyl C 2-4 - alkynyl, C 3 - 7 cycloalkenyl, C 3 - 7 cycloalkenyl Ci -4 alkyl, C 3- 7 cycloalkenyl-C 2-4 alkenyl, C 3-7 cycloalkenyl-C 2-4 alkynyl, heterocyclyl, heterocyclyl-Ci -4 alkyl, heterocyclyl-C 2-4 alkenyl , heterocyclyl-C 2-4 - alkynyl, aryl, aryl-Ci -4 alkyl, aryl C 2-4 alkenyl, arylC 2-4
  • Aryl, heteroaryl, heteroaryl-Ci -3 alkyl, aryl-Ci-6-alkyl-, R 12 -CO- (R 12) N-, R 12 -SO 2 (R 12) N- (R 12 ) 2 N-SO 2 -, (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl, (R 12) 2 N-CO- and HOSO 2 - may be substituted,
  • R 6 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 7 cycloalkyl, C 3-7 -
  • R 7 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy-Ci- 3 - alkyl, C 3 - 7 cycloalkyl, C ⁇ cycloalkyl-Ci-s-alkyl, heterocyclyl-Ci -3 alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl or heteroaryl Ci 3 alkyl, wherein the above-mentioned optionally independently selected from one another with one or more radicals selected from
  • R 8 is hydrogen, fluorine, chlorine, bromine, iodine, cyano, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 -AIkJ nyl-, C 3 - 7 cycloalkyl, C ⁇ - cycloalkyl-Ci-e-alkyl-, C 3-7 cycloalkyl
  • Ci -6 alkyl Group consisting of Ci -6 alkyl, Ci -6 alkoxy, fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R 12) 2 N-, ( R 12 ) 2 N-CO-, R 12 -CO- (R 12 ) N-, (R 12 ) 2 N-CO- (R 12 ) N-, (R 12 ) 2 N-SO 2 -, (R 12 ) 2 N-SO 2 - (R 12 ) N-, F 3 C-, HF 2 C-, FH 2 C-, F 3 CO-, HF 2 CO-, FH 2 CO- or R 12 -SO 2 - (R 12 ) N- may be substituted, R 9 are each independently hydrogen, fluorine, chlorine, bromine, iodine, Ci 3 alkyl, R 13 -O- or (R 12) 2 N-, wherein the above-mentioned Ci -3 alkyl group optionally
  • R 10 Ci 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 7 cycloalkyl alkyl, C 3-7 cycloalkyl Ci- 4, C 3 - 7 cycloalkyl-C 2 - 4 alkenyl, C 3-7 cycloalkenyl, Cs- 7 cycloalkenyl-Ci-ralkyl-, C 3 - 7 cycloalkenyl-C 2-4 - alkenyl, C 3 - 7 cycloalkenyl-C 2-4 alkynyl, heterocyclyl -, heterocyclyl-Ci -4 - alkyl, heterocyclyl, -C 2-4 alkenyl, heterocyclyl-C 2-4 alkynyl, aryl, aryl-Ci-
  • R 12 Group consisting of fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C- ⁇ - 3 alkyl, heterocyclyl, heterocyclyl-C- ⁇ - alkyl 3, R 13 O-, R 13 -O-Ci -3 alkyl, R 12 -CO (R 12) N-, R 12 -SO 2 (R 12) N-, (R 12) 2 N-SO 2 - , R 12 -SO 2 -, -SO- R 12, R 12 -S-, (R 12) (R 12) 2 N-Ci -3 alkyl 2 N-, and (R 12) 2 N-CO - may be substituted,
  • R 11 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C, C 3 -7-cycloalkyl, C 3-7 alkynyl 2-6 - cycloalkyl-Ci -3 alkyl, heterocyclyl -, heterocyclyl-Ci- 3 alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alki nyl-, aryl, aryl-Ci -3 alkyl, heteroaryl, heteroaryl-C 3- alkyl, heteroaryl-C 2-3 alkenyl or
  • Heteroaryl-C 2-3 -alki nyl- wherein the above-mentioned radicals optionally independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, oxo, carboxy, formyl, cyano , nitro, Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci -3 -alkyl-
  • R, R 13 -alkyl- O- 13 -O-Ci -3 (R 12) 2 N-SO 2 -, R 12 -SO 2 -, -SO- R 12, R 12 -S-, (R 12 ) 2 N-, (R 12 ) 2 NC 1 -3 -alkyl- and R 12 CO- may be substituted, or
  • R 10 and R 11 together form a C 2-6 alkylene bridge such that with the inclusion of the nitrogen atom attached to R 11 and with
  • R 10 connected SO 2 - or CO group is formed a heterocyclic ring, wherein one or two -CH 2 groups of the C2-6-alkylene bridge independently of each other by O, S, SO, SO 2 or -N (R 12 ) - can be replaced so that in each case two O or S atoms or an O are not directly connected to an S atom, and wherein the carbon atoms of the above-mentioned C2-6-alkylene bridge optionally with a or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxyl,
  • Carboxy, formyl, cyano, F 3 C, C 1-6 -alkyl, C 1-6 -alkoxy, oxo and nitro may be substituted
  • R 12 are each independently hydrogen, Ci-6-alkyl, Ci-6-alkoxy-C- ⁇ - 3 alkyl, C 3 - 6 -Cyclyoalkyl-, C 3 - 6 -Cyclyoalkyl-Ci- 3 alkyl , Heterocyclyl,
  • Heteroaryl-Ci - 3 alkyl, wherein two bound to the same nitrogen atom may form a C 2-6 -alkylene bridge -6 alkyl groups together so that with the inclusion atom formed of a heterocyclic ring with the radicals R 12 associated nitrogen where a -CH 2 group of the C 2-6 -alkylene bridge is replaced by O, S or
  • N (R 13 ) - may be replaced, and wherein the above-mentioned radicals and the heterocyclic ring optionally independently of one another with one or more
  • R 13 are each independently hydrogen, Ci 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, Cs-y-Cyclyoalkyl-Cis-alkyl, heterocyclyl,
  • Carboxy, formyl, cyano, nitro, Ci -3 alkyl, and Ci -3 alkoxy may be substituted
  • the compounds of the general formula (I) according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibiting effect of the ⁇ -secretase activity, in particular of the ⁇ -secretase mediated cleavage of APP.
  • the compounds are also suitable for suppressing the metastasis of tumor cells.
  • the present invention also relates to the physiologically tolerable salts of the compounds according to the invention with inorganic or organic acids.
  • the use of the compounds of the invention, including the physiologically acceptable salts, as a medicament is also an object of this invention.
  • Another object of this invention are pharmaceutical compositions containing at least one compound of the invention or a physiologically acceptable salt according to the invention in addition to optionally one or more inert carriers and / or diluents.
  • a further subject of this invention are pharmaceutical compositions comprising one or more, preferably one active ingredient, selected from the compounds according to the invention and / or the corresponding salts, and one or more, preferably one active ingredient, for example selected from the group consisting of beta- Secretase inhibitors; gamma-secretase inhibitors; Amyloid aggregation inhibitors such. Alzhemed; direct or indirect neuroprotective substances; anti-oxidants, e.g. Vitamin E or Ginkolide; anti-inflammatory substances, such. Cox inhibitors, NSAIDs with additional or sole Aß lowering properties; HMG-CoA reductase inhibitors (statins); Acetylcholinesterase inhibitors such as donepezil,
  • a further subject of this invention are pharmaceutical compositions containing one or more, preferably one active ingredient, which is selected from the compounds according to the invention and / or the corresponding salts, and one or more, preferably one active ingredient, selected from the group consisting of Alzhemed, vitamin E, ginkolide, donepezil, rivastigmine, tacrine, galantamine, memantine, NS-2330, Ibutamoren mesylate, capromorelin, minocycline and / or rifampicin in addition to optionally one or more inert carriers and / or diluents.
  • Another object of this invention is the use of at least one of the compounds of the invention for the inhibition of ß-secretase.
  • Another object of this invention is the use of at least one compound of the invention or a physiologically acceptable salt of such a compound for the manufacture of a medicament suitable for the treatment or prophylaxis of diseases or conditions associated with abnormal processing of the amyloid precursor protein (APP) or Aggregation of the Abeta peptide.
  • APP amyloid precursor protein
  • Another object of this invention is the use of at least one compound of the invention or a physiologically acceptable salt of such a compound for the manufacture of a medicament for the treatment or
  • Prophylaxis of diseases or conditions is suitable, which can be influenced by inhibiting the ß-secretase activity.
  • Another object of this invention is the use of at least one compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament useful for the treatment and / or prevention of Alzheimer's Disease (AD) and other diseases associated with abnormal processing of APP or aggregation of Abeta Peptides are associated, as well as diseases that can be treated or prevented by inhibition of ß-secretase, in particular AD, is suitable.
  • AD Alzheimer's Disease
  • other diseases associated with abnormal processing of APP or aggregation of Abeta Peptides are associated, as well as diseases that can be treated or prevented by inhibition of ß-secretase, in particular AD, is suitable.
  • Corresponding disorders include MCI (mild cognitive impairment), trisomy 21 (Down syndrome), cerebral amyloid angiopathy, degenerative dementia, hereditary cerebral hemorrhages with Dutch type amyloidoses (HCHWA-D), Alzheimer's dementia with Lewy bodies, trauma, stroke, pancreatitis, inclusion body myositis (IBM), as well as other peripheral amyloidoses, diabetes and arteriosclerosis.
  • MCI mimild cognitive impairment
  • trisomy 21 Down syndrome
  • cerebral amyloid angiopathy degenerative dementia
  • HHWA-D hereditary cerebral hemorrhages with Dutch type amyloidoses
  • Alzheimer's dementia with Lewy bodies trauma, stroke, pancreatitis
  • inclusion body myositis IBM
  • other peripheral amyloidoses diabetes and arteriosclerosis.
  • Another object of this invention is a method for inhibiting the ß-secretase activity, characterized in that ß-secretase is brought into contact with an inhibitory effective amount of one of the compounds of the invention.
  • radicals, substituents or groups in a compound may have the same or different meanings.
  • the group means
  • the group has
  • the group means a 5- or 6-membered aromatic heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S, wherein at most one O or S atom may be contained.
  • the group means
  • a thienyl, thiazolyl, pyrazolyl or pyridyl radical is considered particularly preferred.
  • the substituent L preferably in each case independently of one another denotes hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 6 -alkyl -, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-Ci- 3 alkyl, aryl, aryl-C- ⁇ - 3 alkyl, heterocyclyl, heterocyclyl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 - alkyl-, R, R 13 -O-Ci alkyl 13 -3 -O-, (R 12) 2 N, (R 12 ) 2 N-CO-, R 12 -CO- (R 12 ) N-, (R 12 ) 2 N-CO- (R 12 ) 2 N-CO- (R 12 ) 2 N-
  • the substituent L in each case independently of one another hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, C 3- 7 cycloalkyl, Cs-y-cycloalkyl -Cis-alkyl, phenyl, (R 12 ) 2 N-, (R 12 ) 2 N-CO-, R 12 -CO- (R 12 ) N-, (R 12 ) 2 N-CO- (R 12 ) N, R 12 -SO 2 - (R 12 ) N- or (R 12 ) 2 N-SO 2 -, where the above mentioned radicals may optionally be substituted by one or more fluorine atoms.
  • substituents L are each independently each independently hydrogen, fluorine, chlorine, bromine, hydroxy, Ci -4 alkyl or Ci -4 alkoxy, wherein the above groups optionally substituted with one or more Fluorine atoms may be substituted.
  • substituent L are each independently of one another hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy.
  • the index i can preferably assume the values 0, 1 or 2. In particularly preferred embodiments, the value of the index i is 0 or 1.
  • the group B is a Ci -4 -alkylene bridge is optionally independently more radicals selected from the group consisting of fluoro, hydroxy, carboxy, cyano, nitro with one or, F 3 C-, HF 2 C-, FH 2 C-, Ci -4 alkyl, C3-7 - cycloalkyl, Cs-y-cycloalkyl-cis-alkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl, aryl, aryl-d- 3- alkyl, heteroaryl, heteroaryl-C 1 -3 -alkyl, R 13 -O-, (R 12 ) 2 N-SO 2 - and (R 12 ) 2 N may be substituted, and wherein two -4 alkylene bridge bound to the same carbon atom of the Ci Ci -4 alkyl radicals to form a C 3-7 cycloalkyl group may be linked together, and where the radicals mentioned above
  • the group B denotes a Ci -4 -alkylene bridge, wherein the Ci -4 -alkylene bridge may optionally be substituted independently more radicals selected from the group consisting of fluorine, Ci -4 alkyl with one or, Phenyl or benzyl may be substituted, and wherein two 4 -alkylene bridge bound to the same carbon atom of the Ci Ci -4 alkyl radicals to form a C 3 - 6 may be cycloalkyl group connected to each other, and wherein the above-mentioned radicals and formed from the Ci -4 alkyl radicals C 3 - 6 -cycloalkyl optionally independently of one another with one or more radicals selected from the group consisting of fluorine, hydroxy, and Ci-3-alkoxy may be substituted ,
  • B is a C 1 -to-C 2 -alkylene bridge, where the C-2-alkylene bridge is optionally substituted by one or more C 1 -C 4 -alkylene bridges.
  • 4- alkyl radicals may be substituted, and wherein two on the same carbon atom of the Ci- 2 -alkylene bridge bound Ci -4 alkyl radicals may be joined together to form a cyclopropyl group, and wherein one or more hydrogen atoms of the above ci 2 Alkylene bridge and / or the Ci -4 alkyl groups and / or the cyclopropyl group formed therefrom may optionally be replaced by one or more fluorine atoms.
  • one or more hydrogen atoms may optionally be replaced by fluorine.
  • group B is selected from the group consisting of wherein one or more hydrogen atoms may optionally be replaced by fluorine.
  • Another preferred embodiment comprises those compounds according to the invention in which the partial formula (II)
  • the radical R 1 is preferably selected from the group consisting of hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Cs-y cycloalkyl, C 3 -7-cycloalkyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl, aryl, aryl-C- ⁇ - 3 alkyl, heteroaryl or heteroaryl-Ci- 3 -alkyl-, where the abovementioned radicals, where appropriate, independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, carboxy, cyano, nitro, F 3 C, C- ⁇ 3-alkyl, C- ⁇ -3-alkoxy and hydroxy-C 1-3 -alkyl may be substituted.
  • radicals R 1 are particularly preferably selected from the group consisting of hydrogen, Ci -4 alkyl, C 3 - 4 alkenyl, Cs-e-cycloalkyl, Cs-e-cycloalkyl-Ci-s-alkyl, where the radicals mentioned above may optionally be substituted independently of one another more radicals selected from the group consisting of fluoro, hydroxy and C- ⁇ - with one or 3 alkoxy.
  • the radicals R 1 are particularly preferably selected from the group consisting of hydrogen or Ci -4 alkyl, wherein the Ci -4 alkyl group may be substituted with one or more fluorine atoms.
  • the radical R 2 is preferably selected from the group consisting of Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci- 6 - alkoxy-Ci- 3 alkyl, Ci-C6 alkyl alkyl-S-Ci- 3, C 3-7 cycloalkyl, C 3-7 cycloalkyl-Ci alkyl 3, heterocyclyl, heterocyclyl -C -3 alkyl, aryl, aryl-Ci -3 alkyl, heteroaryl or heteroaryl-Ci -3 alkyl, wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting from fluorine, chlorine, bromine, iodine, F 3 C, HF 2 C, FH 2 C, hydroxy, carboxy, cyano, nitro, C 1-3 -alkyl, (R 12 ) 2 N- , (R 12) 2 N-SO 2
  • radicals R 2 are radicals selected from the group consisting of Ci- 6 alkyl, C 2-6 nyl- -AIkJ, C 3 - 6 cycloalkyl-Ci- alkyl 3, heterocyclyl-Ci-s-alkyl -, phenyl, phenyl-Ci -3 alkyl, heteroaryl or heteroaryl-C, wherein to be understood by the above-mentioned heteroaryl groups 5- or 6-membered aromatic heteroaryl -3 alkyl containing 1, 2 or 3 heteroatoms selected from N, O and S and wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, Ci -3 alkyl , F 3 C-, HF 2 C-, FH 2 C-, H 2 N and C may be substituted alkoxy -3.
  • radicals R 2 which are selected from the group consisting of n-propyl, n-butyl, 2-propynyl, 2-butynyl, cyclohexylmethyl, cyclopentylmethyl, benzyl, 2-phenylethyl, Pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl, where the abovementioned propyl, butyl, propynyl, butynyl, cyclohexylmethyl and cyclopentylmethyl radicals optionally have one or more fluorine atoms and the benzyl, 2-phenylethyl, pyridylmethyl, Furanylmethyl-, thienylmethyl or Thiazolylmethyl radicals optionally be substituted independently of one another with one or more radicals selected from the group fluorine, chlorine, bromine, methyl, F 3 C, HF 2 C, FH 2 C- and H 2 N- substituted
  • radicals R 2 which are selected from the group consisting of benzyl, pyridylmethyl, especially 2-pyridylmethyl-thienylmethyl, especially 3-thienylmethyl and thiazolylmethyl, in particular 4-thiazolylmethyl.
  • the radical R 3 is preferably hydrogen, fluorine, methyl, F 3 C-, HF 2 C- or FH 2 C- and particularly preferably R 3 is hydrogen.
  • the radical R 4 is preferably hydrogen or fluorine, particularly preferably hydrogen.
  • the radical R 3 is selected from the group consisting of hydrogen, fluorine, methyl, F 3 C, HF 2 C or FH 2 C- and the radical R 4 is hydrogen or fluorine.
  • radicals R 3 and R 4 are hydrogen.
  • the radical R 5 is preferably selected from the group consisting of hydrogen, C- ⁇ -6 alkyl, C 2- 6 alkenyl, C 2 e-alkynyl, C 3 -7- cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkenyl, C 3- 7 cycloalkenyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, aryl, aryl-Ci -3 alkyl, heteroaryl, or heteroaryl-Ci- 3 alkyl, wherein the above mentioned radicals optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, or with a, iodo, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, Ci -3 alkoxy , Ci -3 alkyl-S-, aryl, heteroaryl, heteroaryl, heteroaryl, wherein
  • radicals optionally particularly preferred radicals R 5 are selected from the group consisting of Ci- 6 alkyl, cyclopropyl, Cs-e-cycloalkyl-Ci-s-alkyl or phenyl-Ci -3 alkyl, selected independently with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, carboxy, Ci -4 alkyl, Ci -4 alkoxy, and (R 12) 2 N - may be substituted.
  • R 5 is a Ci -4 alkyl or cyclopropyl group, wherein one or more hydrogen atoms of the above radicals may optionally be replaced by fluorine atoms.
  • Ci -4 alkyl group is particularly especially the n-butyl group is particularly preferred.
  • the radical R 6 is preferably selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2- e alkynyl, C 3-7 cycloalkyl, Cs-y-cycloalkyl-Ci-s-alkyl-, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl-Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl , aryl, aryl-Ci -3 alkyl, heteroaryl or heteroaryl-Ci -3 alkyl, wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, or with a, iodine, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, C 3 - 6 cycloalkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl
  • radicals R 6 are groups selected from the group consisting of hydrogen, Ci -6 alkyl, C 2 -6 alkenyl, C2 -6 alkynyl, Cs-e-cycloalkyl, C 3 -e- cycloalkyl-Ci- 3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, phenyl, phenyl-Ci -3 - alkyl, heteroaryl or heteroaryl Ci 3 alkyl, wherein the above-mentioned under the Heteroaryl groups are to be understood as meaning 5- or 6-membered aromatic heteroaryl groups which contain 1, 2 or 3 heteroatoms selected from N, O and S, and where the abovementioned radicals are, if desired, independently of one another with one or more radicals selected from the group consisting of fluorine , chloro, bromo, carboxy, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, Ci- 3 alkoxy-C
  • radicals R 6, which are selected from the group are very particularly preferably consisting of hydrogen, C- ⁇ - 6 alkyl, C 2-6 alkenyl, Cs-6 cycloalkyl, C 3-5 - cycloalkyl Ci -3 alkyl, cyclopentyl-cis-alkyl, phenyl-Ci- 3 alkyl or tetrahydropyranyl-Ci- 3 alkyl, wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting from fluoro, pyrrolidin-1 -ylmethyl-, hydroxy, cyano, Ci-C3 alkyl, Ci- 3 alkoxy, Ci-C3 alkyl-S-, hydroxy-Ci -3 alkyl, (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl, (R 12) 2 N-CO- N (R 12) - may be substituted - and (R 12) 2 N-SO 2.
  • R 6 is a Ci -6 alkyl, cyclopropyl-Cis-alkyl or phenyl-Ci-3-alkyl group, wherein the phenyl group may be optionally substituted with an amino group such as a cyclopropylmethyl, or 4- Amino-phenylmethyl group.
  • the radical R 7 is preferably selected from the group consisting of hydrogen or Ci -4 alkyl, wherein one or more hydrogen atoms of the Ci -4 alkyl group may be replaced by fluorine. Particularly preferred are those compounds in which R 7 represents a hydrogen atom.
  • the radical R 8 is preferably selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, C 1 -6 -AIkVl-, C 2 - 6 alkenyl, C 2 -6 -AIkJ nyl-, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, aryl, aryl-Ci- 3 alkyl, heteroaryl, heteroaryl-C 1 -3 alkyl, R 13 -O-, R 13 -O-C 1-3 -alkyl-, R 10 -SO 2 - (R 11) N- or R 10 - CO- (R 11) N-, where the above mentioned groups optionally substituted independently more groups selected from the group consisting of Ci -6 alkyl, Ci -6 with one or - alkoxy, Fluorine,
  • radicals R 8 are radicals selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, Ci -4 alkyl, Ci -4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-oxy-, C 3-6 cycloalkyl-Ci -3 alkoxy, phenyl, pyridyl, thienyl, furyl, R 10 -CO- (R 11) N-, or R 10 -SO 2 - (R 11) N-, where the above mentioned groups optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, carboxy, cyano, Ci-4 alkyl with one or Ci -4 alkoxy -, F 3 C-, HF 2 C-, FH 2 C-, F 3 CO-, HF 2 CO-, FH 2 CO- and (R 12 ) 2 N-CO- may be substituted.
  • the radical R 8 has the meaning R 10 -SO 2 - (R 11 ) N- or R 10 -CO- (R 11 ) N-.
  • Preferred radicals R 9 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, F 2 HC, FH 2 C or F 3 C-, wherein the radicals hydrogen, fluorine, chlorine or bromine are particularly preferred and the remainder of hydrogen is most preferred.
  • R 8 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, Cyano, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ cycloalkyl, C 3-7 -Cycloalky 1-Ci -3 - alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, aryl, aryl-Ci- 3 alkyl, heteroaryl, heteroaryl-C 1 -3 alkyl, R 13 -O-, R 13 -OC 1-3 -alkyl-, R 10 -SO 2 - (R 11 ) N- or R 10 -CO- (R 11 ) N-, where the abovementioned radicals are, if desired, independently of one another with one or more radicals selected from among A group consisting of C 1 -C 6 -alkyl, C 1 -
  • R 8 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, Ci -4 alkyl, Ci -4 alkoxy, C 3 - 6 cycloalkyl, Cs 6 cycloalkyl-oxy-, C 3 - 6 cycloalkyl Ci -3 alkoxy, phenyl, pyridyl, thienyl, furyl, R 10 -CO- (R 11) N-, or R 10 - SO 2 - (R 11) N-, where the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, carboxy, cyano, Ci -4 alkyl, Ci - 4- alkoxy, F 3 C, HF 2 C, FH 2 C, F 3 CO, HF 2 CO, FH 2 CO and (R 12 ) 2 N-CO- may be substituted, and R means 9 are each independently hydrogen, fluorine, chlorine or bro
  • R 8 is an R 10 -SO 2 - (R 11 ) N or R 10 -CO- (R 11 ) N group
  • R 9 is each independently hydrogen, fluorine, Chlorine or bromine, particularly preferably hydrogen.
  • the radical R 10 is preferably selected from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C 2-6 -AIkJ nyl-, C 3- 7 - cycloalkyl, Cs-yCycloalkyl-Ci-s-alkyl-, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl-Ci -3 - alkyl, heterocyclyl-Ci -3 alkyl heterocyclyl, aryl , aryl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, or (R 12) 2 N-, wherein the above groups optionally substituted by one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl, Ci- 3 alkoxy, hydroxy-C
  • R 10 are groups selected from the group C- ⁇ -6-alkyl, heterocyclyl, phenyl, phenyl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, or (R 12 ) 2 N-, where the above-mentioned heteroaryl radicals are to be understood as meaning 5- or 6-membered aromatic heteroaryl radicals which contain 1, 2 or 3 heteroatoms selected from N, O and S and where the abovementioned radicals are, if desired, independently of one another or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci- 3 alkyl, Ci -3 alkyl alkoxy, heterocyclyl, heterocyclyl-Ci- 3, hydroxy-C -3 alkyl, (R 12) 2 N-, and (R 12) 2 N-Ci -3 alkyl may be substituted.
  • the above-mentioned heteroaryl radicals are to be understood as meaning 5- or 6-membere
  • Very particularly preferred radicals R 10 are selected from the group consisting of Ci -4 alkyl radicals, especially methyl or ethyl, morpholinyl, piperidinyl, 4- Methylpiperidinyl-, pyrrolidinyl, phenyl, benzyl, 4- Fluorophenyl, pyridyl and (CH 3 ) 2 N-, wherein the above-mentioned radicals may optionally be substituted independently of one another with one or more radicals selected from the group fluorine, chlorine and bromine.
  • the radical R 11 is preferably selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-7 cycloalkyl, Cs-T-cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl, aryl, aryl-Ci -3 alkyl, heteroaryl or heteroaryl -C -3 - alkyl, wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci -3 alkyl with one or Ci -3 alkoxy, hydroxy Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, (R 12) 2 N-, and (R 12) 2 N-Ci- 3 may be substituted alkyl.
  • R 11 are groups selected from the group consisting of hydrogen, Ci 6 alkyl, Cs- ⁇ -cycloalkyl, Cs- ⁇ -cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, phenyl, phenyl-Ci -3 alkyl, heteroaryl or heteroaryl-Ci -3 - wherein under the above-mentioned heteroaryl groups 5- or 6-membered aromatic heteroaryl radicals are understood to be alkyl, the 1, 2 or 3 heteroatoms selected from N, O and S and wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci -3 alkyl , Cl, hydroxy-Ci -3 alkyl -3 alkoxy, heterocyclyl, heterocyclyl-Ci- 3 alkyl, (R 12) 2 N-, and (R 12) 2 N-C
  • R 11 are radicals selected from the group consisting of hydrogen, methyl, ethyl, phenyl and 4-fluorophenyl, where the abovementioned radicals are, if desired, independently of one another with one or more radicals selected from the group of fluorine, chlorine and bromine may be substituted,
  • R 10 is selected from the group consisting of C- ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Cs-7-cycloalkyl , Cs-y-cycloalkyl-cis-alkyl, C3 -7 cycloalkenyl, C3 -7 cycloalkenyl-Ci- 3 - alkyl, heterocyclyl-Ci- 3 alkyl, aryl, heterocyclyl, aryl C 1 -C 3 -alkyl-, heteroaryl-, heteroaryl-C 1 -C 3 -alkyl- or (R 12 ) 2 N-, wherein the abovementioned groups optionally have one or more radicals selected from the group consisting of fluorine, chlorine , bromo, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, heterocyclyl, heterocyclyl-C 1 -3 alkyl
  • R 11 is selected from the group consisting of hydrogen, hydrogen, Ci 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cs-7 cycloalkyl, Cs-Ci-s-yCycloalkyl alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl or
  • Heteroaryl-C- ⁇ - 3 -alkyl- wherein the above-mentioned radicals optionally independently of one another with one or more radicals selected from the group consisting from fluorine, chlorine, bromine, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, hydroxy-Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, (R 12 ) 2 N- and (R 12 ) 2 N-Ci- may be substituted 3- alkyl.
  • R 10 is selected from the group consisting of C- ⁇ - 6 alkyl, heterocyclyl, phenyl, phenyl-Ci- 3 alkyl, heteroaryl, heteroaryl-Ci -3 - Alkyl- or (R 12 ) 2 N-, where the heteroaryl radicals mentioned above are 5- or 6-membered aromatic heteroaryl radicals which contain 1, 2 or 3 heteroatoms selected from N, O and S and where the abovementioned radicals optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, heterocyclyl, heterocyclyl-cis-alkyl having one or, hydroxy-Ci -3 - alkyl-, (R 12) 2 N-, and (R 12) 2 N-Ci -3 alkyl may be substituted, and R 11 is selected from the group consisting of hydrogen, Ci -6 - alkyl, C
  • R 10 is selected from the group consisting of Ci -4 alkyl, particularly methyl or ethyl, morpholinyl, piperidinyl, 4-Methylpiperidinyl-, pyrrolidinyl, phenyl, 4- Fluorophenyl, benzyl, pyridyl and (CH 3 ) 2 N-, wherein the above-mentioned radicals may optionally be independently substituted with one or more radicals selected from the group consisting of fluorine, chlorine and bromine, and R 11 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and 4-fluorophenyl, where the abovementioned radicals are, if appropriate independently of one another may be substituted by one or more radicals selected from the group fluorine, chlorine and bromine.
  • a C 2-6 alkylene bridge is preferred such that, including the nitrogen atom joined to R 11 and the SO 2 or CO group attached to R 10 a heterocyclic ring is formed, wherein one or two -CH 2 - groups of the C 2 -6-alkylene bridge independently of one another by O, S, SO, SO 2 or -N (R 12 ) - may be replaced such that in each case two O or S atoms or an O with an S atom are not directly connected to each other, and wherein the C atoms of the above-mentioned C2-6 alkylene bridge optionally independently of one another with one or more radicals selected from the group consisting of fluorine, hydroxy, carboxy, F 3 C, Ci-3-alkyl and Ci-3-alkoxy may be substituted .
  • heterocyclic rings of the formulas (IIa), (IIb), (Mc) or (Nd) are particularly preferred.
  • radical R 8 in combination with the radicals R 10 and R 11 forms heterocyclic rings of the formulas (IIa), (IIb), (Nc) or (Md), and other radicals and groups are defined as above or below.
  • the radical R 12 is preferably independently selected from the group consisting of hydrogen and Ci- 6 alkyl group, wherein one or more hydrogen atoms of the Ci may be 6 alkyl group replaced by fluorine.
  • radicals R 12 are each independently of one another hydrogen or a C 1-6 -alkyl group.
  • the most preferred radicals R 12 are each independently hydrogen or a methyl group.
  • the radical R 13 is preferably independently selected from the group consisting of hydrogen and Ci -3 alkyl, wherein one or more hydrogen atoms of the Ci -3 - group may be replaced by fluorine.
  • radicals R 13 are each independently of one another hydrogen or a methyl group.
  • A, B, L, i, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined above have.
  • Ci -4 -alkylene bridge is a Ci -4 -alkylene bridge, wherein the Ci -4 -alkylene bridge may optionally be substituted independently more radicals selected from the group consisting of fluoro, hydroxy, carboxy, cyano, nitro, F 3 C-, HF 2 C-, FH with one or 2 C -, Ci- 4 alkyl, Cs-7 cycloalkyl, Cs-yCycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, aryl, aryl-Ci -3 alkyl , Heteroaryl, heteroaryl
  • R 1 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 - cycloalkyl-Ci -3 alkyl, heterocyclyl -, heterocyclyl-Ci -3 alkyl, aryl, aryl Ci -3 alkyl, heteroaryl or heteroaryl-Ci -3 alkyl, wherein the above mentioned groups optionally selected independently with one or more groups selected from the group consisting of fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro, F 3 C-, Ci -3 alkyl, Ci -3 alkoxy and hydroxy-Ci -3 alkyl substituted could be,
  • R 2 Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 -AIkJ nyl-, Ci -6 alkoxy-Ci- 3 alkyl, Ci -6 alkyl S-Ci -3 alkyl-, Cs- 7 cycloalkyl, Cs-rCycloalkyl-cis-alkyl, heterocyclyl, heterocyclyl-cis-alkyl, aryl, aryl-Ci -3 alkyl, heteroaryl or heteroaryl-C 3- alkyl-, wherein the abovementioned radicals optionally together with one or more radicals selected from among fluorine, chlorine, bromine, iodine, F 3 C-, HF 2 C-, FH 2 C-, Hydroxy, carboxy, cyano, nitro, C 1 -3 alkyl, (R 12 ) 2 N, (R 12 ) 2 N-SO 2 -, R 12 -CO- (R 12 ) N- , R 12
  • R 5 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 7 cycloalkyl, C 3-7 -
  • R 6 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cs-y-cycloalkyl, C3-7- cycloalkyl-Ci- 3 alkyl, C 3 - 7 -Cycloalkenyl, Cs-yCycloalkenyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci 3 -alkyl, aryl, aryl-C 3 -alkyl, heteroaryl or heteroaryl-C 3 -alkyl -, Wherein the above mentioned radicals optionally independently of one another With one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, C 3 - 6 cycloalkyl, heterocyclyl, heterocyclyl C- ⁇ - 3 alkyl, aryl, aryl-Ci- 3 alkyl
  • R, R 13 -O-Ci alkyl 13 -3 -O-, -S- R 13 or R 13 -S-Ci -3 alkyl may be substituted
  • R 7 is hydrogen or Ci -4 alkyl, wherein one or more hydrogen atoms of the Ci -4 alkyl group by
  • R 8 is hydrogen, fluorine, chlorine, bromine, cyano -, Ci -6 alkyl, C 2 - 6 alkenyl, C 2-6 - alkynyl, Cs-7 cycloalkyl, Cs-Ci-s-yCycloalkyl alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, aryl, aryl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, R 13 -O-, R 13 -O-Ci -3 -alkyl-, R 10 -SO 2 - (R 11 ) N- or R 10 -CO- (R 11 ) N-, where the abovementioned radicals, where appropriate, independently of one another one or more radicals selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkoxy, fluoro, chloro, brom
  • HF 2 C, FH 2 C, F 3 CO, HF 2 CO, FH 2 CO and R 12 -SO 2 - (R 12 ) N- may be substituted, and
  • R 10 de-alkyl, C 2-6 alkenyl, C 2-6 -AIkJ nyl-, Cs.y-cycloalkyl, C3-7 cycloalkyl Ci 3 alkyl, C 3-7 - Cycloalkenyl, Cs-ycycloalkenyl-Ci-s-alkyl, heterocyclyl,
  • R 12 is -CO (R 12) N-, R 12 -SO 2 (R 12) N-, (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl, and (R 12) 2 N-
  • R 11 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, Cs.y-cycloalkyl-, C 3-7 -
  • Ci -3 alkoxy, hydroxy-Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, (R 12) 2 N-, and (R 12) 2 N-Ci -3 alkyl substituted can be, or R 10 and R 11 together form a C 2-6 alkylene bridge such that under
  • a heterocyclic ring is formed, one or two -CH 2 groups of the C 2-6 -alkylene bridge being independently of each other represented by O , S, SO, SO 2 or -N (R 12 ) - may be replaced such that in each case two O or S atoms or an O are not directly connected to an S atom, and wherein the C atoms of the above C2-6 -alkylene bridge are optionally substituted independently of one another more radicals selected from the group consisting of fluoro, hydroxy, carboxy, or with a, F 3 C-, Ci -3 alkyl and Ci -3 alkoxy substituted could be.
  • R 12 is hydrogen or a C- ⁇ -6-alkyl group wherein one or more hydrogen atoms of the Ci-6-alkyl group by
  • Fluorine can be replaced,
  • R 13 is hydrogen or a Ci -3 alkyl group wherein one or more hydrogen atoms of the alkyl group by Ci -3
  • Fluorine can be replaced,
  • a thienyl, thiazolyl, pyrazolyl or pyridyl
  • Ci- 4 alkylene bridge is a Ci- 4 alkylene bridge, wherein the Ci -4 -alkylene bridge may optionally be substituted independently more radicals selected from the group consisting of fluorine, Ci -4 alkyl, phenyl or benzyl may be substituted with one or , and wherein two -4 -alkylene bridge bound to the same carbon atom of the Ci Ci -4 alkyl radicals to form a C 3-6 cycloalkyl group may be linked together, and where the radicals mentioned above and consisting of the Ci -4 6 cycloalkyl radical may be optionally substituted independently with one or more radicals selected from the group consisting of fluoro, hydroxy and Ci -3 alkoxy, - alkyl radicals formed C3
  • R 1 is hydrogen, Ci -4 alkyl, C 3 - 4 alkenyl, C 3 - 6 cycloalkyl, C 3-6 cycloalkyl d- 3 alkyl, wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting of fluoro, hydroxy and Ci -3 alkoxy may be substituted,
  • Heteroatoms selected from N, O and S contain and wherein the above-mentioned radicals optionally independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, Ci -3 - alkyl, F 3 C, HF 2 C, FH 2 C, H 2 N and C 1 -3 alkoxy may be substituted,
  • R 5 Ci- 6 alkyl, cyclopropyl, C 3 - 6 cycloalkyl-Ci- 3 alkyl or phenyl-Ci -3 - alkyl, wherein the above mentioned groups optionally selected independently with one or more groups selected from of the Group consisting of fluorine, chlorine, bromine, iodine consisting, cyano, hydroxy, carboxy, Ci -4 alkyl, Ci -4 alkoxy, and (R 12) 2 N- may be substituted,
  • R 6 is hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 -6 cycloalkyl, C 3-6 - cycloalkyl-Ci 3 alkyl, heterocyclyl , Heterocyclyl-C 1-3 -alkyl-, phenyl-,
  • R 7 is hydrogen or Ci -4 alkyl, wherein one or more hydrogen atoms of the Ci -4 alkyl group may be replaced by fluorine,
  • R 12 ) 2 N- and (R 12 ) 2 N-Ci- may be substituted 3- alkyl
  • R 11 is hydrogen, C 1-6 -alkyl, Cs-e-cycloalkyl, Cs-e-cycloalkyl-ds-alkyl, heterocyclyl, heterocyclyl-C 3 -alkyl, phenyl, phenyl-C 3 alkyl, heteroaryl or heteroaryl-Ci -3 alkyl, which radicals under the above-mentioned heteroaryl groups 5- or 6-membered aromatic heteroaryl is to be understood that 1, 2 or 3
  • (R 12 ) 2 N- and (R 12 ) 2 N-Ci- may be substituted 3- alkyl, or
  • R 12 is hydrogen or a Ci-6-alkyl group wherein one or more hydrogen atoms of the Ci -6 alkyl group may be replaced by fluorine,
  • Ci -4 alkyl or Ci -4 alkoxy are each independently hydrogen, fluorine, chlorine, bromine, hydroxy, Ci -4 alkyl or Ci -4 alkoxy, wherein the above-mentioned groups may be optionally substituted with one or more fluorine atoms, and
  • B is selected from the group consisting of HH CH 3 HH
  • one or more hydrogen atoms may optionally be replaced by fluorine
  • R 2 is n-propyl, n-butyl, 2-propynyl, 2-butynyl, cyclohexylmethyl, cyclopentylmethyl, benzyl, 2-phenylethyl, pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl, with the above mentioned propyl, butyl, propynyl, butynyl, cyclohexylmethyl and Cyclopentylmethyl radicals optionally with one or more fluorine atoms and the benzyl, 2-phenylethyl, pyridylmethyl, especially 2-pyridylmethyl, furanylmethyl, thienylmethyl or Thiazolylmethyl radicals optionally independently of one another with one or more radicals selected from the group of fluorine, chlorine, bromine, methyl, F 3 C-, HF 2 C-, FH 2 C- and H 2 N- may be substituted,
  • R 5 Ci -4 alkyl in particular n-butyl, or cyclopropyl, wherein one or more hydrogen atoms of the above-mentioned radicals may be optionally replaced by fluorine atoms,
  • R 6 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 3 - 6 cycloalkyl, C 3-5 cycloalkyl, Ci- 3 alkyl, cyclopentyl-Cis-alkyl, phenyl Ci -3 alkyl alkyl or tetrahydropyranyl-Ci -3, wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluorine, pyrrolidin-1 -ylmethyl- with one or, hydroxy, cyano, Ci 3 alkyl, C 1 -3 -AIkOXy-, C 1 -3 alkyl-S-, hydroxy-C 1-3 alkyl, (R 12) 2 N-, (R 12 ) 2 NC 1 -3 -alkyl, (R 12 ) 2 N-CO-N (R 12 ) - and (R 12 ) 2 N-SO 2 - may be substituted,
  • R 10 Ci -4 alkyl in particular methyl or ethyl, morpholinyl, piperidinyl,
  • R 11 is hydrogen, methyl, ethyl, phenyl or 4-fluorophenyl, where the abovementioned radicals may optionally be substituted independently of one another by one or more radicals selected from among fluorine, chlorine and bromine, or
  • R 12 is hydrogen or a Ci -6 alkyl group wherein one or more hydrogen atoms of the Ci -6 alkyl group by
  • Fluorine can be replaced, means.
  • Particularly preferred individual compounds are selected from the group consisting of:
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I.
  • Ci -n- alkyl where n, if not otherwise indicated, may have a value of 1 to 10, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl etc.
  • Ci -n- alkylene where n, if not otherwise indicated, has a value of
  • 1 to 8 means a saturated, branched or unbranched hydrocarbon bridge having 1 to n carbon atoms.
  • groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-methylene (-CH (CH 3 ) -), 1-methyl-ethylene (-CH (CH 3 ) -CH 2 -), 1, 1-dimethyl-ethylene (-C (CH 2 ) 2 -CH 2 -), n-prop-1, 3-ylene (- CH 2 -CH 2 -CH 2 -), 1 - Methylprop-1, 3-ylene (-CH (CHs) -CH 2 -CH 2 -), 2-methylprop-1, 3-ylene (-CH 2 -CH (CH 3 ) -CH 2 -), etc., as well as the corresponding mirror-image forms.
  • C 2-n -alkenyl where n, if not otherwise indicated, has a value of 2 to 6, denotes a branched or unbranched hydrocarbon group with
  • Examples of such groups include ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
  • C 2-n alkynyl where n, if not otherwise indicated, has a value of 2 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and a C ⁇ C triple bond.
  • groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- Pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
  • Ci-n alkoxy or Ci -n alkyloxy denotes a Ci n-alkyl-O group wherein n Ci- alkyl is as defined above.
  • examples of such groups include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • C 3 - n -cycloalkyl denotes a saturated monocyclic group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • C 3 - n cycloalkyloxy denotes a C 3 - s cycloalkyl-O-group, wherein C 3 - n - cycloalkyl is as defined above.
  • Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.
  • C 3 - n -cycloalkyl-ci- n- alkoxy designates a C 3-n -cycloalkyl group, in which C 3-n -cycloalkyl is as defined above and that having a C 1 -n -alkoxy group via a carbon atom the Ci -n alkoxy group is connected.
  • Examples of such groups include cyclopropylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, etc.
  • heterocyclyl denotes a saturated five, six or seven membered ring system or a 5-12 membered bicyclic ring system comprising one, two, three or four heteroatoms selected from N, O and / or S, such as for example, a morpholinyl, piperidinyl, piperazinyl,
  • Thiomorpholinyl oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxathiolanyl, imidazolidinyl, tetrahydropyranyl, pyrrolinyl, Tetrahydrothienyl, oxazolidinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, azetidinyl, 1,3-diazacyclohexanyl or pyrazolidinyl.
  • aryl denotes a phenyl, biphenyl, indanyl, indenyl, 6,7,8,9-tetrahydrobenzocycloheptenyl, 1,2,3,4-tetrahydronaphthyl or naphthyl radical.
  • heteroaryl used in this application denotes a heterocyclic, mono- or bicyclic aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S, where the term heteroaryl also includes the partially hydrogenated heterocyclic, comprising aromatic ring systems.
  • groups are pyrrolyl, furanyl, thienyl, pyridyl-N-oxide, thiazolyl, imidazolyl, oxazolyl, triazinyl, triazolyl, triazolyl, 1, 2,4-oxadiazoyl, 1, 3 , 4-oxadiazoyl, 1, 2,5-
  • Preferred heteroaryl groups are furanyl, thienyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, indolyl, benzofuranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl and 2,3-dihydrobenzo [1 , 4] dioxinyk
  • pyrazole includes the isomers 1 H, 3H and 4H-pyrazole.
  • Pyrazolyl is preferably 1H-pyrazolyl.
  • imidazole includes the isomers 1 H, 2H and 4H imidazole.
  • a preferred meaning of imidazolyl is 1H-imidazolyl.
  • the meaning triazole includes the isomers 1 H, 3H and 4H- [1, 2,4] triazole and 1 H, 2H and 4H [1,2,3> triazole.
  • the meaning triazolyl therefore includes 1 H- [1, 2,4] -triazole-1 -, 3- and 5-yl, 3H- [1, 2,4] -triazol-3 and 5-yl, 4H- [ 1,2,4] -TriazoK3-, 4- and 5-yl, 1H- [1,2,3] -TriazoH-, 4- and 5-yl, 2H- [1,2,3] -triazole 2-, 4- and 5-yl and 4H- [1,2,3] triazole-4 and 5-yl.
  • tetrazole includes the isomers 1H, 2H and 5H-tetrazole.
  • the meaning tetrazolyl therefore includes 1 H-tetrazol-1 - and 5-yl, 2H-tetrazol-2 and 5-yl and 5H-tetrazol-5-yl.
  • indole includes the isomers 1 H and 3H indole.
  • indolyl is preferably 1H-indol-1-yl.
  • the meaning isoindole includes the isomers 1 H and 2H isoindole.
  • the bond can be to one of the abovementioned heterocyclic or heteroaromatic groups, via a C atom or optionally an N atom.
  • these can also be represented in the form of a structural formula.
  • An asterisk ( * ) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule.
  • the residues N-piperidinyl (a), 4-piperidinyl (b), 2-ToIyI (c), 3-ToIyI (d) and 4-thiol (e) are depicted as follows:
  • each hydrogen atom on the substituent can be removed and the valence liberated thereby serves as a binding site to the remainder of a molecule.
  • a bond of a substituent to the center of the group A is shown, unless otherwise stated, means that this substituent may be bonded to any free, H-atom bearing position of the group A.
  • radicals and substituents described above may, unless otherwise indicated, be monosubstituted or polysubstituted by fluorine.
  • Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated Alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.
  • Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid) or as salts with pharmaceutically acceptable Bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid) or as salts with pharmaceutically acceptable Bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammoni
  • the compounds according to the invention can be obtained by using synthesis methods known in principle from those known to those skilled in the art (see, for example: Houben Weyl - Methods of Organic Chemistry, Vol. E22, Synthesis of Peptides and Peptidomimetics, M. Goodman, A. Felix, L. Moroder , C. Toniolo Eds., Georg Thieme Verlag Stuttgart, New York).
  • the skilled worker is the synthesis of the compounds of the invention with knowledge of their structure starting from known starting materials without further information possible.
  • the compounds can be obtained according to the manufacturing method explained in more detail below.
  • Scheme A exemplifies the synthesis of the compounds of the invention.
  • an amide is prepared by standard coupling techniques.
  • the resulting after deprotection amine is reductively aminated with a Boc-protected amino aldehyde.
  • the amine formed after renewed deprotection is coupled to the final product with an isophthalic acid monoamide building block.
  • amino isophthalic acid diester is reacted with a corresponding sulphonyl chloride, the sulphonamide nitrogen is alkylated and one of the two ester groups is cleaved.
  • a Dipeptidbaustein according to Scheme A is prepared by reductive amination, coupled, saponified the ester function and coupled the acid with an appropriate amine to the final product.
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerated salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen by reaction with inorganic bases, the compound of formula (I) can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used.
  • the alkali metal and alkaline earth metal salts of the compound of the formula (I) with acidic hydrogen are preferably the alkali and alkaline earth hydroxides and hydrides into consideration, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium preferably, sodium and Potassium hydroxide are particularly preferred.
  • the compounds of the general formula (I) according to the invention and their corresponding pharmaceutically acceptable salts are in principle suitable for treating and / or preventing all those conditions or diseases which are caused by a pathological form of the ⁇ -amyloid peptide, such as
  • Example ⁇ -amyloid patches characterized or can be influenced by inhibition of ß-secretase.
  • the compounds of the invention are particularly useful for the prophylaxis, treatment or even slowing down the progression of diseases such as Alzheimer's Disease (AD) and other diseases associated with abnormal processing of the amyloid precursor
  • APP Abeta Protein
  • Corresponding diseases include MCI (mild cognitive impairment), trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), Alzheimer's dementia with Lewy bodies, trauma, stroke, pancreatitis , Inclusion body myositis (IBM), as well as other peripheral amyloidoses, diabetes and arteriosclerosis.
  • MCI mimild cognitive impairment
  • trisomy 21 Down Syndrome
  • cerebral amyloid angiopathy degenerative dementia
  • HHWA-D hereditary cerebral hemorrhage with Dutch-type amyloidosis
  • IBM Inclusion body myositis
  • the compounds are preferably suitable for the prophylaxis and treatment of Alzheimer's disease.
  • the compounds of the invention can be used as monotherapy and also in combination with other compounds that can be administered for the treatment of the above-mentioned diseases.
  • the compounds of the invention are particularly useful in mammals, preferably in primates, more preferably in humans, for the treatment and / or prophylaxis of the above-mentioned conditions and diseases.
  • the compounds according to the invention can be administered orally, parenterally (intravenously intramuscularly, etc.), intranasally, sublingually, by inhalation, intrathecally, topically or rectally.
  • the compounds of the invention may be formulated such that the compounds of the invention do not come into contact with the acid gastric juice.
  • Suitable oral formulations may comprise enteric coatings, for example, which release the active substances only in the small intestine. Such tablet coatings are known in the art.
  • Suitable pharmaceutical formulations for administering the compounds according to the invention are, for example, tablets, pellets, dragees, capsules, powders, suppositories, solutions, elixirs, active substance patches, aerosols and suspensions. About 0.1 to 1000 mg of one of the compounds of the invention or a mixture of several of these compounds alone or together with pharmaceutically conventional excipients such as excipients, diluents, binders, stabilizers, preservatives, dispersants, etc. to a dosage unit in a manner known to those skilled in the art and formulated.
  • a dosage unit e.g., tablet
  • a dosage unit preferably contains between 2 and 250 mg, more preferably between 10 and 100 mg of the compounds of the invention.
  • the pharmaceutical formulations are 1, 2, 3 or 4, more preferably 1 -2, most preferably administered once a day.
  • the dosage required to achieve a corresponding effect in treatment or prophylaxis usually depends on the compound to be administered, on the patient, on the nature and severity of the disease or condition and on the nature and frequency of administration, and is at the discretion of the physician to be treated ,
  • the administered amount of the compounds according to the invention is expediently in the range from 0.1 to 1000 mg / day, preferably 2 to 250 mg / day, particularly preferably 5 to 100 mg / day.
  • the compounds according to the invention of the formula (I), optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid , Water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in conventional pharmaceutical preparations such as tablets, Pellets, dragees, capsules, powders, suppositories, solutions, elixirs, drug patches, aero
  • the compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and / or prophylaxis of the diseases and conditions indicated above.
  • active substances for such combinations come as further active substances, in particular those into consideration, for example, enhance the therapeutic efficacy of a compound of the invention with respect to one of the above indications and / or allow a reduction in the dosage of a compound according to the invention.
  • Therapeutics suitable for such combination include e.g. beta-secretase inhibitors; gamma-secretase inhibitors; Amyloid aggregation inhibitors such. Alzhemed; direct or indirect neuroprotective substances; anti-oxidants, e.g. Vitamin E or Ginkolide; anti-inflammatory substances such.
  • HMG-CoA reductase inhibitors (statins); Acetylcholinesterase inhibitors such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such. Eg memantine; AMPA agonists; the concentration or release of neurotransmitters modulating substances such as NS-2330; the release of growth hormone-inducing substances such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; Antibiotics such as minocycline or rifampicin; PDE-IV and PDE-IX inhibitors, GABAA inverse agonists, nicotinic agonists, histamine H3 antagonists, 5 HT-4 agonists or partial agonists, 5HT-6 antagonists, a2-adrenoreceptor antagonists, muscarinic M1 agonists, muscarinic M2 antagonists, metabotropic glutamate Receptor 5 positive modulators,
  • the compounds according to the invention, or their physiologically acceptable salts, and the further active ingredients to be combined therewith can be present together in one dosage unit, for example a tablet or capsule, or separately in two identical or different dosage units, for example as so-called kit-of-parts.
  • the compounds of the invention may also be used in combination with immunotherapies, e.g. active immunization with Abeta or parts thereof or passive immunization with humanized anti-Abeta antibodies for the treatment of the above diseases and conditions.
  • immunotherapies e.g. active immunization with Abeta or parts thereof or passive immunization with humanized anti-Abeta antibodies for the treatment of the above diseases and conditions.
  • the dose for the previously mentioned combination partners is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.
  • Another object of this invention relates to the use of a compound of the invention or a physiologically acceptable salt of such a compound in combination with at least one of the previously described as combination partners active ingredients for the preparation of a medicament, which is suitable for the treatment or prophylaxis of diseases or conditions by Inhibition of ß-secretase can be influenced.
  • both agents are administered to the patient together; in a staggered use both active ingredients are the Patients in a period of less than or equal to 12, in particular less than or equal to 6 hours consecutively administered.
  • a further subject of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active ingredients previously described as combination partners in addition to optionally one or more inert carriers and / or diluents.
  • a pharmaceutical composition according to the invention comprises a combination of a compound of the formula (I) according to the invention or a physiologically tolerated salt of such a compound and at least one other of the abovementioned active compounds besides optionally one or more inert carriers and / or diluents.
  • the compounds of the invention inhibit the proteolysis of the APP protein between the amino acids Met595 and Asp596 (the numbering refers to the APP695 isoform) or the proteolysis of other APP isoforms such as APP751 and APP770 or mutant APP at the corresponding site, also called ⁇ -secretase Interface is called.
  • the inhibition of ⁇ -secretase should thus lead to a reduced production of the ⁇ -amyloid peptide (A ⁇ ).
  • the activity of ⁇ -secretase can be assayed in assays based on different detection technologies.
  • a catalytically active form of ⁇ -secretase is incubated with a potential substrate in a suitable buffer.
  • HPLS-MS analysis, fluorescence assays, fluorescence quenching assays, luminescence assays are a non-representative selection of the different possibilities.
  • Assay systems in which the effectiveness of a compound can be demonstrated are e.g. In US Pat. Nos. 5,942,400 and 5,744,346 and in the following.
  • An alternative Assay format involves the displacement of a known ⁇ -secretase ligand by a test substance (US 2003/0125257).
  • either the APP protein or parts thereof or any amino acid sequence which can be hydrolyzed by the ⁇ -secretase can be used.
  • a selection of such sequences can be found e.g. in Tomasselli et al. 2003 in J. Neurochem 84: 1006.
  • Such a peptide sequence may be coupled to suitable dyes which allow indirect detection of proteolysis.
  • the enzyme source used may be the complete ⁇ -secretase enzyme or mutants with catalytic activity or only parts of the ⁇ -secretase which still contain the catalytically active domain.
  • Various forms of ⁇ -secretase are known and available and can serve as an enzyme source in an appropriate experimental approach. This includes the native enzyme as well as the recombinant or synthetic enzyme.
  • Beta Site APP Cleaving Enzyme BACE
  • Asp2 Asp2
  • memapsin 2 is known e.g.
  • ⁇ -secretase may be, for. B. be extracted from human brain tissue and purified or produced recombinantly in mammalian cell cultures, insect cell cultures, yeasts or bacteria.
  • IC50 value of a substance is defined as the substance concentration at which a 50% reduction of the detected signal is measured compared to the batch without test compound.
  • Substances are considered to inhibit ⁇ -secretase if, under these conditions, their IC50 is less than 50 ⁇ M, preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M and most preferably less than 100 nM.
  • an assay for detecting ⁇ -secretase activity may look like this: the ectodomain of BACE (amino acids 1-454) fuses to the recognition sequence for an anti-Myc antibody, and a poly-histidine is deleted from HEK293 / APP / BACE ec t , Secreted cells in OptiMEM ® (Invitrogen) overnight. A 10 ⁇ l aliquot of this cell culture supernatant serves as an enzyme source. The enzyme is stable for more than 3 months when stored at 4 ° C or -20 ° C in Opii M EM ® .
  • the substrate used is a peptide having the amino acid sequence SEVNLDAEFK, to which the Cy3 fluorophore (Amersham) is coupled at the N-terminal end and the Cy5Q fluorophore (Amersham) at the C-terminus.
  • the substrate is dissolved in DMSO at a concentration of 1 mg / ml and used in the experiment at a concentration of 1 ⁇ M.
  • the test mixture contains 20 mM NaOAc, pH 4.4 and at most 1% DMSO.
  • the experiment is carried out in a 96-well plate in a total volume of 200 ⁇ l for 30 minutes at 30 ° C.
  • the cleavage of the substrate is recorded kinetically in a fluorimeter (ex: 530 nm, em: 590 nm).
  • the assay is started by addition of the substrate.
  • IC 50 value for the test compound is calculated using standard software (eg GraphPad Prism ®) from the percentage inhibition of the substance at different test concentrations. The relative inhibition is calculated from the reduction in the signal intensity in the presence of the substance with respect to the signal intensity without substance.
  • the compounds (1) - (42) mentioned in the above table, as measured by the test described above, have IC 50 values less than 30 ⁇ M.
  • ⁇ -secretase activity can also be studied in cellular systems. Since APP is a substrate for the ⁇ -secretase and A ⁇ is secreted by the cells after processing of APP by the ⁇ -secretase, cellular assay systems for detecting ⁇ -secretase activity are based on detection of the amount of A ⁇ formed over a defined period of time.
  • a selection of suitable cells includes, but is not limited to, human embryonic kidney fibroblasts 293 (HEK293), Chinese hamster ovary (CHO) cells, human H4 neuroglioma cells, human U373 MG astrocytoma glioblastoma cells, mouse neuroblastoma N2a cells, stable or transient APP or mutated forms of APP, such as. As the Swedish or London or Indiana mutation express.
  • the transfection of the cells takes place z.
  • the secretion of A ⁇ can also be obtained from cells without genetic modification with a correspondingly sensitive Aß detection assay such.
  • B ELISA or HTRF are measured.
  • Cells that can be used for this purpose include, among other cells, for example, human IMR32 neuroblastoma cells.
  • the secretion of A ⁇ can also be in mice transgenic from the brain of embryos or pups of APP, such as. In Science of Hsiao et al 1996 Science 274: 99-102, or from other organisms such as e.g. Guinea pig or rat-derived cells are examined. Substances are considered to inhibit ⁇ -secretase if, under these conditions, their IC50 is less than 50 ⁇ M, preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M and most preferably less than 100 nM.
  • U373-MG cells stably expressing the APP are dissolved in water culture in a culture medium such as DMEM + glucose, sodium pyruvate, glutamine and 10% FCS at 37 ° C saturated atmosphere cultivated with 5% CO2.
  • a culture medium such as DMEM + glucose, sodium pyruvate, glutamine and 10% FCS at 37 ° C saturated atmosphere cultivated with 5% CO2.
  • the cells are incubated with different concentrations of the compound between 50 ⁇ M and 50 ⁇ M for 12-24 h.
  • the substance is dissolved in DMSO and is used for the assay
  • a ⁇ Diluted so that the DMSO concentration does not exceed 0.5%.
  • the production of A ⁇ during this period is determined by means of an ELISA, the antibodies 6E10 (Senentek) and SGY3160 (C Eckman, Mayo Clinic, Jacksonville, Fla., USA) as catcher antibodies bound on the microtiter plate and A ⁇ 40 and Aß42 specific antibodies (Nanotools, Germany) coupled to alkaline Phosphatase used as a detection antibody, nachg duplicate.
  • Non-specific binding of proteins to the microtiter plate is prevented by blocking with Block Ace (Serotec) prior to the addition of the A ⁇ -containing culture supernatant.
  • the quantification of the Aß amounts contained in the cell supernatant by adding the substrate for alkaline phosphatase CSPD / Sapphire II (Applied Biosystems) according to the manufacturer. Possible nonspecific effects of the test compound on the vitality of the cell are excluded by determining the same by means of AlamarBlue (resazurin) reduction over 60 minutes.
  • the potency of non-toxic substances is determined by calculating the concentration that causes a 50% reduction in the amount of A ⁇ secreted compared to untreated cells.
  • transgenic animals expressing APP and / or ⁇ -secretase can be used to test the inhibitory activity of compounds of this invention.
  • Corresponding transgenic animals are z.
  • animal models are used that show parts of the characteristics of AD pathology.
  • ⁇ -secretase inhibitors of this invention and subsequent study of the pathology of the animals is another alternative to show ⁇ -secretase inhibition by the compounds.
  • the compounds are applied so that they can reach their site of action in a pharmaceutically effective form and amount.
  • the test for the detection of cathepsin D (EC: 3.4.23.5) inhibition was carried out as follows: In a 96-well dish, 20 ⁇ M recombinant cathespin D (Calbiochem, cat. No. 219401) in 20 mM sodium acetate buffer pH 4.5 are incubated with 5 ⁇ M substrate peptide and various concentrations of the test substance at 37 ° C. and the conversion over 60 minutes in a Fluorescence meter recorded (emission: 535 nm, extinction: 340 nm).
  • the peptide substrate used has the following sequence: NH 2 -Arg- Glu (Edans) -Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys (Dabcyl) -Arg-COOH (Bachern).
  • a peptide or protein substrate with a cathepsin D proteolytically cleavable sequence can also be used.
  • the test substances are dissolved in DMSO and are used diluted to a maximum of 1% DMSO in the assay. The assay is started by addition of the substrate.
  • batches without enzyme or without inhibitor are included on each plate.
  • the IC 5 O value for the test compound is determined using standard software (eg GraphPad
  • Prism ® calculated from the percentage inhibition of the substance at different test concentrations The relative inhibition is calculated from the reduction in the signal intensity in the presence of the substance with respect to the signal intensity without substance.
  • ⁇ * denotes the binding site of a residue
  • HPLC 1 data were generated under the following conditions:
  • a stationary phase used was a Varian column, Microsorb 100 Ci 8 3 ⁇ m, 4.6 mm ⁇ 50 mm, batch no. 2231 108 (column temperature: constant at 25 ° C.).
  • the diode array detection took place in the wavelength range 210-300 nm.
  • HPLC-MS data were generated under the following conditions:
  • the mobile phase used was: A: water with 0.13% TFA B: acetonitrile with 0.10% TFA
  • the stationary phase used was a Waters column, Xterra MS Ci 8 2.5 ⁇ m, 4.6 mm ⁇ 30 mm (column temperature: constant at 25 ° C.).
  • the diode array detection took place in the wavelength range 210-500 nm.
  • Example 1 The diode array detection took place in the wavelength range 210-500 nm.
  • 2-g was prepared analogously to 2-e from 2-f and 1- (1-methyl-1H-pyrazol-4-yl) -ethylamine.
  • active ingredient denotes one or more compounds according to the invention including their salts.
  • active ingredient also includes the other active substances.
  • Composition 1 tablet contains: Active substance 100.0 mg
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a tray drying cabinet at 50 ° C., sieve again (1.5 mm mesh size) and the lubricant is added. The ready-to-use mixture is processed into tablets.
  • Tablet weight 220 mg Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.
  • Composition 1 tablet contains: active substance 150.0 mg
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm.
  • the granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
  • Composition 1 capsule contains:
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules.
  • Example D Suppositories with 150 mg active substance
  • Composition 1 suppository contains: active ingredient 150.0 mg
  • Polyethylene glycol 1500 550.0 mg
  • the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
  • composition active substance 10.0 mg
  • the active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP06778201A 2005-08-11 2006-08-08 Verbindungen zur behandlung der alzheimer erkrankung Withdrawn EP1915352A1 (de)

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EP06778201A EP1915352A1 (de) 2005-08-11 2006-08-08 Verbindungen zur behandlung der alzheimer erkrankung

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EP05017476 2005-08-11
PCT/EP2006/065154 WO2007017509A1 (de) 2005-08-11 2006-08-08 Verbindungen zur behandlung der alzheimer erkrankung
EP06778201A EP1915352A1 (de) 2005-08-11 2006-08-08 Verbindungen zur behandlung der alzheimer erkrankung

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CA (1) CA2618019A1 (enrdf_load_stackoverflow)
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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
CA2603404A1 (en) * 2005-03-30 2006-10-05 Boehringer Ingelheim International Gmbh Substituted 1,2-ethylendiamines, medicaments comprising said compound; their use and their method of manufacture
WO2006110668A1 (en) 2005-04-08 2006-10-19 Comentis, Inc. Compounds which inhibit beta-secretase activity and methods of use thereof
JP2009503027A (ja) * 2005-08-03 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング アルツハイマー病ｉｉの治療のための置換エタン−１，２−ジアミン
WO2007017511A2 (de) * 2005-08-11 2007-02-15 Boehringer Ingelheim International Gmbh Verbindungen zur behandlung der alzheimer erkrankung
EP1915339A1 (de) * 2005-08-11 2008-04-30 Boehringer Ingelheim International GmbH Inhibitoren der beta-sekretase zur behandlung der alzheimer- erkrankung
US20100168070A1 (en) * 2005-08-11 2010-07-01 Niklas Heine Compounds for the treatment of alzheimer's disease
EP2578212B1 (en) 2010-05-24 2016-07-06 Farmalider, S.A. Compound inhibiting activation of the enzyme erk1/2 for use in the treatment of neurogenerative illnesses
AR091994A1 (es) 2012-03-16 2015-03-18 Keclon S A Metodo de remocion de esteril glicosidos

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06507782A (ja) * 1990-06-15 1994-09-08 サイオス　ノバ　インコーポレイテッド アルツハイマー病のアミロイド形成開症状を示すヒト以外の組換え哺乳動物
ATE447016T1 (de) * 1991-01-21 2009-11-15 Elan Pharm Inc Prüfung und modell für alzheimers-krankheit
JPH07506720A (ja) * 1992-01-07 1995-07-27 アテナ　ニューロサイエンシーズ，　インコーポレイテッド アルツハイマー病のトランスジェニック動物モデル
US5604102A (en) * 1992-04-15 1997-02-18 Athena Neurosciences, Inc. Methods of screening for β-amyloid peptide production inhibitors
JPH06186014A (ja) * 1992-10-01 1994-07-08 Kayaba Ind Co Ltd 弾性部材の膨張量測定装置
CZ184194A3 (en) * 1993-08-09 1995-03-15 Lilly Co Eli Aspartylprotease inhibitor and method of identifying thereof
PT730643E (pt) * 1993-10-27 2001-06-29 Lilly Co Eli Animais transgenicos portadores do alelo de app com mutacao sueca
US5877399A (en) * 1994-01-27 1999-03-02 Johns Hopkins University Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease
US5744346A (en) * 1995-06-07 1998-04-28 Athena Neurosciences, Inc. β-secretase
WO1996040885A2 (en) * 1995-06-07 1996-12-19 Athena Neurosciences, Inc. β-SECRETASE, ANTIBODIES TO β-SECRETASE, AND ASSAYS FOR DETECTING β-SECRETASE INHIBITION
EP1453516A2 (de) * 2001-10-17 2004-09-08 Boehringer Ingelheim Pharma GmbH & Co.KG 5-substituierte 4-amino-2-phenylamino-pyrimdinderivate und ihre verwendung als beta-amyloid modulatoren
CH698246B1 (de) * 2001-12-20 2009-06-30 Hoffmann La Roche Test zur Identifizierung von Inhibitoren von Beta-Sekretasen.
BR0306724A (pt) * 2002-01-04 2006-04-11 Elan Pharm Inc carboxamidas amino substituìdas para tratamento de doença de alzheimer
US20050090449A1 (en) * 2003-05-13 2005-04-28 Boehringer Ingelheim International Gmbh Novel statine derivatives for the treatment of Alzheimer's disease
WO2005004802A2 (en) * 2003-06-30 2005-01-20 Merck & Co., Inc. N-alkyl phenylcarboxamide beta-secretase inhibitors for the treatment of alzheimer's disease
EP1750719A2 (en) * 2004-05-19 2007-02-14 Boehringer Ingelheim International GmbH Treatment of diseases associated with altered level of amyloid beta peptides
WO2005113582A1 (en) * 2004-05-22 2005-12-01 Boehringer Ingelheim International Gmbh Substituted ethane-1,2-diamines for the treatment of alzheimer's disease
WO2006050862A1 (en) * 2004-11-10 2006-05-18 Boehringer Ingelheim International Gmbh Statine derivatives for the treatment of alzheimer's disease
WO2006050861A2 (en) * 2004-11-10 2006-05-18 Boehringer Ingelheim International Gmbh Statine derivatives for the treatment of alzheimer's disease
CA2603404A1 (en) * 2005-03-30 2006-10-05 Boehringer Ingelheim International Gmbh Substituted 1,2-ethylendiamines, medicaments comprising said compound; their use and their method of manufacture
JP2009503027A (ja) * 2005-08-03 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング アルツハイマー病ｉｉの治療のための置換エタン−１，２−ジアミン

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007017509A1 *

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US20090042867A1 (en) 2009-02-12
WO2007017509A1 (de) 2007-02-15
CA2618019A1 (en) 2007-02-15

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