EP1915353A2 - Isophthalsäurediamide zur behandlung der alzheimer erkrankung - Google Patents

Isophthalsäurediamide zur behandlung der alzheimer erkrankung

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Publication number
EP1915353A2
EP1915353A2 EP06792736A EP06792736A EP1915353A2 EP 1915353 A2 EP1915353 A2 EP 1915353A2 EP 06792736 A EP06792736 A EP 06792736A EP 06792736 A EP06792736 A EP 06792736A EP 1915353 A2 EP1915353 A2 EP 1915353A2
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Withdrawn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
EP06792736A
Other languages
German (de)
English (en)
French (fr)
Inventor
Niklas Heine
Klaus Fuchs
Christian Eickmeier
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 EP06792736A priority Critical patent/EP1915353A2/de
Publication of EP1915353A2 publication Critical patent/EP1915353A2/de
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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.
  • processes for the preparation of a medicament and of a compound according to the invention are the subject of this invention.
  • 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 inorganic or organic acids. - o -
  • 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)
  • Carboxy, formyl, cyano, nitro, F 3 C-, HF 2 C-, FH 2 C-, hydroxy-Ci-e alkyl, C 1 -3 alkyl, C 1 -6 alkoxy -, (R 12 ) 2 N-, (R 12 ) 2 NC 1 -3 -alkyl, (R 12 ) 2 N-CO- and HOSO 2 - may be substituted,
  • Ci- 4 alkylene bridge is a Ci- 4 alkylene 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
  • R 1 is hydrogen, Ci -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 - - -
  • Ci- 6 alkyl C 2-6 alkenyl, C 2-6 nyl- -AIkJ, Ci- 6 alkoxy-Ci- 3 alkyl, Ci -6 alkyl
  • 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, C 3 -7-cycloalkyl, C 3-7 - cycloalkyl-Ci -4 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, heterocycl
  • R 12 -CO- (R 12) N-, R 12 -SO 2 (R 12) N may be substituted - - (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 .
  • R 6 is hydrogen, Ci -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, C 3- 7 -cycloalkenyl-C 2 - 6 alkenyl, C 3 - 7 cycloalkenyl-C 2 - 6 alkynyl,
  • Heteroaryl-Ci -3 alkyl, aryl-Ci-6-alkyl-, (R 12) 2 N-, (R 12) 2 N-Ci -3 alkyl, (R 12) 2 N-CO-, (R 12 ) 2 N-CO-N (R 12 ) -, (R 12 ) 2 N-SO 2 - and HOSO 2 - may be substituted, - o -
  • 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-C- ⁇ - 3 alkyl, heteroaryl or heteroaryl-Ci -3 alkyl, wherein the above-mentioned optionally independently of 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 nyl- -AIkJ, C 3-7 cycloalkyl, Cs-y -Cycloalkyl-Cie-alkyl, C 3-7 -cycloalkyl
  • Ci -6 alkyl Group consisting of Ci -6 alkyl, fluoro, chloro, bromo, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 2-6 alkenyl, C 2-6 alkynyl, C- ⁇ - 6 alkyl S-, Ci-e-alkyl-S-Ci-s-alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-Ci- 6 alkyl, aryl , aryl -ci- 6 -alkyl, heterocyclyl, heterocyclyl Ci 6 alkyl, heteroaryl, heteroaryl-Ci- 6 alkyl, R 13 -O-, R 13 -O-CO-, R 13 -CO-, R 13 -O-CO- (R 12 ) N-,
  • R 12 2 N-CO-O-, R 13 -O-Ci -3 alkyl, (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-, R 12 -SO 2 -, F 3 C-, 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 .
  • 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 substituted by one or a plurality of fluorine atoms may be substituted, R 10 Ci 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Cs-y-cycloalkyl, C3-7 cycloalkyl Ci-C4 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
  • R 11 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 - cycloalkyl-Ci alkyl -3, heterocyclyl, heterocyclyl-cis-alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alki nyl-, aryl, aryl-Ci -3 alkyl
  • R 10 and R 11 together form a C 2- 6-alkylene bridge form, so that under
  • 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
  • Radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, Ci -3 alkyl,
  • R 13 are each independently hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3 - 7 cycloalkyl, Cs-yCyclyoalkyl-Ci - 3 alkyl, heterocyclyl -, heterocyclyl-Ci- 3 alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl or heteroaryl-Ci - alkyl 3, wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, or with a, iodo, hydroxy, oxo, 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 ⁇ -
  • the present invention also relates to the physiologically tolerable salts of the compounds according to the invention with inorganic or organic acids.
  • 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 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, 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 such as vitamin E or ginkolides; anti-inflammatory substances such.
  • Cox inhibitors NSAIDs with additional or sole Aß lowering properties
  • HMG-CoA reductase inhibitors statins
  • Acetylcholinesterase inhibitors such as donepezil, rivastigmine, tacrine, galantamine
  • NMDA receptor antagonists such as NMDA receptor antagonists
  • Another object of this invention are pharmaceutical compositions containing one or more, preferably an active ingredient, which is selected from the compounds of the invention and / or the corresponding salts, and one or more, preferably an 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, optionally with 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.
  • an 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 amyloid precursor protein (APP) or aggregation from 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 useful in the treatment or prophylaxis of diseases or conditions which are susceptible to inhibition of ⁇ -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 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
  • Another object of this invention is a method for inhibiting ß-secretase activity, characterized in that ß-secretase with an inhibitory effective amount of one of the compounds of the invention is brought into contact.
  • radicals, substituents or groups in a compound may have the same or different meanings.
  • the group means
  • the group has
  • the group means
  • the group means
  • a phenyl, thienyl, thiazolyl, pyrazolyl or a pyridyl radical where the phenyl, the thienyl, in particular the 3-thienyl, the thiazolyl, in particular the 2-thiazolyl and the pyridyl radical, in particular the 2-pyridyl and the 3-pyridyl radical, is particularly preferred.
  • the substituent L 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 1 -alkyl -, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -7-cycloalkyl, C3-rCycloalkyl-Ci-3-alkyl-, aryl, aryl-Ci-3-alkyl-, heterocyclyl -, heterocyclyl-Ci-3-alkyl-, heteroaryl, heteroaryl-Ci -3 - alkyl-, R 13 -O-, R 13 -O-C 1-3 alkyl-, (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-
  • 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, cycloalkyl Cs.y -ds-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 abovementioned radicals may be optionally substituted by one or more fluorine atoms.
  • substituents L are each independently hydrogen, fluorine, chlorine, bromine, hydroxy, Ci -4 alkyl or Ci -4 alkoxy, it being possible for the above-mentioned groups optionally substituted with one or more fluorine atoms, can.
  • Particularly preferred meanings for the 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-yCycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 - alkyl, aryl-Ci- 3 alkyl aryl, heteroaryl, heteroaryl-Ci -3 alkyl, R 13 -O- (R 12) 2 N-SO 2 -, and (R 12) 2 N - Can be substituted, and wherein two bonded to the same carbon atom of the Ci -4 -alkylene bridge Ci -4 alkyl radicals may be joined together to form a C 3 -7-cycloalkyl group, and wherein
  • the group B denotes a Ci -4 -alkylene bridge, wherein the Ci -4 - alkylene bridge optionally substituted independently with one or more radicals selected from the group consisting of fluorine, Ci -4 alkyl, phenyl or benzyl may be substituted, and wherein two on the same carbon atom of the C -4 - bound alkylene bridge Ci 3- 6 cycloalkyl group may be bonded together -4 alkyl residues with formation of a C, and wherein the above-mentioned and formed of the C i -4 alkyl radicals C 3-6 cycloalkyl -3 alkoxy can optionally be substituted independently of one another more radicals selected from the group consisting of fluoro, hydroxy and Ci with one or,
  • B is a Ci- 2- alkylene bridge, wherein the Ci- 2- alkylene bridge may optionally be substituted by one or more Ci- 4- alkyl radicals, and wherein two on the same carbon atom of the - o -
  • Ci- 2- alkylene bridge bonded Ci -4 alkyl radicals may be connected together to form a cyclopropyl group, and wherein one or more hydrogen atoms of the above-mentioned 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.
  • 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, C 1 -6-alkyl, C 2-6 -alkenyl, C-2-e-alkynyl, Cs-y- cycloalkyl, C 3 - 7 cycloalkyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl and 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, Ci -3 alkyl -, Ci -3 -alkoxy and hydroxy-C may be substituted alkyl-3.
  • radicals R 1 are particularly preferably selected from the group consisting of hydrogen, Ci -4 alkyl, C 3-4 alkenyl, C 3 - 6 cycloalkyl, and C 3 - 6 cycloalkyl-Ci- 3 alkyl -, where the radicals mentioned above -3 alkoxy can optionally be substituted independently of one another more radicals selected from the group consisting of fluoro, hydroxy and Ci with one or.
  • 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-6-alkyl-S-Ci -3 alkyl, C 3-7 cycloalkyl, Cs-y-cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 -alkyl-, heteroaryl- and heteroaryl-Ci- 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, F 3 C-, HF 2 C-, FH 2 C-, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, (R 12) 2 N-, (R 12) 2 N- SO 2 -, R 12 - CO-
  • 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 -3 alkyl -, heteroaryl and heteroaryl-Ci -3 alkyl, wherein membered heteroaryl among the 5- or 6- aromatic heteroaryl groups are to be understood that 1, 2 or 3 heteroatoms selected from N, O and S and wherein the above-mentioned Radicals optionally together with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, C 1-3 -alkyl, F 3 C-, HF 2 C-, FH 2 C- , H 2 N-, and Ci -3 alkoxy may be substituted.
  • radicals R 2 which are selected from the group consisting of n-propyl, n-butyl, 2-propynyl, 2-butynyl, cyclohexylmethyl, cyclopentylmethyl, pyridylmethyl, furanylmethyl, thienylmethyl - And Thiazolylmethyl-, wherein the above-mentioned propyl, butyl, propynyl, butynyl, cyclohexylmethyl and Cyclopentylmethyl radicals optionally with one or more fluorine atoms and the pyridylmethyl, furanylmethyl, thienylmethyl or Thiazolylmethyl radicals optionally independently of one another with or a plurality of radicals selected from the group fluorine, chlorine, bromine, methyl, F 3 C, HF 2 C, FH 2 C- and H 2 N- may be substituted.
  • radicals R 2 which are selected from the group consisting of pyridylmethyl, especially 2-pyridylmethyl, thienylmethyl, especially 3-thienylmethyl and thiazolylmethyl, in particular 4-thiazolylmethyl, where the radicals are thiazolylmethyl or 4-thiazolylmethyl are the most preferred radicals.
  • the radical R 2 is a heteroaryl-C 1-3 -alkyl group, preferably a heteroarylmethyl group, where the heteroaryl radicals are to be understood as meaning a 5- or 6-membered aromatic heteroaryl group which is 1 or Contains 2 heteroatoms selected from N, O and S, wherein at most one O or S atom may be contained, wherein the heteroaryl radical may optionally be substituted by fluorine, chlorine or bromine and the other radicals and groups are as defined above or below.
  • the pyridylmethyl, furanylmethyl, thienylmethyl and thiazolylmethyl groups are particularly preferred.
  • the radical R 2 represents a Ci -6 alkyl group, a n- butyl group vozugêt.
  • 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. In a very particularly preferred embodiment of the compounds according to the invention, the radicals R 3 and R 4 are hydrogen.
  • the radical R 5 is preferably selected from the group consisting of hydrogen, Ci -6 alkyl, C 2 -6 alkenyl, C 2 - 6 alkynyl, C ⁇ cycloalkyl -, C 3 - 7 cycloalkyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl and heteroaryl-Ci -3 alkyl, wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, with one or iodine , Hydroxy, carboxy, cyano, nitro, C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkyl-S-, aryl-, heteroary
  • radicals R 5 are selected from the group consisting of Ci-s alkyl, cyclopropyl, C 3 optionally independently of one another with one or more radicals selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, hydroxy, carboxy, Ci 4 alkyl, Ci 4 alkoxy and (R 12 ) 2 May be N-substituted.
  • R 5 is a Ci- 4 alkyl or cyclopropyl group, wherein one or more hydrogen atoms of the above-mentioned radicals may be optionally 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 2nd 6 alkenyl, C 2 e-alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, C 3- 7 cycloalkenyl Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci -3 alkyl, aryl, aryl-Ci -3 alkyl, heteroaryl and heteroaryl-Ci -3 alkyl, wherein the above-mentioned optionally independently selected with one or more radicals from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, carboxy, cyano, nitro, Ci -3 alkyl, C 3-7 cycloalkyl, heterocyclyl, Heterocyclyl-Ci -3 - - (o -
  • radicals R 6 are groups selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (WCycloalkyl-, C 3-6 - cycloalkyl-C -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, phenyl, phenyl-Ci -3 - alkyl, heteroaryl and heteroaryl-Ci -3 alkyl, wherein by the above-mentioned heteroaryl groups 5- or 6-membered aromatic heteroaryl groups are to be understood which contain 1, 2 or 3 heteroatoms selected from N, O and S and wherein the above-mentioned radicals are optionally independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine , carboxy, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, Ci -3 alkoxy-Ci -3 alkyl, hydroxy Ci 3 al
  • radicals R 6, which are selected from the group consisting of hydrogen, Ci -6 alkyl, Cs-e-cycloalkyl, C 3 are very particularly preferred. 5 -cycloalkyl - C 1 . 3 -alkyl- and phenyl-C 1-3 -alkyl-, where the abovementioned radicals, where appropriate, independently of one another with one or more radicals selected from among
  • Group of fluorine can be hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, hydroxy-Ci- 3-alkyl, amino and amino-Ci-3-alkyl-substituted composed.
  • Particularly preferred radical R 6 is a cyclopropyl-C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, where the phenyl group may optionally be substituted by one or more amino groups, for example a cyclopropylmethyl radical. Amino phenylmethyl or 1- (4-amino-phenyl) ethyl group.
  • the radical R 7 is preferably selected from the group consisting of hydrogen and 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, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Cs-y-cycloalkyl-, Cs-y-cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, C 3-7 cycloalkenyl, aryl, aryl Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, R, R 13 -O-Ci alkyl 13 -3 -O-, R 10 -SO 2 - (R 11) N- and R 10 - CO- (R 11) N-, where the above mentioned groups optionally selected independently with one or more groups selected from the group consisting of Ci -4 alkyl, fluoro, chloro, bromo, hydroxy, oxo, Carboxy
  • 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, Cs-e Cycloalkyl-oxy, C 3-6 -cycloalkyl-C 1-3 -alkoxy, phenyl, pyridyl, thienyl, furyl, R 10 -CO- (R 11 ) N and 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 , Ci -4 alkyl-S-, R 13 -CO-, R 13 -O-CO-, R 12 -SO 2 -, F 3 C-, HF 2 C-, FH 2 C-, F 3 CO- , HF 2 CO, FH
  • the radical R 8 has the meaning R 10 -SO 2 - (R 11 ) N-, R 10 -CO- (R 11 ) N -cyanophenyl- or cyanothienyl-, where the abovementioned Cyanophenyl and
  • Cyanothienylreste optionally substituted independently more radicals selected from the group consisting of fluorine, chlorine, bromine, Ci -4 alkyl, Ci- 4 alkoxy, F 3 C-, HF 2 C-, FH 2 C- with one or, F 3 CO, HF 2 CO and FH 2 CO- may be substituted.
  • radical R 8 has the meaning of a 2-cyanophenyl or a 2-carbamoylphenyl group.
  • Preferred radicals R 9 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, F 2 HC, FH 2 C- and 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 -AIkJ nyl -, C 3 - 7 cycloalkyl, C 3-7 -Cycloalky 1-Ci -3 - alkyl, heterocyclyl, heterocyclyl-cis alkyl, C 3-7 cycloalkenyl, aryl, aryl-C - 3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, R 13 -O-, R 13 -O-Ci -3 alkyl, R 10 -SO 2 - (R 11) N- and R 10 - CO- (R 11) N-, where the above mentioned groups consisting optionally substituted independently with one or more groups selected from the group consisting of Ci -4 alkyl, fluoro, chloro, bromo, hydroxy, oxo
  • R 8 is 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- and R 10 -SO 2 - (R 11 ) N-, where the abovementioned radicals, where appropriate, independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, carboxy, cyano, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 alkyl-S-, R 13 -CO-, R 13 -O-CO-, R 12 - SO 2 -, F 3 C-, HF 2 C-, FH 2 C- , F, HF
  • radical R 8 is an R 10 -SO 2 - (R 11 ) N, R 10 -CO- (R 11 ) N, cyanophenyl or cyanothienyl group, the above optionally cyanophenyl and Cyanothienylreste independently of one another with one or more radicals - -i -
  • R 9 is independently of one another hydrogen, fluorine, chlorine or bromine, particularly preferably hydrogen.
  • the radical R 8 is a 2-cyanophenyl or a 2-carbamoylphenyl group
  • the radical R 9 is, independently of one another, 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 alkynyl, C 3- 7 cycloalkyl -, C 3 - 7 cycloalkyl-Ci alkyl 3, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl-Ci- 3 - alkyl, heterocyclyl, heterocyclyl-cis-alkyl, aryl , aryl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 alkyl, and (R 12) 2 N-, wherein the above groups optionally substituted by 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, C 1 -3 alkoxy, hydroxy-C 1 -3 -
  • R 10 are selected from the group consisting of residues C- ⁇ - 6 alkyl, heterocyclyl, phenyl, phenyl-Ci -3 alkyl, heteroaryl, heteroaryl-Ci -3 - alkyl- and ( 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, where appropriate, independently of one another selected with one or more radicals from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci- 3 alkyl, Ci -3 alkoxy, heterocyclyl, heterocyclyl-Ci -3 alkyl, 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
  • radicals R 10 are selected from the group Ci-C4 alkyl, in particular methyl or ethyl, morpholinyl, piperidinyl, 4- Methylpiperidinyl-, pyrrolidinyl, phenyl, benzyl, pyridyl and residues ( CH 3 ) 2 N-, where the above-mentioned radicals may optionally be substituted independently of one another by one or more radicals selected from among 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 -CyClOaIkYl-, C 3 - 7 cycloalkyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci -3 - alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl and 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, cyano, Ci-3-alkyl, C- ⁇ -3-alkoxy , Hydroxy-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, (R 12 ) 2 N- and (R 12 ) 2 N-C
  • R 11 are groups selected from the group consisting of hydrogen, Ci -6 alkyl, C 3 - 6 cycloalkyl, Cs-e-cycloalkyl-Cis-alkyl, heterocyclyl, heterocyclyl-Ci- 3 - alkyl, phenyl, phenyl-Ci -3 alkyl, heteroaryl and heteroaryl-Ci -3 1 - alkyl-, wherein by the above-mentioned heteroaryl 5- or 6-membered aromatic heteroaryl are meant radicals containing from 1, 2 or 3 heteroatoms selected from among N, O and S and where the abovementioned radicals are, where appropriate, independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 -alkyl , C 1-3 -alkoxy-, hydroxy-C 1-3 -alkyl-, heterocyclyl-, heterocyclyl-C 1-3 -
  • radicals R 11 are radicals selected from the group consisting of hydrogen, methyl, HF 2 C, ethyl, phenyl and 4-fluorophenyl, where the radicals mentioned above are optionally selected independently of one another with one or more radicals the group fluorine, chlorine and bromine may be substituted,
  • R 10 is selected nyl- 2-6 -AIkJ from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C, Cs-yCycloalkyl-, Cs-y cycloalkyl-Ci-s-alkyl-, C 3-7 cycloalkenyl, C. 3 7 cycloalkenyl-C 1 . 3 - alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl alkyl, aryl, aryl-Ci -3, heteroaryl, - -IO -
  • R 11 is selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 - alkenyl, C 2-6 alkynyl, Cs-yCycloalkyl-, Cs-y-cycloalkyl-Cis-alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, aryl, aryl-Ci- 3 alkyl, heteroaryl and heteroaryl-Ci -3 alkyl, wherein the above-mentioned selected optionally independently substituted with one or more radicals from the group consisting of 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 -3 alkyl may be substituted
  • R 10 is selected from Ci-6-alkyl, heterocyclyl, phenyl, phenyl-Ci alkyl from the group consisting -3, heteroaryl, heteroaryl-Ci -3 alkyl and (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 are, if appropriate, independently one another or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 -alkyl, C 1-3 -alkoxy, heterocyclyl, heterocyclyl-C 1-3 -alkyl, Hydroxy-C 1-3 -alkyl-, (R 12 ) 2 N- and (R 12 ) 2 -N-C 1-3 -alkyl-, and R 11 is selected from the group consisting of hydrogen, C 1-4
  • R 10 is selected from the group consisting of Ci -4 alkyl, in particular methyl or ethyl, morpholinyl, piperidinyl, 4-Methylpiperidinyl-, pyrrolidinyl, phenyl, benzyl , Pyridyl or (CH 3 ) 2 N-, where the abovementioned radicals may optionally be substituted independently of one another by one or more radicals selected from among fluorine, chlorine and bromine, and
  • R 11 is selected from the group consisting of hydrogen, methyl, ethyl, HF 2 C, phenyl or 4-fluorophenyl, where the abovementioned radicals, where appropriate, independently of one another with one or more radicals selected from the group fluorine, chlorine and bromine may be substituted.
  • 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 associated with R 10 a heterocyclic ring is formed, where 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 in such a way 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 C 2-6 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 may be substituted -3- alkoxy.
  • heterocyclic rings of the formulas (IIa), (IIb), (Mc) or (Md) are particularly preferred.
  • the radical R 12 is preferably independently selected from the group consisting of hydrogen and a Ci -6 alkyl group, wherein one or more hydrogen atoms of the Ci-6 alkyl group may be replaced by fluorine.
  • radical R 8 in combination with the radicals R 10 and R 11 forms heterocyclic rings of the formulas (IIa), (IIb), (Mc) or (Md), and other radicals and groups are defined as above or below.
  • Particularly preferred radicals R 12 are each independently hydrogen or a Ci -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 described above have given meanings.
  • Ci-rAlkylen 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 with one or, F 3 C-, HF 2 C-, FH 2 C-, Ci- 4 alkyl, Cs-7 cycloalkyl, Cs-yCycloalkyl-Ci-s-alkyl, heterocyclyl, Heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -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 C3-7- cycloalkyl group may be bonded together,
  • R 1 is hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, Cs-y-cycloalkyl, C3-7- cycloalkyl-Ci 3 alkyl, heterocyclyl, heterocyclyl-Ci- 3 alkyl, aryl, aryl alkyl Ci- 3 alkyl, heteroaryl or heteroaryl-Ci -3, wherein the above mentioned groups optionally substituted independently with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, carboxy, cyano, nitro, F 3 C-, C- ⁇ -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-y-cycloalkyl-cis-alkyl, heterocyclyl, heterocyclyl-Ci 3 -alkyl, heteroaryl or heteroaryl-Ci 3 -alkyl-, wherein the above Radicals optionally independently of one another with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, F 3 C-, HF 2 C-, FH 2 C-, hydroxyl, 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 -SO 2 (R 12
  • R 5 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cs-y-cycloalkyl, C 3-7 - cycloalkyl-Ci- 3 alkyl, C 3 7 -cycloalkenyl, Cs-y-cycloalkenyl-cis-alkyl, Heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -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, iodine, hydroxy, carboxy,
  • R 6 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cs-y-cycloalkyl, C 3-7 -
  • 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 8 is hydrogen, fluorine, chlorine, bromine, cyano -, Ci -4 alkyl, Ci -4 alkoxy, C3-6 cycloalkyl, C3-6 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-, wherein the above mentioned radicals optionally independently of one another with one or more radicals selected from
  • R 11 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-cis-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 of fluorine, alkyl, chlorine, bromine, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy, hydroxy-Ci -3 alkyl, heterocyclyl, heterocyclyl-Ci- 3, ( R 12) 2 N-, and (R 12) 2 N-Ci -3 alkyl may be substituted, or
  • R 10 and R 11 together form a C 2- 6-alkylene bridge form, so that under
  • a heterocyclic ring is formed, where 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 are not directly connected to an S atom, and wherein the C atoms optionally substituted independently with one or more radicals selected from the group of the above mentioned C 2- 6-alkylene bridge consisting of - -
  • Fluoro, hydroxy, carboxy, F 3 C-, C- ⁇ -3-alkyl and Ci -3 alkoxy may be substituted
  • R 12 are each independently hydrogen or a Ci -6 alkyl group wherein one or more hydrogen atoms of the Ci -6 alkyl group may be replaced by fluorine, and
  • R 13 are each independently hydrogen or a Ci-3-alkyl group wherein one or more hydrogen atoms of the Ci -3 alkyl group may be replaced by fluorine.
  • 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 under Aussometimes ung a C 3-6 cycloalkyl group may be linked together, and where the radicals mentioned above and consisting of the C i -4 alkyl radicals formed C3-6-cycloalkyl group optionally substituted independently with one or more radicals selected from the group consisting of fluorine, hydroxy and Ci -3 alkoxy may be substituted,
  • R 1 is hydrogen, C 1-4 alkyl, C 3 - 4 alkenyl, C 3 - 6 cycloalkyl, C 3-6 cycloalkyl- d 3 -alkyl-, wherein the above-mentioned radicals are optionally independent of each other with one or more radicals selected from the group consisting of fluorine, hydroxy and Ci -3 alkoxy may be substituted,
  • Alkyl, F 3 C-, HF 2 C-, FH 2 C-, H 2 N-, and Ci -3 alkoxy may be substituted, - oo -
  • R 5 Ci-6-alkyl, cyclopropyl, Cs-e-cycloalkyl-Cis-alkyl or phenyl-Ci -3 - alkyl, wherein the above mentioned groups consisting optionally substituted independently more radicals selected from the group having one or from fluorine, chlorine, bromine, iodine, cyano, hydroxy,
  • 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, Cs-e-cycloalkyl, C 3-6 - cycloalkyl-Ci 3 alkyl, heterocyclyl , heterocyclyl-Ci- 3 alkyl, phenyl, phenyl-C- ⁇ - 3 alkyl, heteroaryl or heteroaryl Ci 3 alkyl, wherein among the heteroaryl groups named above 5- or 6-membered aromatic heteroaryl groups are understood, the 1, 2 or 3 heteroatoms selected from N, O and S contain and wherein the above-mentioned radicals are optionally selected independently of one another with one or more radicals selected from
  • 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,
  • C- ⁇ - 3 alkoxy, heterocyclyl, heterocyclyl-Cis-alkyl, hydroxy-Ci- 3 alkyl, (R 12) 2 N-, and (R 12) 2 N-Ci- 3 alkyl substituted can be, and
  • R 11 is hydrogen, Ci -6 alkyl, C 3 - 6 cycloalkyl, Cs-e-cycloalkyl-Ci-s-alkyl, heterocyclyl, heterocyclyl-Ci- 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 heteroatoms selected from N, O and S and wherein the above- radicals are optionally substituted independently with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, hydroxy, cyano, Ci-3-alkyl, C- ⁇ - 3 alkoxy, hydroxy-Ci -3 - alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, (R 12 ) 2 N- and (R 12 ) 2 N-C 1-3 -alkyl, or
  • R 10 and R 11 together form a C 2 - 6 alkylene bridge, so that under
  • R 12 are each independently 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
  • Ci-2-alkylene bridge is a Ci-2-alkylene bridge, wherein the Ci-2-alkylene bridge optionally with one or more
  • Ci -4 alkyl radicals may be substituted, and wherein two bonded to the same carbon atom of the Ci-2-alkylene bridge Ci -4 alkyl radicals may be joined together to form a cyclopropyl group, and wherein one or more hydrogen atoms of the above C1 -2-
  • Alkylene bridge and / or the Ci -4 alkyl groups and / or the cyclopropyl group formed therefrom optionally by one or more
  • Fluorine atoms can be replaced, - -
  • B is selected from the group consisting of
  • R 2 is n-propyl, n-butyl, 2-propynyl, 2-butynyl, cyclohexylmethyl,
  • n is propyl, butyl, propynyl, butynyl,
  • Cyclohexylmethyl and cyclopentylmethyl radicals optionally with one or more fluorine atoms and the pyridylmethyl, furanylmethyl,
  • Thienylmethyl or thiazolylmethyl radicals may optionally be 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 C- ⁇ - 4 alkyl or cyclopropyl wherein one or more hydrogen atoms of the above-mentioned radicals may be optionally replaced by fluorine atoms,
  • R 6 is hydrogen, C 1-6 alkyl, C 3 - 6 cycloalkyl, Cs-s-cycloalkyl-d-alkyl or
  • Phenyl-Ci- 3 alkyl wherein the above-mentioned optionally substituted independently more radicals selected from the group consisting of fluoro, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy with one or, Hydroxy-Ci- ⁇ - amino-C-3 alkyl, amino and 3-alkyl may be substituted,
  • R 10 Ci 4 alkyl, morpholinyl, piperidinyl, 4-Methylpiperidinyl-, pyrrolidinyl, phenyl, benzyl, pyridyl or (CHs) 2 N-, wherein the above mentioned groups optionally substituted independently with one or a plurality of radicals selected from the group of fluorine, chlorine and bromine may be substituted,
  • R 11 is hydrogen, methyl, HF 2 C, ethyl, phenyl or 4-fluorophenyl, where the abovementioned radicals may be optionally substituted independently of one another by one or more radicals selected from the group of fluorine, chlorine and bromine, or
  • 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
  • i 0, 1 or 2, preferably 0 or 1
  • Ci-2-alkylene bridge is a Ci-2-alkylene bridge, wherein the Ci-2-alkylene bridge optionally with one or more
  • Ci -4 alkyl radicals may be substituted, and wherein two 2 -alkylene bridge bound to the same carbon atom of the Ci Ci -4 alkyl radicals may be bonded together to form a cyclopropyl group, and wherein the above-mentioned C1, one or more hydrogen atoms -2-
  • Alkylene bridge and / or the Ci -4 alkyl groups and / or the cyclopropyl group formed therefrom optionally by one or more
  • Fluorine atoms may be replaced, or, in a preferred embodiment,
  • B is selected from the group consisting of - -
  • one or more hydrogen atoms may optionally be replaced by fluorine
  • R 2 is n-propyl, n-butyl, 2-propynyl, 2-butynyl, cyclohexylmethyl,
  • Thiazolylmethyl wherein the above-mentioned propyl, butyl, propynyl, butynyl, cyclohexylmethyl and Cyclopentylmethyl radicals optionally with one or more fluorine atoms and the pyridylmethyl, furanylmethyl, thienylmethyl or Thiazolylmethyl radicals optionally 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- may be substituted,
  • R 5 Ci- 4 alkyl or cyclopropyl wherein one or more hydrogen atoms of the above-mentioned radicals may be optionally replaced by fluorine atoms,
  • R 6 is hydrogen, C 1-6 alkyl, C 3 - 6 cycloalkyl, Cs-s-cycloalkyl-d-alkyl or phenyl-Ci- 3 alkyl, wherein the above mentioned groups optionally substituted independently with a or more radicals selected from the group consisting of fluoro, hydroxy, cyano, Ci -3 alkyl, Ci -3 alkoxy,
  • Hydroxy-C- ⁇ - 3 alkyl, amino and amino-Ci- 3-alkyl may be substituted, - -
  • 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 with 1 to n C atoms examples 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, may have a value of 1 to 8, means a saturated, branched or unbranched - -
  • Hydrocarbon bridge with 1 to n C atoms examples 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.
  • 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 such as defi ned above.
  • 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 Cs-n-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-alkoxy refers to a C 3- n -cycloalkyl group in which C 3- n -cycloalkyl is as defined above and which is substituted by a C 1 -n- alkoxy group via a carbon atom 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 pyrazolidin
  • 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.
  • Examples of such 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-oxadiazoyl, isothiazolyl, isoxazolyl, 1, 2,4-thiadiazolyl, 1, 3,4-thiadiazolyl, 1, 2,5-thiadiazolyl, pyrazolyl , Pyrimidyl, pyridazinyl, pyrazinyl, tetrazolyl, pyridyl, indolyl, isoindoyl, indolizinyl, imidazopyridinyl, imidazo [1,2-a] pyridinyl, - -I -
  • Pyrrolopyrimidinyl purinyl, pyridopyrimidinyl, pteridinyl, pyrimidopyrimidinyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, isobenzofuranyl, isobenzothienyl, thieno [3,2 b] thiophenyl, thieno [3,2-b] pyrrolyl, thieno [2,3-d] imidazolyl, naphthyridinyl, indazolyl, pyrrolopyridinyl, oxazolopyridinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl , Benzoisothiazolyl, benzoxadiazolyl, benzo
  • 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] -triazoh3, 4- and 5-yl, 1 H- [1,2,3] -TriazoM-, 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.
  • 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.
  • the compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions.
  • 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.
  • the compounds according to the invention are obtainable by using synthesis methods known in principle from starting compounds known to those skilled in the art (see, for example: Houben Weyl - Methods of Organic Chemistry, Vol. E22,
  • the compounds can be obtained according to the manufacturing method explained in more detail below.
  • Aminoisophthal Acidimethylester prepared by sequentially sulfonated, methylated and then mono-saponified. The resulting acid is coupled with an amine and, after further saponification, is available for the abovementioned final amide coupling.
  • Scheme B exemplifies an alternative route to the synthesis of the compounds of the invention.
  • a Boc-protected amino aldehyde is prepared by reduction to the alcohol and subsequent oxidation. This is coupled by reductive amination with an amino acid amide obtained from a Boc-protected amino acid. After contact protection, a diamine is obtained which is selectively attached to the - -
  • isophthalic monoester is prepared from Aminoisophthal Acidimethylester by sequentially sulfamoylated, methylated and then mono-saponified.
  • the ester obtained therefrom in the abovementioned amide coupling is saponified and coupled with an amine in the last step.
  • Scheme C exemplifies another alternative to the synthesis of the compounds of the invention.
  • a Boc-protected amino aldehyde is prepared by reduction to the alcohol and subsequent oxidation. This is coupled by reductive amination with an amino acid amide obtained from a Boc-protected amino acid.
  • Deprotection yields a diamine which is selectively coupled to the primary amino functionality with a biphenyl-dicarboxylic acid monoamide.
  • the latter is obtained from a biphenyl-dicarboxylic acid dimethyl ester which is prepared in a palladium-catalyzed Suzuki coupling of dimethyl isophthalate and an arylboronic acid.
  • Mono-saponification, coupling of the resulting acid with an amine and further saponification give the acid required for the abovementioned final amide coupling.
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable 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 Treated by a pathological form of the ß-amyloid peptide, such as ß-amyloid patches, or can be influenced by inhibition of ß-secretase.
  • the compounds of the present invention are particularly useful for preventing, treating, or even slowing the progression of diseases such as Alzheimer's disease (AD) and other diseases associated with abnormal amyloid precursor protein (APP) processing or Abeta peptide aggregation. as well as diseases which can be treated or prevented by an inhibition of ß-secretase or cathepsin D, respectively.
  • Corresponding diseases include MCI (mild cognitive impairment), trisomy 21 (Down syndrome), cerebral
  • Amyloid angiopathy degenerative dementias, 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.
  • HHWA-D Dutch-type amyloidoses
  • 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.
  • Suitable oral formulations may include, for example, enteric coatings containing the active ingredients first release 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.
  • 0.1 to 1000 mg of one of the compounds according to the invention or a mixture of several of these compounds is used alone or together with pharmaceutically customary auxiliaries such as carriers, diluents, binders, stabilizers, preservatives, dispersants, etc. to form a dosage unit in a manner known to the person skilled in the art and formulated.
  • pharmaceutically customary auxiliaries such as carriers, diluents, binders, stabilizers, preservatives, dispersants, etc.
  • 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 of the formula (I) according to the invention cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in conventional galenic preparations such as tablets, pellets, dragees, capsules, powders, suppositories, solutions, elixirs, active substance
  • 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 of 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, galanthamine; 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, GABA A 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 modul
  • 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-A ⁇ a antibodies for the treatment of the above-mentioned diseases and conditions.
  • immunotherapies e.g. active immunization with Abeta or parts thereof or passive immunization with humanized anti-A ⁇ a antibodies for the treatment of the above-mentioned 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 as
  • Combination partner described drugs for the manufacture of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions that can be influenced by inhibiting the ß-secretase.
  • 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.
  • the decrease of the substrate concentration or the increase in the product concentration can be carried out with the aid of various technologies depending on the substrate used: HPLS-MS analysis, fluorescence assays, fluorescence fluorescence quenching assays, luminescence assays are a non-representative selection of the various 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).
  • a test substance US 2003/0125257
  • the substrate 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, for example, 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.
  • Beta Site APP Cleaving Enzyme BACE
  • Asp2 Asp2
  • memapsin 2 a group consisting of Asp2 and memapsin 2 and is known e.g. In US Patent 5,744,346 and WO 98/22597, WO 00/03819, WO 01/23533, and WO 00/17369, and in the scientific literature (Hussain et al., 1999, Mol. Cell., Neurosci 14: 419-427; Vassar et al., 1999, Science 286: 735-741; Yan et al.
  • BACE Beta Site APP Cleaving Enzyme
  • ⁇ -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 the detection of ⁇ -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 produced by - IO -
  • HEK293 / APP / BACE ect 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 OptiMEM ® .
  • the substrate used is a peptide with the amino acid sequence SEVNLDAEFK, to the N-terminal the Cy3 fluorophore (Amersham) and C-terminal the Cy5Q fluorophore
  • 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 kinetically recorded in a fluorimeter (ex: 530 nm, em: 590 nm).
  • the assay is started by addition of the substrate.
  • IC 5 O value for the test compound is calculated using standard software (eg GraphPad Prism ®) from percentage of inhibition of the substance at various 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) - (78) mentioned in the table above have, as measured by the test described above, 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 include, but are not limited to, human embryonic kidney fibroblasts 293 (HEK293), Chinese hamster ovary (CHO) cells, human H4 neuroglioma cells, human U373 MG
  • the transfection of the cells takes place z. B. in which the cDNA of human APP in an expression vector such as pcDNA3 (Invitrogen) is cloned and added with a transfection reagent such as Lipofectamin (Invitrogen) according to the manufacturer's instructions to the cells.
  • 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 which are suitable for this purpose are, among other cells, e.g. 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 counted as inhibiting the beta-secretase if under these conditions their IC O value is less than 50 microns, preferably less than 10 microns, more preferably less than 1 micron and most preferably less than 100 nM. 5
  • 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 with 5% CO 2 cultured.
  • a culture medium such as DMEM + glucose, sodium pyruvate, glutamine and 10% FCS
  • 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 diluted for assay in culture medium so that the DMSO concentration does not exceed 0.5%.
  • a ⁇ The production of A ⁇ during this period is monitored by means of an ELISA containing 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 A ⁇ 42-specific antibodies (Nanotools, Germany) coupled to alkaline phosphatase used as the detection antibody.
  • 6E10 the antibodies 6E10
  • SGY3160 C Eckman, Mayo Clinic, Jacksonville, Fla., USA
  • a ⁇ 40 and A ⁇ 42-specific antibodies (Nanotools, Germany) coupled to alkaline phosphatase used as the detection antibody.
  • Microtiter plate is prevented by blocking with Block Ace (Serotec) prior to the addition of the A ⁇ -containing culture supernatant.
  • Block Ace Surotec
  • test compound 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.
  • 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 IC50 value for the test compound is determined using standard software (e.g., GraphPad
  • ⁇ * denotes the binding site of a residue
  • HPLC 1 data were generated under the following conditions:
  • the 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 2 data were generated under the following conditions: Waters ZQ2000, HP1 100LC, Gilson Autosampler 215, HP1 100PDA diode array detector A: water with 0.1% TFA B: acetonitrile with 0.1% TFA time in min.% A% B flow rate in ml / Min 0.00 95 5 1.00 - -
  • the stationary phase used was a Waters column, Xterra MS Ci 8 2.5 ⁇ m, 4.6 mm.
  • HPLC 3 data were generated under the following conditions: Waters ZQ2000, Alliance 2795, Waters996 PDA diode array detector A: water with 0.1% TFA B: acetonitrile with 0.1% TFA time in min.% A% B flow rate in ml / min
  • the stationary phase used was a Waters column, Xterra MS Ci 8 2.5 ⁇ m, 4.6 mm.
  • HPLC-MS data were generated under the following conditions:
  • 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.
  • Analog 1 -m was prepared by reacting 1-a with 4-aminobenzylamine and BOC-L-alanine with BOC-L-alpha-aminobutyric acid (Step 1b) and BOC-L-4-thiazolylalanine with BOC-L 3-thienylalanine (step 1 d) was substituted: - -
  • step 1 b 4-aminobenzylamine and BOC-L-alanine through BOC-L-alpha-aminobutyric acid
  • Analog 1-m was prepared by reacting 1-a with cyclopropylmethylamine and BOC-L-alanine with BOC-L-alpha-aminobutyric acid (step 1b) and BOC-L-4-thiazolylalanine with BOC-L-3-thienylalanine (Step 1 d) was substituted:
  • step 1 b 1-a by cyclopropylmethylamine and BOC-L-alanine by BOC-L-alpha-aminobutyric acid (step 1 b),
  • Analog 1-m was prepared by reacting 1-a with cyclopropylmethylamine and BOC-L-alanine with BOC-L-alpha-aminobutyric acid (step 1b) and BOC-L-4-thiazolylalanine with BOC-L-2. Pyridylalanine (step 1 d) substituted:
  • step 1 b 1-a by cyclopropylmethylamine and BOC-L-alanine by BOC-L-alpha-aminobutyric acid (step 1 b),
  • Analog 1-m was prepared by reacting 1-a with cyclobutylamine and BOC-L-alanine with BOC-L-alpha-aminobutyric acid (step 1b) and BOC-L-4-thiazolylalanine with BOC-L-norleucine (Ste " I d) was substituted:
  • Analog 1-m was prepared by replacing 1-c with BOC-L-alanineamide hydrochloride (step 1c) and BOC-L-4-thiazolylalanine with BOC-L-norleucene (step 1 d): - -
  • Analog 1-m was prepared by substituting 1-a with 4-nitrobenzylamine and BOC-L-4-thiazolylalanine with BOC-L-norleucene (step " Id):"
  • step 1 b 4-aminobenzylamine and BOC-L-alanine through BOC-L-alpha-aminobutyric acid
  • 2-d was prepared analogously to 1-g by substituting BOC-L-alanine with BOC-L-aminobutyric acid and 1-a with cyclopropylmethylamine (step 1 b).
  • 2-g was prepared analogously to 1-k from 2-f and (R) -1- (4-fluoro-phenyl) -ethylamine.
  • 3-e was prepared analogously to 1-m from 3-d and the analogous to 1-g amine obtained by substitution of BOC-L-alanine by BOC-L-aminobutyric acid and 1-a by
  • Analog 3-e the following compound was prepared from the 3-d analogue acid, which was obtained by substitution of 2-carbamoyl-phenylboronic acid by 2-cyanophenylboronic acid (step 3b), and the amine analogous to 1-g, which by Substitution of BOC-L-alanine by BOC-L-aminobutyric acid and 1-a - -
  • Analog 3-e the following compound was prepared from the 3-d analogue acid, which was obtained by substitution of 2-carbamoyl-phenylboronic acid by 2-cyanophenylboronic acid (step 3a), and the amine analogous to 1-g, which by Substitution of BOC-L-alanine by BOC-L-aminobutyric acid and 1-a by 4-aminobenzylamine (step 1 b) and BOC-L-4-thiazolylalanine by BOC-L-3-thienylalanine (step 1 d) was obtained:
  • Analog 4 the following compounds of 4-d and the corresponding alaninamide (analog 4-e) were prepared:
  • Example 5 was prepared analogously to Example 1 from 5-c and the corresponding precursors.
  • Example 6 was prepared analogously to Example 1 from 6-d and the corresponding precursors.
  • 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 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:
  • Corn starch drink about 180.0 mg
  • 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.
  • Composition 1 suppository contains:
  • Polyethylene glycol 1500 550.0 mg
  • the active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.
  • Active ingredient 50.0 mg 0.01 n hydrochloric acid s. q.
  • 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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EP06792736A 2005-08-11 2006-08-08 Isophthalsäurediamide zur behandlung der alzheimer erkrankung Withdrawn EP1915353A2 (de)

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JP5608655B2 (ja) 2008-09-18 2014-10-15 エヴォテック アーゲー Ｐ２ｘ３受容体活性のモジュレーター
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