DE10341535A1 - New N,N-disubstituted (hetero)arylsulfonamide derivatives are gamma-secretase inhibitors useful for treatment or prophylaxis of Alzheimer's disease - Google Patents

Abstract

N-(Carbamoyloxyalkyl)-N-phenyl-(hetero)arylsulfonamide derivatives (I) are new. N-(Carbamoyloxyalkyl)-N-phenyl-(hetero)arylsulfonamide derivatives of formula R1>SO2-N(R2>)-CR3>R4>-CH2-O-CO-NR5>R6> (I) and their salts, solvates and solvated salts are new. R1>phenyl or heteroaryl (both optionally substituted by one or more halo, CN, CF3, OCF3, 1-6C alkyl, hydroxy-1-6C alkyl, 3-8C cycloalkyl, 1-6C alkoxy or 1-6C alkylthio); R2>phenyl (optionally substituted by one or more halo, CN, CF3, OCF3, 1-6C alkyl, hydroxy-1-6C alkyl, 3-8C cycloalkyl, 1-6C alkoxy or 1-6C alkylthio); R3>H, CN or CF3, or 1-6C alkyl or 3-8C cycloalkyl (both optionally substituted by one or more OH, 1-6C alkoxy, CN, CF3, OCF3, NO2, NH2, amino-1-6C alkyl, COOH or 2-7C alkoxycarbonyl); R4>H or 1-6C alkyl; R5>H, 1-6C alkyl or 3-8C cycloalkyl; R6>-A1-A2-(A3)d-CO-R8>; or NR5>R6>heterocycle, substituted by -A4-(A5)d-CO-R8> and optionally substituted by one or more 6-10C aryl, 1-6C alkyl, =O and OH; d : 0 or 1; A11-6C alkylene; A26-10C arylene, heteroarylene or heterocyclylene (all optionally substituted by one or more halo, CN, =O, OH, 1-6C alkyl, 1-6C alkoxy, CF3 or OCF3); A3, A41-6C alkylene (optionally having one CH2 replaced by O or NR9>); R9>H or 1-6C alkyl; R8>OR1>0> or NR1>1>R1>2>; R1>0>H, 1-6C alkyl, 3-10C cycloalkyl or heterocyclyl; R1>1>, R1>2>H, 1-6C alkyl or 3-10C cycloalkyl; or NR1>1>R1>2>heterocycle; A56-10C arylene or heteroarylene; An independent claim is also included for the preparation of (I). ACTIVITY : Nootropic; Neuroprotective; Cerebroprotective; Tranquilizer; Antiparkinsonian; Anticonvulsant; Anti-HIV; Neuroleptic. MECHANISM OF ACTION : gamma -Secretase inhibitor; beta -amyloid synthesis inhibitor. In tests for inhibition of amyloid-beta peptide release in cultures of human cells (H4, HEK293) stably expressing human amyloid precursor peptide (APP), 2-(1-((rac-2-((2,5-difluorophenyl)-((4-chlorophenyl)-sulfonyl)-amino)-propyl)-oxycarbonyl)-4-piperidyl)-acetic acid (Ia) had an IC50 value of less than 3 MicroM.

Description

The invention relates to phenylsulfonamide derivatives and methods of making them and their use in making them medicines for the treatment and / or prophylaxis of diseases, especially Alzheimer's Illness.

Alzheimer's disease (AD) is progressive neurodegenerative disease caused by memory loss, personality disorders, Language and orientation difficulties, weakness in decisions and Listlessness is marked. Up to 50% of those over 85 are affected by neurodegeneration, with Alzheimer's disease Dementia with the highest prevalence is.

The most histopathologically striking Characteristic of Alzheimer's Disease are the "senile" amyloid plaques, that are found in the brain and there especially in areas that with memory and thinking are connected. The main protein component of the plaques is the β-amyloid peptide (Aβ, βA4) with a length of 40-42 amino acids and a molecular weight of approximately 4 kilo-Daltons (kDa). Aβ is found also in plasma and cerebrospinal fluid (CSF) from healthy individuals; however, its function is unknown: in Alzheimer's patients leads one Above all, increased production and / or reduced Aβ breakdown of the 42 amino acids long shape, too elevated Mirroring of the polypeptide in plasma and CSF, followed by oligomerization of the peptide and accumulation in the brain, which eventually leads to Leads to the formation of the plaques. Either Aβ oligomers or lead the plaques finally for neurodegeneration.

Aβ arises by proteolytic processing of the amyloid precursor protein (Amyloid Precursor Protein, APP) in successive steps through various enzymes called secretases. The last Aβ generation step is carried out thereby by the so-called γ-secretase, which releases the carboxyl terminus of Aβ by cleavage of the peptide bond. Neither the gene encoding γ-secretase, nor the protein itself has so far been identified. Because of the present However, data can be assumed from the existence of this enzyme (see also M.S. Wolfe, J. Med. Chem. 2001, 44, 2039-2060).

So there is a need for substances which the formation of Aβ by Prevent APP proteolytic processing.

Phenylsulfonamide derivatives as γ-secretase inhibitors are described in WO 00/50391. Structurally different γ-secretase inhibitors are for example from Rishton et al., J. Med. Chem. 2000, 43, 2297-2299 and known from WO 01/77086, WO 01/77144 and WO 01/53255.

in welcher
R¹ Phenyl oder Heteroaryl, die gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, Hydroxy-C₁-C₆-alkyl, C₃-C₈-Cycloalkyl, C₁-C₆-Alkoxy und C₁-C₆-Alkylthio substituiert sind,
R² Phenyl, das gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, Hydroxy-C₁-C₆-alkyl, C₃-C₈-Cycloalkyl, C₁-C₆-Alkoxy und C₁-C₆-Alkylthio substituiert ist,
R³ Wasserstoff, Cyano, Trifluormethyl, C₁-C₆-Alkyl oder C₃-C₈-Cycloalkyl, wobei C₁-C₆-Alkyl und C₃-C₈-Cycloalkyl gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Hydroxy, C₁-C₆-Alkoxy, Cyano, Trifluormethyl, Trifluormethoxy, Nitro, Amino, Amino-C₁-C₆-alkyl, Hydroxycarbonyl und (C₁-C₆-Alkoxy)-carbonyl substituiert sind,
R⁴ Wasserstoff oder C₁-C₆-Alkyl,
R⁵ Wasserstoff, C₁-C₆-Alkyl oder C₃-C₈-Cycloalkyl, und
R⁶ einen Rest der Formel

bedeuten, worin
d Null oder 1,
A C₁-C₆-Alkylen,
B C₆-C₁₀-Arylen, Heteroarylen oder Heterocyclylen, die jeweils gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Halogen, Cyano, Oxo, Hydroxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Trifluormethyl und Trifluormethoxy substituiert sind,
D C₁-C₆-Alkylen, worin gegebenenfalls eine CH₂-Gruppe gegen ein Sauerstoffatom oder gegen eine Gruppe der Formel -NR⁹- ausgetauscht ist, worin
R⁹ für Wasserstoff oder C₁-C₆-Alkyl steht, und
R⁸ -OR¹⁰ oder einen Rest der Formel -NR¹¹R¹², worin
R¹⁰ für Wasserstoff, C₁-C₆-Alkyl, C₃-C₁₀-Cycloalkyl oder Heterocyclyl steht,
R¹¹ und R¹² unabhängig voneinander für Wasserstoff, C₁-C₆-Alkyl oder C₃-C₁₀-Cycloalkyl,
oder
R¹¹ und R¹² zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclus bilden,
bedeuten, oder
R⁵ und R⁶ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclus bilden, der gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe C₆-C₁₀-Aryl, C₁-C₆-Alkyl, Oxo und Hydroxy substituiert ist,
wobei der R⁵ und R⁶ enthaltende Heterocyclus obligatorisch mit einem Rest der Formel

substituiert ist, worin
f Null oder 1,
E C₁-C₆-Alkylen, worin gegebenenfalls eine CH₂-Gruppe gegen ein Sauerstoffatom oder gegen eine Gruppe der Formel -NR¹³- ausgetauscht ist, worin
R¹³ für Wasserstoff oder C₁-C₆-Alkyl steht,
F C₆-C₁₀-Arylen oder Heteroarylen,
bedeuten und
R⁸ die oben angegebenen Bedeutungen aufweist,
sowie deren Salze, Solvate und Solvate der Salze.The present invention relates to compounds of the formula

in which
R ^{1 is} phenyl or heteroaryl, which are optionally selected independently of one another from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkylthio are substituted,
R ² phenyl, which is optionally selected independently of one another from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, hydroxy-C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkylthio is substituted,
R ^{3 is} hydrogen, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl optionally being selected independently of one another by radicals from the group hydroxyl , C ₁ -C ₆ alkoxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, amino-C ₁ -C ₆ alkyl, hydroxycarbonyl and (C ₁ -C ₆ alkoxy) carbonyl are substituted,
R ^{4 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{5 is} hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, and
R ^{6 is} a radical of the formula

mean what
d zero or 1,
AC ₁ -C ₆ alkylene,
B C ₆ -C ₁₀ arylene, heteroarylene or heterocyclylene, each optionally optionally selected from the group halogen, cyano, oxo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl and trifluoromethoxy by radicals are substituted,
DC ₁ -C ₆ alkylene, in which a CH ₂ group is optionally replaced by an oxygen atom or by a group of the formula -NR ⁹ -, in which
R ^{9 represents} hydrogen or C ₁ -C ₆ alkyl, and
R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ¹² , wherein
R ^{10 represents} hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or heterocyclyl,
R ¹¹ and R ¹² independently of one another are hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl,
or
R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a heterocycle,
mean or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle which is optionally substituted by radicals selected independently of one another from the group C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, oxo and hydroxy is
wherein the heterocycle containing R ⁵ and R ⁶ is mandatory with a radical of the formula

is substituted, wherein
f zero or 1,
EC ₁ -C ₆ alkylene, in which a CH ₂ group is optionally replaced by an oxygen atom or by a group of the formula -NR ¹³ -, wherein
R ^{13 represents} hydrogen or C ₁ -C ₆ alkyl,
FC ₆ -C ₁₀ arylene or heteroarylene,
mean and
R ^{8 has} the meanings given above,
and their salts, solvates and solvates of the salts.

The compounds of the invention can in dependence their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomers isolate uniform components in a known manner.

The invention relates in dependence on the structure of the compounds also tautomers of the compounds (I) and their salts, solvates and solvates of the salts.

Salts are within the scope of the invention physiologically acceptable salts of the compounds (I) are preferred.

Physiologically acceptable salts include acid addition salts of mineral acids, Carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

Physiologically acceptable salts also include salts more commonly Bases such as, by way of example and by way of preference, alkali metal salts (e.g. Sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, for example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

As solvates within the scope of Invention such solid or liquid Forms of connections, which are coordinated with Solvent molecules one Have formed complex. Hydrates are a special form of solvate, where coordination has been done with water.

In the context of the present invention, unless otherwise specified, the radicals have the following meaning:
In the context of the invention, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl and C ₁ -C ₃ alkyl represent a straight-chain or branched alkyl radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4, particularly preferably having 1 to 3, carbon atoms is preferred. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

In the context of the invention, C ₁ C ₆ alkylene stands for a straight-chain or branched alkanediyl radical having 1 to 6 carbon atoms, the two free valences of the alkanediyl radical on a carbon atom (geminal), on adjacent carbon atoms (vicinal) or not adjacent carbon atoms can be. A straight-chain or branched alkanediyl radical having 1 to 4 carbon atoms is preferred, particularly preferably a straight-chain or branched alkanediyl radical having 1 to 3 carbon atoms. The following may be mentioned by way of example and preferably: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, propane-1,2-diyl, propane-2,2-diyl, 2- Methyl-propane-1,3-diyl, 2,2-dimethyl-propane-1,3-diyl,. Butane-1,2-diyl, butane-1,3-diyl, pentane-1,3-diyl, pentane-2,4-diyl and 3,3-dimethylpentane-2,4-diyl.

In the context of the invention, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₅ cycloalkyl stand for a monocyclic or optionally bicyclic cycloalkyl group with 3 to 10, 3 to 8, 3 to 6 or 3 to 5 carbon atoms. A monocyclic cycloalkyl group having 3 to 6, particularly preferably having 3 to 5, carbon atoms is preferred. The following may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2] decyl and bicyclo [4.3.1] decyl.

In the context of the invention, C ₆ -C ₁₀ aryl represents an aromatic hydrocarbon radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, C ₆ -C ₁₀ arylene stands for a divalent aryl radical having 6 to 10 carbon atoms. Preferred are o-phenylene, m-phenylene and p-phenylene.

C ₁ C ₆ alkoxy and C ₁ C ₄ alkoxy are within the scope of the invention a straight-chain or branched allcoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, C ₁ -C ₆ alkoxy) carbonyl and (C ₁ -C ₄ alkoxy) carbonyl stand for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group , An alkoxycarbonyl radical having 1 to 4, particularly preferably having 1 to 2, carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, C ₁ -C ₆ alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. A straight-chain or branched alkylthio radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

In the context of the invention, hydroxy-C ₁ -C ₆ -alkyl and hydroxy-C ₁ -C ₄ -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, which is substituted by a hydroxy group. A hydroxyalkyl radical with 1 to 4, particularly preferably with 1 to 2, carbon atoms is preferred. The following may be mentioned by way of example and preferably: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4- Hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl, 3-hydroxybut-2-yl, 1-hydroxybut-3-yl, 1-hydroxy-2-methylprop-1-yl, 2-hydroxy 2-methylprop-1-yl, 3-hydroxy-2-methylprop-1-yl, 1-hydroxy-2-methylprop-2-yl, 5-hydroxypentyl and 6-hydroxyhexyl.

In the context of the invention, amino-C ₁ -C ₆ -alkyl stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which is substituted by an amino group. An aminoalkyl radical having 1 to 4, particularly preferably having 1 to 2, carbon atoms is preferred. The following may be mentioned by way of example and preferably: aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 2-aminoprop-2-yl, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4- Aminobutyl, 1-aminobut-2-yl, 2-aminobut-2-yl, 3-aminobut-2-yl, 1-aminobut-3-yl, 1-amino-2-methylprop-1-yl, 2-amino 2-methylprop-1-yl, 3-amino-2-methylprop-1-yl, 1-amino-2-methylprop-2-yl, 5-aminopentyl and 6-aminohexyl.

Heteroaryl stands for one aromatic, mono- or bicyclic radical with 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preferred is a 5- to 6-membered heteroaryl radical with up to 3 heteroatoms. The heteroaryl residue can be over a carbon or over be attached to a nitrogen atom. Include non-limiting examples Furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, Isothiazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, Indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, Quinoxalinyl.

Heteroarylene is part of the Invention for a divalent, mono- or bicyclic heteroaryl radical with 5 to 10 ring atoms and up to 5 heteroatoms from the S, O series and / or N. A 5- to 6-membered heteroarylene radical with up to 4 is preferred Heteroatoms. Non-limiting examples include pyridylene, pyrimidylene, Pyridazinylene, pyrazinylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, Imidazolylene, isoxazolylene, isothiazolylene, tetrazolylene, isoxazolylene, Furylen, pyrazolylene.

A heterocycle bonded via a nitrogen atom represents a mono- or bicyclic, preferably monocyclic, non-aromatic heterocyclic radical having 4 to 7, preferably 5 to 6 ring atoms, with at least one ring nitrogen atom via which the heterocyclyl radical is bonded, and also with up to two, preferably up to a further ring hetero atom and / or hetero group from the series N, O, S, SO and SO ₂ . The heterocycle can be saturated or partially unsaturated. A 5- to 6-membered, monocyclic, saturated N-heterocyclyl radical with up to one further ring heteroatom from the series O, N and S, such as, for example and preferably, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, is preferred.

Heterocyclylene in the context of the invention represents a double-bonded 5- to 7-membered, mono- or bicyclic, saturated or partially unsaturated heterocyclyl radical with up to three ring heteroatoms and / or hetero groups from the series N, O, S, SO and SO ₂ , which can be linked both via ring carbon atoms and optionally via ring nitrogen atoms. A 5- to 6-membered, monocyclic, saturated heterocyclylene radical having up to two ring heteroatoms from the series N, O and S, such as, for example and preferably, tetrahydrofurylene, pyrrolidinylene, piperidinylene, piperazinylene and morpholinylene is preferred.

Halogen closes within the scope of the invention Fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.

If residues in the compounds of the invention can be substituted the residues, unless otherwise specified, one or more times be substituted the same or different. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

bedeuten, worin
d Null oder 1,
A C₁-C₃-Alkylen,
B Phenylen, Pyridylen, Pyrimidylen, Thienylen, Pyrrolylen, Oxazolylen, Thiazolylen, Piperidinylen, Piperazinylen oder Pyrrolidinylen, die jeweils gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Fluor, Chlor, Brom, Cyano, Oxo, C₁-C₄-Alkyl, C₁-C₄-Alkoxy substituiert sind,
D C₁-C₄-Alkylen, worin gegebenenfalls eine CH₂-Gruppe gegen ein Sauerstoffatom oder gegen eine Gruppe der Formel -NR⁹- ausgetauscht ist, worin
R⁹ für Wasserstoff oder C₁-C₄-Alkyl steht, und
R⁸ -OR¹⁰ oder einen Rest der Formel -NR¹¹R¹², worin
R¹⁰ für Wassserstoff C₁-C₄-Alkyl, C₃-C₆-Cycloalkyl oder Heterocyclyl steht,
R¹¹ und R¹² unabhängig voneinander für Wasserstoff, C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl,
oder
R¹¹ und R¹² zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Piperidin-, Pyrrolidin- oder Morpholin-Ring bilden,
bedeuten, oder
R⁵ und R⁶ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclus bilden, der gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Phenyl, C₁-C₄-Alkyl, Oxo und Hydroxy substituiert ist,
wobei der R⁵ und R⁶ enthaltende Heterocyclus obligatorisch mit einem Rest der Formel

substituiert ist, worin
f Null oder 1,
E C₁-C₄-Alkylen, worin gegebenenfalls eine CH₂-Gruppe gegen ein Sauerstoffatom oder gegen eine Gruppe der Formel -NR¹³- ausgetauscht ist, worin
R¹³ für Wasserstoff oder C₁-C₆-Alkyl steht, F Phenylen, Pyridylen, Pyrimidylen, Thienylen, Pyrrolylen, Oxazolylen oder Thiazolylen,
bedeuten und
R⁸ die oben angegebene Bedeutung aufweist,
sowie deren Salze, Solvate und Solvate der Salze.Compounds of the formula (I) in which
R ^{1 is} phenyl or thienyl, which are optionally substituted independently of one another by radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy and C ₁ -C ₄ -alkyl,
R ^{2 is} phenyl which is optionally selected independently of one another from the group fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkyl and C ₁ -C ₄ - Alkoxy is substituted,
R ^{3 is} hydrogen, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl optionally being selected independently of one another by radicals from the group hydroxyl , C ₁ -C ₆ alkoxy, cyano, trifluoromethyl, amino-C ₁ -C ₆ alkyl, hydroxycarbonyl and (C ₁ -C ₆ alkoxy) carbonyl are substituted,
R ^{4 is} hydrogen or C ₁ -C ₃ alkyl,
R ^{5 is} hydrogen, C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl and
R ^{6 is} a radical of the formula

mean what
d zero or 1,
AC ₁ -C ₃ alkylene,
B phenylene, pyridylene, pyrimidylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, piperidinylene, piperazinylene or pyrrolidinylene, each of which is optionally selected independently of one another from the group fluorine, chlorine, bromine, bromine, cyano, oxo, C ₁ -C ₄ -alkyl, C ₁ -C ₄ alkoxy are substituted,
DC ₁ -C ₄ alkylene, in which a CH ₂ group is optionally replaced by an oxygen atom or by a group of the formula -NR ⁹ -, wherein
R ^{9 represents} hydrogen or C ₁ -C ₄ alkyl, and
R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ¹² , wherein
R ^{10 represents} hydrogen C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or heterocyclyl,
R ¹¹ and R ¹² independently of one another are hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl,
or
R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring,
mean or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle, the counter is optionally substituted by radicals selected independently of one another from the group phenyl, C ₁ -C ₄ alkyl, oxo and hydroxy,
wherein the heterocycle containing R ⁵ and R ⁶ is mandatory with a radical of the formula

is substituted, wherein
f zero or 1,
EC ₁ -C ₄ alkylene, in which a CH ₂ group is optionally replaced by an oxygen atom or by a group of the formula -NR ¹³ -, in which
R ^{13 represents} hydrogen or C ₁ -C ₆ alkyl, F phenylene, pyridylene, pyrimidylene, thienylene, pyrrolylene, oxazolylene or thiazolylene,
mean and
R ^{8 has} the meaning given above,
and their salts, solvates and solvates of the salts.

bedeuten, worin
d Null oder 1,
A C₁-C₃-Alkylen,
B Phenylen oder Pyridylen, die gegebenenfalls durch Fluor substituiert sind,
D C₁-C₂-Alkylen,
R⁸ -OR¹⁰ oder einen Rest der Formel -NR¹¹R¹², worin
R¹⁰ für Wassserstoff C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl steht,
R¹¹ und R¹² unabhängig voneinander für Wasserstoff, C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl,
oder
R¹¹ und R¹² zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Piperidin- oder Morpholin-Ring bilden,
bedeuten, oder
R⁵ und R⁶ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclus bilden, der gegebenenfalls durch Reste unabhängig voneinander ausgewählt aus der Gruppe Phenyl, C₁-C₄-Alkyl, Oxo und Hydroxy substituiert ist, wobei der R⁵ und R⁶ enthaltende Heterocyclus obligatorisch mit einem Rest der Formel

substituiert ist, worin
f Null oder 1,
E C₁-C₃-Alkylen,
F Phenylen oder Pyridylen bedeuten und
R⁸ die oben angegebenen Bedeutungen aufweist,
sowie deren Salze, Solvate und Solvate der Salze.Compounds of the formula (I) in which
R ^{1 is} phenyl which is optionally substituted in the 4-position by a radical selected from the group fluorine, chlorine, bromine and trifluoromethyl, or 2-thienyl which is optionally in the 5-position substituted by a radical selected from the group fluorine, chlorine, bromine and trifluoromethyl is substituted,
R ² phenyl which is substituted twice by fluorine,
R ^{3 is} hydrogen or methyl,
R ⁴ C ₁ -C ₃ alkyl,
R ^{5 is} hydrogen or C ₁ -C ₃ alkyl and
R ^{6 is} a radical of the formula

mean what
d zero or 1,
AC ₁ -C ₃ alkylene,
B phenylene or pyridylene, which are optionally substituted by fluorine,
DC ₁ -C ₂ alkylene,
R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ¹² , wherein
R ^{10 represents} hydrogen C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl,
R ¹¹ and R ¹² independently of one another are hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl,
or
R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a piperidine or morpholine ring,
mean or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle which is optionally substituted by radicals selected independently of one another from the group phenyl, C ₁ -C ₄ alkyl, oxo and hydroxyl, the R ⁵ and R ^6- containing heterocycle is mandatory with a radical of the formula

is substituted, wherein
f zero or 1,
EC ₁ -C ₃ alkylene,
F is phenylene or pyridylene and
R ^{8 has} the meanings given above,
and their salts, solvates and solvates of the salts.

substituiert ist, worin
E C₁-C₃-Alkylen, und
R⁸ Hydroxy,
bedeuten, sowie deren Salze, Solvate und Solvate der Salze.Compounds of the formula (I) in which
R ^{1 is} phenyl which is substituted in the 4-position by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl,
R ² phenyl which is substituted twice by fluorine,
R ^{3 is} hydrogen,
R ⁴ methyl,
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle,
the mandatory with a remainder of the formula

is substituted, wherein
E C ₁ -C ₃ alkylene, and
R ⁸ hydroxy,
mean, and their salts, solvates and solvates of the salts.

Also particularly preferred are compounds of formula (I) in which
R ^{1 is} phenyl which is substituted in the 4-position with trifluoromethyl and R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given above.

• [A] Verbindungen der Formel
  
  in welcher R¹ bis R⁴ die oben angegebenen Bedeutungen haben, gegebenenfalls in Gegenwart einer Base mit einer Verbindung der Formel
  
  in welcher R⁵ und R⁶ die oben angegebenen Bedeutungen aufweisen und Y¹ für eine geeignete Abgangsgruppe wie beispielsweise Halogen steht, oder, falls R⁵ in Formel (I) für Wasserstoff steht, mit einer Verbindung der Formel O=C=N-R⁶ (IV),in welcher R⁶ die oben angegebenen Bedeutungen aufweist, umsetzt oder
• [B] Verbindungen der Formel (II) zunächst, gegebenenfalls in Gegenwart einer Base, mit einer Verbindung der Formel
  
  in welcher Y² und Y³ gleich oder verschieden sind und für eine geeignete Abgangsgruppe, wie beispielsweise Halogen oder eine Gruppe der Formel
  
  stehen, zu Verbindungen der Formel
  
  in welcher R¹ bis R⁴ und Y³ die oben angegebenen Bedeutungen haben, umsetzt, diese dann, gegebenenfalls in Gegenwart einer Base und/oder eines geeigneten Katalysators, mit einer Verbindung der Formel
  
  in welcher R⁵ und R⁶ die oben angegebenen Bedeutungen haben, umsetzt oder
• [C] Verbindungen der Formel
  
  in welcher R¹ und R² die oben angegebenen Bedeutungen aufweisen, in einem inerten Lösungsmittel in Gegenwart von Triphenylphosphin und eines Di-(C₁-C₄-alkyl)-azodicarboxylats unter Mitsunobu-Bedingungen mit einer Verbindung der Formel
  
  in welcher R³, R⁴, R⁵ und R⁶ die oben angegebenen Bedeutungen aufweisen, oder unter alkylierenden Bedinungen in einem inerten Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit einer Verbindung der Formel
  
  in welcher G für eine geeignete Abgangsgruppe, vorzugsweise Brom, Chlor, Mesyl oder Tosyl steht, und R³, R⁴, R⁵ und R⁶ die oben angegebenen Bedeutungen aufweisen,

umsetzt, und die resultierenden Verbindungen (I) gegebenenfalls mit den entsprechenden Lösungsmitteln und/oder Basen oder Säuren in ihre Solvate, Salze und/oder Solvate der Salze überführt.The invention further relates to processes for the preparation of the compounds according to the invention, characterized in that

• [A] Compounds of the formula
  
  in which R ¹ to R ^{4 have} the meanings given above, optionally in the presence of a base with a compound of the formula
  
  in which R ⁵ and R ^{6 have} the meanings given above and Y ^{1 is} a suitable leaving group such as halogen, or, if R ⁵ in formula (I) is hydrogen, with a compound of the formula O = C = NR ⁶ (IV), in which R ^{6 has} the meanings given above, or
• [B] Compounds of the formula (II) first, optionally in the presence of a base, with a compound of the formula
  
  in which Y ² and Y ^{3 are the} same or different and for a suitable leaving group, such as halogen or a group of the formula
  
  stand to compounds of the formula
  
  in which R ¹ to R ⁴ and Y ^{3 have} the meanings given above, then reacting them, optionally in the presence of a base and / or a suitable catalyst, with a compound of the formula
  
  in which R ⁵ and R ^{6 have} the meanings given above, or
• [C] Compounds of the formula
  
  in which R ¹ and R ^{2 have} the meanings given above, in an inert solvent in the presence of triphenylphosphine and a di- (C ₁ -C ₄ -alkyl) -azodicarboxylate under Mitsunobu conditions with a compound of the formula
  
  in which R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given above, or under alkylating conditions in an inert solvent, optionally in the presence of a base, with a compound of the formula
  
  in which G represents a suitable leaving group, preferably bromine, chlorine, mesyl or tosyl, and R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given above,

reacted, and the resulting compounds (I) optionally with the appropriate solvents and / or bases or acids are converted into their solvates, salts and / or solvates of the salts.

in welcher R³ und R⁴ die oben angegebenen Bedeutungen aufweisen und
L für eine geeignete Hydroxy-Schutzgruppe, wie beispielsweise Trimethylsilyl, tert.-Butyldiphenylsilyl oder tert.-Butyldimethylsilyl, steht,
zu Verbindungen der Formel

umsetzt und die Hydroxy-Schutzgruppe anschließend unter geeigneten Bedingungen entfernt.The compounds (II) can be prepared by combining compounds of the formula (VIII) in an inert solvent in the presence of triphenylphosphine and a di (C ₁ -C ₄ alkyl) azodicarboxylate under Mitsunobu conditions with a compound of the formula

in which R ³ and R ^{4 have} the meanings given above and
L represents a suitable hydroxyl protective group, such as trimethylsilyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl,
to compounds of the formula

implemented and the hydroxy protective group then removed under suitable conditions.

Hydroxy functions can after known methods protected by protective groups and finally again deprotected (see e.g. T.W. Greene, P. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., Wiley, New York, 1991).

Compounds of formula (VIII) can be prepared by using compounds of formula R ¹ -SO ₂ -Y ⁴ (XIII), in which
R ^{1 has} the meanings given above and
Y ^{4 represents} a suitable leaving group, such as chlorine, bromine or iodine,
optionally in the presence of a base with a compound of the formula R ² -NH ₂ (XIV), in which R ^{2 has} the meanings given above.

Compounds of formula (X) can according to known Methods are prepared from compounds of formula (IX).

in welcher
R³, R⁴ und L die oben angegebenen Bedeutungen haben,
gegebenenfalls in Gegenwart einer Base mit einer Verbindung der Formel (III) oder, falls R⁵ in Formel (IX) für Wasserstoff steht, mit einer Verbindung der Formel (IV) umsetzt oder
Verbindungen der Formel (XV) zunächst, gegebenenfalls in Getgenwar einer Base, mit einer Verbindung der Formel (V) zu Verbindungen der Formel

in welcher
R³, R⁴, L und Y³ die oben angegebenen Bedeutungen haben, umsetzt,
diese dann, gegebenenfalls in Gegenwart einer Base und/oder eines geeigneten Katalysators, mit einer Verbindung der Formel (VII) umsetzt.Compounds of formula (IX) can be prepared by using a compound of formula

in which
R ³ , R ⁴ and L have the meanings given above,
optionally in the presence of a base with a compound of the formula (III) or, if R ⁵ in formula (IX) is hydrogen, with a compound of the formula (IV) or
Compounds of formula (XV) first, optionally in a base, with a compound of formula (V) to give compounds of formula

in which
R ³ , R ⁴ , L and Y ^{3 have} the meanings given above,
this, if appropriate in the presence of a base and / or a suitable catalyst, is then reacted with a compound of the formula (VII).

The compounds (III), (IV), (V), (VII), (XI), (XIII), (XIV) and (XV) are commercially available, known from the literature or can be produced by methods customary in the literature.

As a solvent for the acylation in process step [A] (II) + (III) / (IV) → (I) and (XV) + (III) / (IV) → (IX) also for the sulfonylation in process step (XIII) + (XIV) → (VIII) are suitable inert organic solvents. For this belong Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, Xylene, toluene, hexane, cyclohexane or petroleum fractions, nitroalkanes such as Nitromethane, esters such as ethyl acetate, ketones such as acetone, heteroaromatics such as pyridine, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetonitrile. It is also possible to use mixtures of the above solvent use. Preferred are dichloromethane, pyridine, tetrahydrofuran, Acetonitrile, dimethylformamide and mixtures thereof.

As base for the acylation step (II) + (III) / (IV) → (I) and (XV) + (III) / (IV) → (IX) and process step (XIII) + (XIV) → (VIII) are the usual ones inorganic or organic bases. These preferably include alkali or Alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, amides such as lithium bis (trimethylsilyl) amide or Lithium diisopropylamide, organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, Triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or organometallic compounds such as butyllithium or Phenyllithium. Pyridine, optionally in, is particularly preferred The presence of catalytic amounts (approx. 10 mol%) of 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine.

The base comes in a lot from 1 to 10, preferably 1 to 3, mol per mol of the compound (II), (X) or (XIV) used. In process steps (II) + (III) and (XV) + (III) / (IV) → (IX) or (II) + (IV) → (I) are preferred catalytic amounts (about 10 mol%) of 4-N, N-dimethylaminopyridine used.

The acylation in process step (II) + (III) / (IV) → (I) and (XV) + (III) / (IV) → (IX) and process step (XIII) + (XIV) → (VIII) generally take place in a temperature range of -30 ° C up to + 100 ° C, preferably in a temperature range from 0 ° C to + 60 ° C.

The implementations can be normal, elevated or carried out at reduced pressure (e.g. from 0.5 to 5 bar). Generally you work at Normal pressure.

As a solvent for the process step [B] (V) + (II) → (VI) and (V) + (XV) → (XVI) all inert solvents are suitable. This includes Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, Xylene, toluene, hexane, cyclohexane or petroleum fractions, nitroalkanes such as Nitromethane, esters such as ethyl acetate, ketones such as acetone, heteroaromatics such as pyridine, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetonitrile. It is also possible to use mixtures of the above solvent use. Preferred are dichloromethane, tetrahydrofuran, acetonitrile, Dimethylformamide or mixtures thereof.

As a base for these process steps are the usual ones inorganic or organic bases. These preferably include alkali or Alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, amides such as lithium bis (trimethylsilyl) amide or Lithium diisopropylamide, organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or organometallic compounds such as butyllithium or Phenyllithium. Triethylamine and ethyldiisopropylamine are particularly preferred.

The base comes in a lot from 1 to 10, preferably 1 to 3, mol per mol of the compound (II) or (X) used.

The implementation is generally done in a temperature range from -30 ° C to + 100 ° C, preferably in a temperature range from 0 ° C up to + 60 ° C.

With normal, increased or carried out at reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

In the case of compounds of the formula (VI) / (XVI) in which Y ^{3 is} imidazolide, process step (VI) / (XVI) + (VII) → (I) is preferably carried out in the presence of equivalent amounts of methyl trifluoromethanesulfonate or methyl iodide as catalyst.

Under Mitsunobu conditions is in Generally the use of inert solvents in the presence of a Azodicarboxylates, optionally in the presence of an additional reagent, preferably in a temperature range from 0 ° C to room temperature at normal pressure meant.

Additional reagents are customary additional reagents for Mitsunobu reaction conditions, such as triphenylphosphine, diphenyl- (2-pyridyl) phosphine or (4-dimethylaminophenyl) diphenylphosphine; triphenylphosphine is preferred.

Azodicarboxylates are for example Diethylazodicarboxylate, dimethylazodicarboxylate, diisopropylazodicarboxylate or di-tert-butylazodicarboxylate; diisopropyl azodicarboxylate is preferred.

Inert solvents are, for example Halogenated hydrocarbons such as chloroform, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or Toluene, nitroaromatics such as nitrobenzene, carboxamides such as dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, aliphatic Nitriles such as acetonitrile, esters such as ethyl benzoate or other solvents such as N-methylpyrrolidone, preference is given to tetrahydrofuran.

Schema 2

The synthesis of the compounds according to the invention can be illustrated by the following formula schemes 1 and 2: Scheme 1

Scheme 2

The compounds of the invention show a unpredictable, valuable pharmacological and pharmacokinetic Spectrum.

They are therefore suitable for use as a medicine for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds according to the invention inhibit γ-secretase.

In addition, the compounds according to the invention are distinguished by advantageous properties with regard to their metabolic stability and / or a potential inhibition of liver enzymes.

The compounds of the invention can be based on their pharmacological properties alone or in combination with other active substances for treatment and / or prevention of neurodegenerative diseases, especially Alzheimer's disease become.

The compounds of the invention can be based on their pharmacological properties alone or in combination with other medicines for the treatment and / or prophylaxis of Diseases related to increased education, release, Accumulation or deposition of amyloid peptides, e.g. A, stand, are used, especially for treatment or prophylaxis Alzheimer's Illness and / or associated cognitive disorders, that occur in situations / diseases / syndromes, for example like "Mild cognitive impairment ", age-related learning and memory disorders, age-associated memory loss, vascular Dementia, traumatic brain injury, Stroke, dementia that occurs after a stroke (“post stroke dementia "), post-traumatic Traumatic brain injury, general Difficulty concentrating, difficulty concentrating in children with learning and memory problems, Attention Deficit Hyperactivity Disorder, Alzheimer's Disease, Dementia with Lewy bodies, Dementia with degeneration of the frontal lobes including the Pick's syndrome, Parkinson's Disease, progressive nuclear palsy, dementia with corticobasal Degeneration, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Multiple Sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia or schizophrenia with dementia.

Furthermore, the compounds of the invention can be used in combination with other drugs that the formation, release, accumulation or deposition of amyloids Prevent peptides in the brain. It is conceivable in this context the combination with other drugs that inhibit β- or γ-secretase are medicines that, due to their presence, cause the deposition of Complicate, delay or prevent amyloid plaques. A further use of the compounds according to the invention is possible in Combined with therapy that has an increased immune response to amyloids Peptides.

In addition, the compounds of the invention can be used in combination with other medicinal products learning and memory increase.

Another subject of the present Invention are medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliary substances or carriers included, and their use for the aforementioned purposes.

The active ingredient can be systemic and / or act locally. For this purpose, it can be applied in a suitable manner such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.

For the active substance can administer these administration routes in suitable administration forms be administered.

For oral application are known, the active ingredient quickly and / or modified delivery forms of application, such as tablets (not coated as well as coated Tablets, e.g. tablets coated with enteric coatings or Film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, Suspensions, solutions and aerosols.

Parenteral administration can bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with activation absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral application are suitable as application forms Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes are e.g. Inhalation dosage forms (e.g. powder inhalers, nebulizers), nose drops / solutions, Sprays, lingual, sublingual or buccal tablets or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active ingredients can be in a manner known per se in the listed Application forms are transferred. This is done using inert non-toxic, pharmaceutical suitable auxiliaries. Which includes et al excipients (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersing agents (e.g. polyvinylpyrrolidone), synthetic and natural Biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), Colorants (e.g. inorganic pigments such as iron oxides) or taste and / or odor correctives.

In general, it has proven to be beneficial proven with parenteral administration amounts from about 0.001 to 10, preferably about 0.005 to 3 mg / kg body weight to achieve more effective Deliver results. In the case of oral application, the amount is about 0.001 to 100, preferably about 0.005 to 30 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. In some cases len be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

The percentages in the following Unless otherwise stated, tests and examples are percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and obtain concentration information from liquid / liquid solutions each on the volume.

Abbreviations:

• DCI direct chemical ionization (for MS)
• DMF N, N-dimethylformamide
• DMSO dimethyl sulfoxide
• theory the theory (with yield)
• ESI electrospray ionization (for MS)
• GC / MS gas chromatography-coupled mass spectroscopy
• HPLC high pressure, high performance liquid chromatography
• LC / MS liquid chromatography-coupled Mass Spectroscopy MS Mass Spectroscopy
• NMR nuclear magnetic resonance spectroscopy
• quant. quantitatively
• R _t retention time (with HPLC)
• TFA trifluoroacetic acid
• THF tetrahydrofuran

HPLC, LC / MS and GC / MS methods:

Method 1:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A = 5 mL HClO ₄ / L water, eluent B = acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 mL / min; Temp .: 30 ° C; UV detection: 210 nm.

Method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A = 5 mL HClO ₄ / L water, eluent B = acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 mL / min; Temp .: 30 ° C; UV detection: 210 nm.

Method 3:

Instrument: Micromass Quattro LCZ, with HPLC Agilent series 1100; Pillar: Grom-Sil 120 ODS-4 U, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 L water + 1 mL 50% formic acid, Eluent B: 1 L acetonitrile + 1 mL 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 mL / min; UV detection: 208-400 nm.

Method 4:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 mL / min → 4.5 min 0.75 mL / min → 5.5 min 1.25 mL / min; UV detection: 210 nm.

Method 5:

Instrument: Micromass Platform LCZ, with HPLC Agilent series 1100; Pillar: Grom-Sil 120 ODS-4 HE, 50 mm × 2.0 mm, 3 µm; Eluent A: 1 L water + 1 mL 50% formic acid, Eluent B: 1 L acetonitrile + 1 mL 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 mL / min; UV detection: 208-400 nm.

Method 6:

Instrument: Micromass GCT, GC 6890; Pillar: Restek RTX-35MS, 30m x 250 µm x 0.25 µm; constant Flow with helium: 0.88 mL / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (for 0.30 min), 50 ° C / min → 120 ° C, 16 ° C / min → 250 ° C, 30 ° C / min → 300 ° C (for 1.7 min).

Method 7:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm × 4 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A flow 1 mL / min → 2.5 min 30% A flow 2 mL / min → 3.0 min 5% A flow 2 mL / min → 4.5 min 5% A flow 2 mL / min; Oven: 50 ° C; UV detection: 210 nm.

example 1

2- {1 - [(rac-2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

Stage a):

rac-1- (tert -butyldiphenylsilanyloxy) -propan-2-ol

4.3 g (15.8 mmol) of tert-butyldiphenylsilyl chloride and 1.8 g (26.3 mmol) of imidazole are added to a solution of 1.0 g (13.1 mmol) of 1,2-propanediol in 13 ml of DMF. The mixture is stirred at room temperature for 2 h. It is then diluted with water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 8: 2).
Yield: 4.1 g (99% of theory)
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.75-7.57, 7.45-7.28 (2 m, 10H), 4.01-3.84 (m, 1H), 3.62 (dd, 1H), 3.45 (dd, 1H) , 2.56 (d, 1H), 1.06 (s, 9H), 1.03 (d, 3H).

Level 6):

4-Chloro-N- (2,5-difluorophenyl) benzenesulfonamide

5.5 g (42.6 mmol) of 2,5-difluoroaniline in 50 ml of pyridine are added at room temperature, 9.0 g (42.6 mmol) of 4-chlorobenzenesulfonic acid chloride are added and the mixture is stirred until the reaction is complete. The pyridine is then distilled off in vacuo and the residue is taken up in 25 ml of acetonitrile. The mixture thus obtained is slowly stirred into 350 ml of 1N hydrochloric acid. The precipitated solid is filtered off, washed neutral with water and dried in vacuo. Yield: 11.0 g (85% of theory)
HPLC (method 1): R _t = 4.64 min.
MS (DCI / NH ₃ ): m / z = 321 (M + NH ₄ ) ⁺ .

Stage c):

rac-N- [2- (tert--butyldiphenylsilanyloxy) -1-methyl-ethyl] -4-chloro-N- (2,5-difluorophenyl) benzenesulfonamide

At room temperature, 196 mg (0.65 mmol) of N-2,5-difluorophenyl-4-chlorophenylsulfonamide, 406 mg (1.29 mmol) of 1- (tert-butyldiphenylsilanyloxy) propan-2-ol and 339 mg (1.29 mmol) of triphenylphosphine are added 2 ml of THF and 261 mg (1.29 mmol) of diisopropylazodicarboxylate were added. The mixture is stirred for 16 h at room temperature and the crude mixture is first purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1) and then by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid) / Acetonitrile).
Yield: 330 mg (85% of theory)
HPLC (method 1): R _t = 6.80 min. MS (DCI / NH ₃ ): m / z = 617 (M + NH ₄ ) ⁺ .

Stage d):

4-Chloro-N- (2,5-difluorophenyl) -N- (rac-2-hydroxy-1-methyl-ethyl) -benzenesulfonamide

A solution of 320 mg (0.53 mmol) of the compound from step c) in 2 ml of a 1 M solution of tetrabutylammonium fluoride in THF is stirred for 16 h at room temperature. The mixture is freed from volatile constituents in vacuo and purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 160 mg (83% of theory)
HPLC (method 1): R _t = 4.41 min. MS (DCI / NH ₃ ): m / z = 378.9 (M + Na) ⁺ .

Stage e):

Carbonic acid rac-2 - {[(4-chlorophenyl) sulfonyl] - (2,5-difluorophenyl) amino} propyl ester 2,5-dioxopyrrolidin-1-yl ester

A solution of 160 mg (0.44 mmol) of the compound from step d) in 7.5 ml of acetonitrile is successively mixed with 231 μl (1.33 mmol) of N, N-DÜsopropylethylamine and 170 mg (0.66 mmol) of N, N'-disuccinimidyl carbonate and at room temperature Stirred for 3 hours. The mixture is then diluted with ethyl acetate, washed twice with saturated sodium bicarbonate solution, the combined aqueous phases are extracted again with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The crude product thus obtained is pure enough for further reactions.
Yield: 233 mg (quant.)

Level f):

Ethyl 2- {1 - [(rac-2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetate

A solution of 58 mg (0.12 mmol) of the compound from step e), 24 mg (0.14 mmol) of ethyl piperidinyl acetate and 60 μl (0.35 mmol) of N, N-diisopropylethylamine in 2 ml of DMF / acetonitrile (1: 1, v / v) is stirred for 3 hours at room temperature and then freed from volatile constituents in vacuo. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 27 mg (42% of theory)
LC / MS (Method 3): R _t = 4.47 min., M / z = 559 (M + H) ⁺ .

Level g):

2- {1 - [(rac-2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

A solution of 25 mg (45 μmol) of the compound from stage f) in 0.5 ml of THF is mixed with 0.4 ml of 1 N sodium hydroxide solution and stirred at 50 ° C. until the reaction is complete. The mixture is then neutralized with 0.4 ml of 1 N hydrochloric acid and the THF is distilled off in vacuo after adding 2 ml of DMSO. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 18 mg (75% of theory)
200 MHz, CDCl ₃ ): δ = 7.71 (d, 2H), 7.42 (d, 2H), 7.18-6.70 (m, 3H), 4.76-4.53 (m, 1H), 4.25-3.55 (2 m, 4H) , 2.88-2.62 (m, 2H), 2.30 (d, 2H), 2.09-1.65 (2 m, 3H), 1.35-1.10 (m, 2H), 1.04 (d, 3H).
HPLC (method 2): R _t = 4.67 min.
MS (ESIpos): m / z = 531 (M + H) ⁺ .

Example 1a

2- {1 - [((2R) -2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

The R enantiomer of Example 1 is obtained in an analogous manner starting from 5-1,2-propanediol in step a).
R _t = 8.1 min. (Column: Daicel Chiralpak AD, 10 μm; eluent: 35% isohexane / 65% ethanol with 1% water and 0.2% TFA; flow: 1.0 mUmin .; detection: 220 nm).

Example 1b

2- {1 - [((2S) -2- {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

The S enantiomer of Example 1 is obtained in an analogous manner starting from R-1,2-propanediol in step a).
R _t = 4.2 min. (Column: Daicel Chiralpak AD, 10 μm; eluent: 35% isohexane / 65% ethanol with 1% water and 0.2% TFA; flow: 1.0 ml / min; detection: 220 nm).

Example 2

2- (1 - {[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxycarbonyl} -4-piperidyl) acetic acid

Stage a):

(2S) -1- (1,1,2,2-tetramethyl-1-silapropoxy) propan-2-ol

2.75 ml (19.7 mmol) of triethylamine, 0.10 g (0.8 mmol) of 4-N, N-dimethylaminopyridine and 2.97 g (19.7 mmol) are added to a solution of 1.50 g (19.7 mmol) of 5-1,2-propanediol in 15 ml of dichloromethane. added tert-butyldimethylsilyl chloride. The reaction mixture is stirred for 16 h at room temperature. The mixture is then diluted with dichloromethane and washed twice with water, saturated ammonium chloride solution and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The residue is used in the next stage without further purification.
Yield: 2.55 g, 80% purity (54% of theory)
GC / MS (Method 6): R _t = 2.62 min., M / z = 191 (M + H) ⁺ .

Level b):

4-trifluoromethyl-N- (2,5-difluorophenyl) benzenesulfonamide

2.38 g (18.4 mmol) of 2,5-difluoroaniline in 25 ml of pyridine are initially charged, 4.50 g (18.4 mmol) of 4-trifluoromethylbenzenesulfonyl chloride are added and the mixture is left to stir until the reaction is complete The pyridine is then distilled off in vacuo and the residue is taken up in 15 ml of acetonitrile. The mixture thus obtained is slowly stirred into 750 ml of 1N hydrochloric acid. The precipitated solid is filtered off, washed neutral with water and dried in vacuo.
Yield: 5.50 g (84% of theory)
HPLC (method 1): R _t = 4.79 min.

MS (DCI / NH ₃ ): m / z = 338 (M + NH ₄ ) ^+
1 H-NMR 300 MHz, CDCl ₃ ): δ = 7.94 (d, 2H), 7.73 (d, 2H), 7.42-7.32 (m, 1H), 7.00-6.90 (m, 1H), 6.83-6.72 (m , 2H).

Stage c):

RN- [2- (tert-butyldimethylsilanyloxy) -1-methyl-ethyl] -4-trifluoromethyl-N- (2,5-difluorophenyl) benzenesulfonamide

At room temperature, 300 mg (0.89 mmol) of 4-trifluoromethyl-N- (2,5-difluorophenyl) benzene sulfonamide, 423 mg (1.78 mmol, 80%) (2S) -1- (1,1,2,2 -Tetramethyl-l-silapropoxy) propan-2-ol and 262 mg (1.78 mmol) triphenylphosphine in 4 ml dichloromethane and mixed with 202 mg (1.78 mmol) diisopropylazodicarboxylate. The mixture is stirred for 16 h at room temperature and, after evaporation and absorption in DMSO, the crude mixture is purified by preparative HPLC
(YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 400 mg (88% of theory)
MS (DCI / NH ₃ ): m / z = 527 (M + NH ₄ ) ⁺ .

Stage d):

((IR) -2-hydroxy-isopropyl) - (2,5-difluorophenyl) - {[4- (trifluoromethyl) phenyl] sulfonyl} amine

A solution of 400 mg (0.79 mmol) of the compound from step c) in 2 ml of a 1 M solution of tetrabutylammonium fluoride in THF is stirred at room temperature for 16 h. The mixture is freed from volatile constituents in vacuo and purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 210 mg (68% of theory)
MS (DCI / NH ₃ ): m / z = 413 (M + Na) ^+
1 H-NMR (300 MHz, CDCl ₃ ): δ = 7.94 (d, 2H), 7.76 (d, 2H), 7.16-7.08 (m, 3H), 4.52-4.38 (m, 1H), 3.60-3.45 ( m, 1H), 3.40-3.30 (m, 1H), 1.88 (br. S, 1H), 1.01 (d, 3H).

Stage e):

Carbonic acid (2R) -2 - ((2,5-difluorophenyl) - {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl ester 2,5-dioxopyrrolidin-1-yl ester

The title compound is obtained from stage d) analogously to example 1, stage e). The
Raw product is pure enough for further implementations.
Yield: 286 mg (quant.)

 Level: f)

Ethyl 2- (1 - {[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxycarbonyl} -4-piperidyl) acetate

The title compound is obtained from stage e) analogously to example 1, stage f).
Yield: 140 mg (45% of theory)
LC / MS (Method 4): R _t = 3.93 min., M / z = 593 (M + H) ⁺ .

Level g):

2- (1 - {[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxycarbonyl} -4-piperidyl) acetic acid

The title compound is obtained from stage f) analogously to Example 1, stage g).
Yield: 120 mg (90% of theory)
¹ H NMR 300 MHz, CDCl ₃ ): δ = 7.88 (d, 2H), 7.73 (d, 2H), 7.18-6.85 (m, 3H), 4.78-4.49 (m, 1H); 4.25-3.55 (2m, 4H), 2.88-2.65 (m, 2H), 2.30 (d, 2H), 2.03-1.88 (m, 1H), 1.83-1.65 (m, 2H), 1.35-1.00 (m, 5H ).
LC / MS (Method 3): R _t = 2.97 min.
MS (ESIpos): m / z = 565 (M + H) ⁺ .
R _t = 8.8 min. (Column: Daicel Chiralpak AD, 10 μm; eluent: 35% isohexane / 65% ethanol with 1% water and 0.2% TFA; flow: 1.0 ml / min; detection: 220 nm).

Example 2a

2- (1 - {[(2S) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxycarbonyl} -4-piperidyl) acetic acid

The S enantiomer of Example 2 is obtained in an analogous manner starting from R-1,2-propanediol in step a).
R _t = 4.0 min. (Column: Daicel Chiralpak AD, 10 μm; eluent: 35% isohexane / 65% ethanol with 1% water and 0.2% TFA; flow: 1.0 ml / min; detection: 220 nm).

Example 3

rac-3 - {[(2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propoxy) carbonylamino] methyl} benzoic acid

Stage a):

3- (aminomethyl) benzoic acid trifluoroacetate

58 mg (0.12 mmol) of 3 - {[(tert-butoxy) carbonylamino] methyl} benzoic acid are stirred in 2 ml of TFA / dichloromethane (1: 1, v / v) for 1 h at room temperature and the volatile constituents are then evaporated off in Vacuum. The residue is used directly in the following stage without further purification.
Yield: quant.

Level b):

rac-3 - {[(2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propoxy) carbonylamino] methyl} benzoic acid

The title compound is obtained from stage a) analogously to example 1, stage f).
Yield: 30 mg (48% of theory)
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.03 (d, 2H), 7.73 (d, 2H), 7.57 (dd, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.15 -7.05 (m, 2H), 7.02-6.86 (m, 1H), 4.87 (br. T, 1H), 4.71-4.54 (m, 1H), 4.42 (d, 2H), 4.20-4.00 (m, 1H) , 3.80-3.55 (m, 1H), 1.08 (d, 3H).
LC / MS (Method 3): R _t = 4.23 min.
MS (ESIneg): m / z = 537 (M-H) ^- .

Example 4

rac-4 - {[(2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propoxy) carbonylamino] methyl} benzoic acid

Stage a):

Methyl 4 - {[(rac-2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propoxy) carbonylamino] methyl} benzoate

The title compound is obtained starting from methyl 4-aminomethylbenzoate analogously to Example 1, stage f).
Yield: 33 mg (51% of theory)
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 8.02 (d, 2H), 7.70 (d, 2H), 7.42 (d, 2H), 7.38 (d, 2H), 7.16-6.85 (2m, 3H) , 4.85 (br. T, 1H), 4.71-4.54 (m, 1H), 4.40 (d, 2H), 4.18-4.02 (m, 1H), 3.90 (s, 3H), 3.80-3.55 (m, 1H) , 1.07 (d. 3H).
LC / MS (Method 3): R _t = 4.40 min.
MS (ESIpos): m / z = 553 (M + H) ⁺ .

Level b):

rac-4 - {[(2 - {(2,5-difluorophenyl) [(4-chlorophenyl) sulfonyl] amino} propoxy) carbonylamino] methyl} benzoic acid

The title compound is obtained from stage a) analogously to example 1, stage g). Yield: 20 mg (68% of theory)
¹ H-NMR 300 MHz, CDCl ₃ ): δ = 8.08 (d, 2H), 7.71 (d, 2H), 7.48-7.33 (m, 4H), 7.16-6.85 (2m, 3H), 4.89 (br. T , 1H), 4.71-4.54 (m, 1H), 4.42 (d, 2H), 4.20-4.04 (m, 1H), 3.80-3.57 (m, 1H), 1.07 (d, 3H).
HPLC (method 2): R _t = 4.69 min.
MS (DCI / NH ₃ ): m / z = 556 (M + NH ₄ ) ⁺ .

Example 5

2- {1 - [((2R) -2 - {(2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

Stage a):

(2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amine

A solution of 500 mg (3.87 mmol) of 2,5-difluoroaniline in 5 ml of pyridine is mixed with 925 mg (4.26 mmol) 5-chlorothiophene-2-sulfonyl chloride was added and the mixture was stirred at room temperature for 16 h. After dilution with ethyl acetate, the organic phase is washed once with saturated sodium hydrogen carbonate solution, three times with 1 N hydrochloric acid and again with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. The crude product obtained is chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 → 7: 1, v / v). The product-containing fraction is evaporated and stirred in a mixture of pentane and diethyl ether (20: 1, v / v). The precipitated solid is filtered off and dried in vacuo.
Yield: 550 mg (46% of theory)
HPLC (method 2): R _t = 4.67 min.
MS (DCI / NH ₃ ): m / z = 327 (M + NH ₄ ) ⁺ .

Level b):

[(1R) -1-methyl-2- (1,1,2,2-tetramethyl-1-silapropoxy) ethyl] (2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amine

At room temperature, 244 mg (0.79 mmol) (2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amine, 190 mg (1.58 mmol, 80%) (2S) -1- (1 , 1,2,2-tetramethyl-1-silapropoxy) propan-2-ol and 413 mg (1.58 mmol) triphenylphosphine in 9 ml THF and 319 mg (1.58 mmol) diisopropylazodicarboxylate were added. A further 5 ml of THF are added to the resulting suspension. The mixture is stirred at room temperature for 54 h and, after evaporation and absorption in DMSO, the crude mixture is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 208 mg (53% of theory)
LC / MS (Method 4): R _t = 4.48 min.
MS (ESIpos): m / z = 482 (M + H) ⁺ .

Stage c):

((IR) -2-hydroxy-isopropyl) (2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amine

The title compound is obtained from stage b) analogously to example 1, stage d).
Yield: 231 mg (95% of theory)
¹ H NMR 300 MHz, CDCl ₃ ): δ = 7.38 (d, 1H), 7.20-6.99 (m, 3H), 6.92 (d, 1H), 4.41 (ddt, 1H), 3.60-3.47 (m, 1H ), 3.43-3.32 (m, 1H), 1.96 (br, 1H), 1.07 (d, 3H).
HPLC (method 2): R _t = 4.61 min.
MS (ESIpos): m / z = 368 (M + H) ⁺ .

Stage d):

Carbonic acid (2R) -2 - {(2,5-difluorophenyl) - [(5-chloro (2-thienyl)) sulfonyl] amino} propyl ester 2,5-dioxopyrrolidin-1-yl ester

The title compound is obtained from stage c) analogously to example 1, stage e).
Yield: 204 mg (94% of theory)
LC / MS (Method 4): R _t = 3.52 min.
MS (ESIpos): m / z = 509 (M + H) ⁺ .

Stage e):

Ethyl 2- {1 - [((2R) -2 - {(2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetate

The title compound is obtained from stage d) analogously to example 1, stage f).
Yield: 44 mg (53% of theory)
¹ H-NMR 400 MHz, CDCl ₃ ): δ = 7.32 (d, 1H), 7.18-7.07 (m, 2H), 7.05-6.93 (m, 1H), 6.91 (d, 1H), 4.70-4.57 (m , 1H), 4.21-4.07 (m, 4H), 4.03-3.88 (m, 1H), 3.83-3.65 (m, 1H), 2.75 (t, 2H), 2.23 (d, 2H), 2.02-1.89 (m , 1H), 1.78-1.65 (m, 2H), 1.23 (t, 3H), 1.21-1.08 (m, 5H).
LC / MS (Method 5): R _t = 4.03 min.
MS (ESIpos): m / z = 565 (M + H) ⁺ .

Level f):

2- {1 - [((2R) -2 - {(2,5-difluorophenyl) [(5-chloro (2-thienyl)) sulfonyl] amino} propyl) oxycarbonyl] -4-piperidyl} acetic acid

The title compound is obtained from stage e) analogously to example 1, stage g). Yield: 40 mg (quant.)
¹ H-NMR 200 MHz, CDCl ₃ ): δ = 7.31 (d, 1H), 7.20-7.07 (m, 2H), 7.05-6.93 (m, 1H), 6.91 (d, 1H), 4.75-4.53 (m , 1H), 4.28-3.88 (m, 3H), 3.83-3.63 (m, 1H), 2.78 (dt, 2H), 2.30 (d, 2H), 2.07-1.88 (m, 1H), 1.83-1.67 (m , 2H), 1.46-1.05 (m, 6H).
LC / MS (Method 5): R _t = 4.66 min.
MS (ESIpos): m / z = 537 (M + H) ⁺ .

Example 6

2- [1 - ({[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxy} carbonyl) -4-piperidinyl] -2- methylpropionic

Stage a):

2-Methyl-2- (4-piperidinyl) propionic acid ethyl ester hydrochloride

The title link becomes analogous to method described in literature [see e.g. J.L. Binet, C. Grandvincent, D.M. Thomas, Heterocycles 51 (7), 1573-1584 (1999)].

Level b):

2-Methyl-2- (4-piperidinyl) propionic acid hydrochloride

A mixture of 10.8 g (45.8 mmol) of 2-methyl-2- (4-piperidinyl) propionic acid hydrochloride, 41.1 g (366.5 mmol) of potassium tert-butoxide and 1.7 ml (91.6 mmol) of water in 500 ml of THF becomes 16 h stirred at room temperature. It is acidified with 1N hydrochloric acid and the mixture is evaporated to dryness in vacuo. The raw product is used without further purification.
MS (DCI / NH ₃ ): m / z = 172 (M + H) ⁺ .

Stage c):

2- [1 - ({[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxy} carbonyl) -4-piperidinyl] -2-methylpropionic acid ethyl ester

The title compound is obtained analogously to Example 1, stage f) starting from Example 6, stage b) and Example 2, stage e).
LC / MS (Method 7): R _t = 3.11 min.
MS (ESIpos): m / z = 621 (M + H) ⁺ .

Stage d):

2- [1 - ({[(2R) -2 - ((2,5-difluorophenyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] oxy} carbonyl) -4-piperidinyl] -2-methylpropionic acid

Method a):

50 mg (0.08 mmol) of the compound from stage c) are introduced in 1 ml of THF and 72 mg (0.65 mmol) of potassium tert-butoxide and 3 μl (0.16 mmol) of water are added. The mixture is stirred for 1 h at room temperature, then acidified with 1 N hydrochloric acid and taken up in 4 ml of acetonitrile. The crude mixture is separated by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm, gradient 0.1% formic acid / acetonitrile).
Yield: 8 mg (15% of theory).

Method b):

A solution of 18.6 g (34.6 mmol) from Example 2, stage e) and 60.3 ml (346.3 mmol) of N, N-diisopropylethylamine in 200 ml of acetonitrile is mixed with 9.4 g (45.0 mmol) of 2-methyl-2- (4-piperidinyl ) propionic acid hydrochloride are added and the mixture is stirred at room temperature for 16 h. The mixture is then concentrated in vacuo, the residue is taken up in 200 ml of ethyl acetate, washed twice with 1N hydrochloric acid, dried over sodium sulfate and again concentrated in vacuo. The residue is purified by means of preparative HPLC (column: Inertsil ODS-35 μm, 250 × 20 mm; eluent: 65% methanol, 35% 0.2% trifluoroacetic acid).
Yield: 2.54 g (12% of theory)
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.90 (d, 2H), 7.73 (d, 2H), 7.17-6.82 (m, 3H), 4.78-4.50 (m, 1H), 4.43-3.92 ( 2m, 3H), 3.83-3.62 (m, 1H), 2.78-2.58 (m, 2H), 1.83-1.22 (3m, 5H), 1.15 (s, 6H), 1.08 (d, 3H).
LC / MS (Method 7): R _t = 2.52 min.
MS (ESIpos): m / z = 593 (M + H) ⁺ .

1. Determination the inhibition of the release of A-beta in cell culture

a) Cell culture:

In order to be able to measure the inhibition of Aβ release, human cell lines (H4, HEK293) were generated which stably overexpress the 695 amino acid-long, neuronal splice variant of human APP. In order to further increase the amount of Aβ generated, the familial Alzheimer's double mutation "Swedish" was also introduced, in which the lysine and methionine residues at positions 595 and 596 of the APP695 molecule are replaced by the amino acids asparagine and leucine. The cells were cultivated in "Dulbecco's Modified Eagles Medium" (DMEM, with 4500 mg / l glucose, 110 mg / l sodium pyruvate, 5 vol.% fetal calf serum (FCS), 1% non-essential amino acids), to which the selection marker geniticin G418 was added was [all cell culture methods were carried out according to standard methods; Sambrook, J., Fritsch, EF, and Maniatis, T. (1989) Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory Press]. To test the effect of substances on the inhibition of APP processing, approximately 20,000 cells were diluted in a 96-well plate. The next day, the culture medium was removed and replaced with biotin and serum-free medium, in which the substances were diluted so that a concentration of 10 μM with a dimethyl sulfoxide (DMSO) content of 0.5% was reached. 0.5% DMSO was used as a control. In addition, substances that showed an inhibition of Aβ generation also became dose-response relationships tested by using different concentrations. After 16 hours the supernatant was removed and analyzed.

b) Detection of Aβ with the IGEN Analyzer:

The following components were used to detect the total amount of Aβ: 50 μl of cell culture supernatant were treated with 25 μl of biotinylated antibody 4G8 (recognizes amino acids 17-25 of Aβ), 25 μl of ruthenium complex-labeled antibody 6E10 (recognizes the N-terminus of Aβ) and 50 ul magnetic streptavidin-coupled beads. The following components were used for the detection of Aβ40: 50 μl cell culture supernatant was treated with 25 μl biotinylated antibody G2-10 (recognizes the C-terminus of Aβ 40), 25 βl ruthenium complex-labeled antibody W02 (recognizes the N-terminus of Aβ) and 50 βl magnetic streptavidin-coupled beads were added. A dilution series with synthetic Aβ 40 was prepared in parallel. The samples were shaken at room temperature and then measured using the IGEN analyzer. Typically, each sample was measured three times in at least two independent experiments. The antibodies and solutions used were prepared according to the instructions of the analyzer manufacturer, IGEN, Inc. (Gaitersburg, Maryland, USA). The measurement was also carried out according to the manufacturer's instructions. The exemplary embodiments show IC ₅₀ values of <3 μM in this test.

2. Microsomal incubation assay

In order to estimate the metabolic stability and the maximum possible bioavailability, selected test substances were incubated with rat liver microsomes. These incubations were carried out in a total volume of 1.5 ml at 37 ° C. on a modified Multiprobe II ^® robot system (Canberra Packard). The incubation mixture contained 0.2 mg / ml microsomal protein, approx. 1 μM substrate, 0.05 M phosphate buffer (pH = 7.4), 1 mM EDTA, 5 mM glucose-6-phosphate and 1.5 U / ml glucose-6-phosphate dehydroxygenase from Leuconostoc mesenteroides. Although the reaction was started by the addition of NADP ⁺ (final concentration: 1 mM), the FMO activity could be retained (data not shown here). The final acetonitrile concentration in the assay was 1%.

Aliquots of 125 μl were made up from the incubation solutions 1, 2.5, 5, 10, 15, 20 and 30 minutes removed and placed on a microtiter filter plate pipetted, the 125 ul an acetonitrile / water mixture (50:50) contained to make the enzymatic Stop reaction. After centrifugation, the samples were analyzed by HPLC-MS (MSD-Agilent) analyzed.

"CL _blood well-stirred" and "F _max well-stirred" values were calculated from the respective half-lives of the compounds in the microsomal incubations. The substrate degradation can be described using the following formula [JB Houston, Utility of in-vitro drug-metabolism data in predicting in-vivo metabolic-clearance, Bioch. Pharm. 47 (9), 1469-1479 (1994); RS Obach et al., The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data, J. Pharmacol. Exp. Ther. 283 (1), 46-58 (1997)]: CL ' _intrinsic [ml / (min × kg)] = (0.693 / in vitro t _1/2 [min]) × (liver weight [g liver / kg body weight]) × (microsomal protein [mg] / liver weight [g]) / (microsomal protein [mg] / incubation volume [ml]).

The blood clearance "CL _blood " was described without taking protein binding into account by the "well-stirred" model [KS Pang, M. Rowland, Hepatic clearance of drugs. I. Theoretical considerations of a "well-stirred" model and a "parallel tube" model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance, J. Pharmacokinet. Biopharm. 5 (6), 625-53 (1977)]: CL blood well-stirred [L / (h × kg)] (Q H [L / (h × kg)] × CL ' intrinsic [L / (h × kg)]) / (Q H [L / (h × kg)] + CL ' intrinsic [L / (h × kg)]).

For the rats had a specific liver weight of 32 g / kg body weight and hepatic blood flow 4.2 L / (h × kg). The specific microsomal Protein levels in the rat liver were estimated to be 40 mg / g liver.

F _max values that reflect the maximum possible bioavailability were calculated using the following formula: F Max well-stirred [%] = (1- (CL blood well-stirred [L / (h × kg)] / Q H [L / (h × kg)])) × 100.

3. Inhibition of cytochrome P 450 isoforms

The potential of test substances to inhibit cytochrome P 450 isoforms, which are important for metabolism, is automatically examined in 96-well format. This involves two different assays used.

In the assay based on the formation of fluorescent metabolites, recombinant enzymes (eg CYP1A2, 2C8, 2C9, 2C19, 2D6 or 3A4) and substrates containing fluorescein or coumarin substructures in general are used. A substrate concentration and 8 concentrations of the potential inhibitor are used in each case. After incubation with the respective recombinant CYP isoenzyme, the extent of fluorescent metabolites in comparison to the control (without test substance) is determined using a fluorescence reader and an IC ₅₀ value is calculated [Anal. Biochem. 248, 188 (1997)].

In a second assay, human liver microsomes are used as the enzyme source and phenacetin (CYP1A2), diclofenac (CYP2C9), dextromethorphan (CYP2D6) and midazolam (CYP3A4) are used as the CYP isoform-selective substrates. The formation of the respective metabolite is measured using LC-MS / MS. Assuming competitive inhibition, K _i values (one substrate, three substance concentrations) are estimated from the reduction in metabolite formation compared to the control.

embodiments for pharmaceutical compositions

The compounds of the invention can be pharmaceutical as follows Preparations are transferred:

Tablet:

Composition:

100 mg of the compound of example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) and 2 mg magnesium stearate. Tablet weight 212 mg. diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of active ingredient, lactose and strength comes with a 5% solution (m / m) of the PVP granulated in water. The granulate is after Dry with the magnesium stearate for 5 min. long mixed. This mix comes with a usual Tablet press pressed (for tablet format see above). As Guide value for the pressing uses a pressing force of 15 kN.

Oral suspension:

Composition:

1000 of the compound of Example 1, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the Fa. FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg compound of the invention correspond to 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol the active ingredient is added to the suspension. The mixture is added with stirring Water. Until the swelling of the Rhodigel is completed, approx. 6 h stirred.

Claims (10)

Compounds of the formula

in which R ^{1 is} phenyl or heteroaryl, which are optionally selected independently of one another from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₃ -C ₈ - cycloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkylthio are substituted, R ² phenyl, which is optionally selected independently of one another from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, hydroxy- C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkylthio, R ^{3 is} hydrogen, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl optionally selected independently of one another from the group hydroxy, C ₁ -C ₆ alkoxy, cyano, trifluoromethyl, trifluoromethoxy, nitro , Amino, amino-C ₁ -C ₆ -alkyl, hydroxycarbonyl and (C ₁ -C ₆ -alkoxy) -carbonyl are substituted, R ^{4 is} hydrogen or C ₁ -C ₆ -alkyl, R ^{5 is} hydrogen, C ₁ -C ₆ Alkyl or C ₃ -C ₈ cycloalkyl, and R ^{6 is} a radical of the formula

mean in which d is zero or 1, AC ₁ -C ₆ alkylene, B C ₆ -C ₁₀ arylene, heteroarylene or heterocyclylene, each optionally selected independently of one another from the group halogen, cyano, oxo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl and trifluoromethoxy are substituted, DC ₁ -C ₆ alkylene, in which a CH ₂ group is optionally replaced by an oxygen atom or by a group of the formula -NR ⁹ - , in which R ^{9 represents} hydrogen or C ₁ -C ₆ -alkyl, and R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ^I2 , in which R ^{10 represents} hydrogen, C ₁ -C ₆ -alkyl, C ₃ - C ₁₀ cycloalkyl or heterocyclyl, R ¹¹ and R ¹² independently of one another are hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, or R ¹¹ and R ¹² together with the nitrogen atom to which they are attached , form a heterocycle, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle which, if appropriate is independently substituted by radicals selected from the group C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, oxo and hydroxy, the heterocycle containing R ⁵ and R ^{6 being} obligatory with a radical of the formula

is substituted, wherein f is zero or 1, EC ₁ -C ₆ alkylene, in which optionally a CH ₂ group is replaced by an oxygen atom or by a group of the formula -NR ¹³ -, wherein R ^{13 is} hydrogen or C ₁ -C ₆ alkyl, F is C ₆ -C ₁₀ arylene or heteroarylene, and R ^{8 has} the meanings given above, and the salts, solvates and solvates of the salts thereof. Compounds according to Claim 1 of the formula (I), in which R ^{1 is} phenyl or thienyl, which are optionally substituted independently of one another by radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy and C ₁ -C ₄ -alkyl, R ^{2 is} phenyl which is optionally selected independently of one another from the group fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkyl and C ₁ -C ₄ - Alkoxy is substituted, R ^{3 is} hydrogen, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl optionally being selected independently of one another by radicals from the group hydroxy, C ₁ -C ₆ -alkoxy, cyano, trifluoromethyl, amino-C ₁ -C ₆ -alkyl, hydroxycarbonyl and (C ₁ -C ₆ -alkoxy) -carbonyl, R ^{4 is} hydrogen or C ₁ - C ₃ alkyl, R ⁵ hydrogen, C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl and R ^{6 is} a radical of the formula

mean in which d is zero or 1, AC ₁ -C ₃ alkylene, B phenylene, pyridylene, pyrimidylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, piperidinylene, piperazinylene or pyrrolidinylene, each of which is optionally selected independently of one another from the group fluorine, Chlorine, bromine, cyano, oxo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy are substituted, DC ₁ -C ₄ alkylene, where optionally a CH ₂ group against an oxygen atom or against a group of the formula -NR ⁹ - is replaced, in which R ^{9 is} hydrogen or C ₁ -C ₄ -A1ky1, and R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ¹² , in which R ^{10 is} hydrogen C ₁ -C ₄ - Alkyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, R ¹¹ and R ¹² independently of one another are hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, or R ¹¹ and R ¹² together with the nitrogen atom, to which they are attached form a piperidine, pyrrolidine or morpholine ring, or R ⁵ and R ⁶ together with the nitrogen atom, to which they are bound form a heterocycle which is optionally substituted by radicals independently selected from the group phenyl, C ₁ -C ₄ alkyl, oxo and hydroxy, the heterocycle containing R ⁵ and R ^{6 being} obligatory with a radical of the formula

is substituted, in which f is zero or 1, EC ₁ -C ₄ -alkylene, in which optionally a CH ₂ group is replaced by an oxygen atom or by a group of the formula -NR ¹³ -, in which R ^{13 is} hydrogen or C ₁ -C ₆ alkyl, F is phenylene, pyridylene, pyrimidylene, thienylene, pyrrolylene, oxazolylene or thiazolylene, and R ^{8 has} the meaning given above, and the salts, solvates and solvates of the salts thereof. Compounds according to Claim 1 of the formula (I), in which R ^{1 is} phenyl which is optionally substituted in the 4-position by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl, or 2-thienyl which is optionally in the 5-position is substituted by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl, R ² phenyl which is substituted twice by fluorine, R ^{3 is} hydrogen or methyl, R ^{4 is} C ₁ -C ₃ alkyl, R ^{5 is} hydrogen or C ₁ -C ₃ alkyl and R ^{6 is} a radical of the formula

mean in which d is zero or 1, AC ₁ -C ₃ alkylene, B phenylene or pyridylene, which are optionally substituted by fluorine, DC ₁ -C ₂ alkylene, R ⁸ -OR ¹⁰ or a radical of the formula -NR ¹¹ R ¹² , wherein R ^{10 represents} hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, R ¹¹ and R ¹² independently of one another represent hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, or R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a piperidine or morpholine ring, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle, which may be through Residues independently selected from the group phenyl, C ₁ -C ₄ alkyl, oxo and hydroxy is substituted, the heterocycle containing R ⁵ and R ^{6 being} mandatory with a radical of the formula

is substituted, in which f is zero or 1, EC ₁ -C ₃ alkylene, F is phenylene or pyridylene and R ^{8 has} the meanings given above, and the salts, solvates and solvates of the salts thereof. Compounds according to Claim 1 of the formula (I) in which R ^{1 is} phenyl which is substituted in the 4-position by a radical selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl, R ² phenyl which is substituted twice by fluorine, R ³ hydrogen, R ⁴ methyl, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycle, which is mandatory with a radical of the formula

is substituted, in which E is C ₁ -C ₃ alkylene and R ^{8 is} hydroxy, and the salts, solvates and solvates of the salts thereof. and their salts, solvates and solvates of the salts. Process for the preparation of the compounds according to the invention, characterized in that [A] compounds of the formula

in which R ¹ to R ^{4 have} the meanings given in claim 1, optionally in the presence of a base with a compound of the formula

in which R ⁵ and R ^{6 have} the meanings given in Claim 1 and Y ^{1 represents} a suitable leaving group such as halogen, or, if R ⁵ in formula (I) represents hydrogen, a compound of the formula O = C = NR ⁶ (IV), in which R ^{6 has} the meanings given in claim 1, or [B] reacting compounds of the formula (II) first, optionally in the presence of a base, with a compound of the formula

in which Y ² and Y ^{3 are the} same or different and for a suitable leaving group, such as halogen or a group of the formula

stand to compounds of the formula

in which R ¹ to R ⁴ and Y ^{3 have} the meanings given in Claim 1 and above, then reacting these, optionally in the presence of a base and / or a suitable catalyst, with a compound of the formula

in which R ⁵ and R ^{6 have} the meanings given in Claim 1, or [C] compounds of the formula

in which R ¹ and R ^{2 have} the meanings given in claim 1, in an inert solvent in the presence of triphenylphosphine and a di- (C ₁ -C ₄ -alkyl) -azodicarboxylate under Mitsunobu conditions with a compound of the formula

in which R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given in claim 1, or under alkylating conditions in an inert solvent, optionally in the presence of a base, with a compound of the formula

in which G represents a suitable leaving group, preferably bromine, chlorine, mesyl or tosyl, and R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given in Claim 1, and the resulting compounds (I) optionally with the corresponding solvents and / or bases or acids are converted into their solvates, salts and / or solvates of the salts. Compounds according to claims 1, 2, 3 and 4 for treatment and / or prophylaxis of diseases. Medicament containing at least one compound according to claims 1, 2, 3 and 4 in combination with at least one pharmaceutical acceptable pharmaceutically acceptable carrier or excipients. Use of compounds according to claims 1, 2, 3 and 4 for the manufacture of a medicament for treatment and / or Prophylaxis of Alzheimer's Illness. Medicament according to claim 7 for treatment and / or Prophylaxis of Alzheimer's Illness. Process for combating Alzheimer's disease in Humans and animals by administering an effective amount at least a connection according to claims 1, 2, 3 and 4.