DE10043282A1

DE10043282A1 - Medicaments containing amyloid-beta-protein formation and/or secretion inhibitors, are used for treating hypertension, diabetes, arteriosclerosis, rheumatism, cardiac infarction, inflammation or sepsis

Info

Publication number: DE10043282A1
Application number: DE2000143282
Authority: DE
Inventors: Kurt Heininger
Original assignee: Individual
Current assignee: Individual
Priority date: 2000-09-02
Filing date: 2000-09-02
Publication date: 2002-03-28

Abstract

The use of amyloid- beta -protein formation and/or secretion inhibitors (I) is novel in the production of medicaments for the treatment of diseases other than Alzheimer's disease, Down's syndrome or Dutch type cerebral hemorrhage.

Description

Die vorliegende Erfindung betrifft die Verwendung von Inhibitoren der Amyloid-β-Protein- Bildung und/oder Amyloid-β-Protein-Sekretion zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten mit Ausnahme der Alzheimer-Erkrankung, des Down- Syndroms und cerebraler Hämorrhagien des holländischen Typs.The present invention relates to the use of inhibitors of amyloid-β-protein Formation and / or amyloid-β-protein secretion for the manufacture of drugs for Treatment of diseases with the exception of Alzheimer's disease, down Dutch type syndrome and cerebral hemorrhage.

Die Ursache der Alzheimer Erkrankung ist unklar. Die Erkrankung ist gekennzeichnet durch einen progredienten Verlust kognitiver Fähigkeiten und eine zunehmende Atrophie des Gehirns, die durch bildgebende Verfahren (CT, MRT) in vivo sichtbar wird. Die Diagnose wird gesichert durch den autoptischen Befund einer Vielzahl sogenannter seniler Plaques, rundlicher Ablagerungen, in den Gehirnen der Erkrankten. Gestützt durch den Befund, dass ein Bestandteil dieser Plaques, fibrilläres Amyloid-β-Protein (Aβ), in vitro neurotoxisch ist, schreibt ein weitverbreitet akzeptiertes Konzept (Hardy und Higgins, Science 256: 184, 1992) den Plaques die entscheidende pathogenetische Bedeutung zu. Fibrilläres Aβ entsteht durch Konformationsänderung aus löslichem Aβ. Lösliches Aβ ist ein normales zelluläres Stoffwechselprodukt das durch proteolytische Spaltung aus einem grösseren membranständigen Protein, dem Amyloid Precursor Protein (APP), entsteht. Vielfältige, zum Teil widersprüchliche zelluläre Wirkungen von löslichem Aβ wurden beschrieben. So kann es sowohl neurotrophisch (Whitson et al., Science 243: 1488, 1989; Yankner et al., Science 250: 279, 1990) als auch neurotoxisch (Shearman et al., Proc Natl Acad Sci USA 91: 1470, 1994) wirken. Insgesamt bestehen derzeit aber keine konkreten Vorstellungen, wie lösliches Aβ in der pathophysiologischen Kaskade, die zur Alzheimer Erkrankung führt, beteiligt sein könnte.The cause of Alzheimer's disease is unclear. The disease is marked through a progressive loss of cognitive skills and an increasing Atrophy of the brain, which becomes visible in vivo by imaging methods (CT, MRI). The diagnosis is confirmed by the autoptic findings of a large number of so-called senile plaques, roundish deposits, in the brains of the sick. supported by finding that a component of these plaques, fibrillar amyloid β protein (Aβ), which is neurotoxic in vitro, writes a widely accepted concept (Hardy and Higgins, Science 256: 184, 1992) the plaques the crucial pathogenetic Meaning too. Fibrillar Aβ arises from the change of conformation from soluble Aβ. Soluble Aβ is a normal cellular metabolite by proteolytic Cleavage from a larger membrane-bound protein, the amyloid precursor Protein (APP) is created. Diverse, sometimes contradicting cellular effects of soluble Aβ have been described. So it can be both neurotrophic (Whitson et al., Science 243: 1488, 1989; Yankner et al., Science 250: 279, 1990) as well as neurotoxic (Shearman et al., Proc Natl Acad Sci USA 91: 1470, 1994) act. Overall exist currently no concrete ideas, such as soluble Aβ in the pathophysiological cascade leading to Alzheimer's disease could.

Als Mittel zur Behandlung der Alzheimer-Erkrankung und des Down-Syndroms werden in einer großen Zahl von Patentanmeldungen verschiedene Substanzen vorgeschlagen, die die Bildung und Sekretion von Amyloid-β-Protein hemmen. As a means of treating Alzheimer's disease and Down syndrome various substances proposed in a large number of patent applications, which inhibit the formation and secretion of amyloid-β protein.

Überraschenderweise wurde gefunden, daß diese bekannten Wirkstoffe nicht nur zur Behandlung der Alzheimer-Erkrankung und des Down-Syndroms geeignet sind, sondern ebenso zur Vorbeugung und Behandlung von Krankheiten vielfältiger Genese.Surprisingly, it was found that these known active ingredients not only for Treatment of Alzheimer's disease and Down syndrome are suitable, but also for the prevention and treatment of diseases of various origins.

Es ist Aufgabe der vorliegenden Erfindung, eine Verfahren zu beschreiben und pharmazeutisch wirksame Substanzen anzugeben, die durch Hemmung der Bildung und Sekretion von Amyloid-β-Protein beim Menschen und bei Säugetieren die Vorbeugung und Behandlung von Krankheiten vielfältiger Genese bewirken.It is an object of the present invention to describe a method and specify pharmaceutically active substances by inhibiting education and Prevention of secretion of amyloid beta protein in humans and mammals and treatment of diseases of diverse origins.

Über die gesamte Dauer der Evolution lassen sich einheitliche, stereotype Reaktionsweisen von Zellen erkennen, deren Muster durch einzellige Organismen (Protisten) festgelegt und durch mehrzellige Lebewesen (Metazoa) variiert und hierarchisiert, aber nicht entscheidend verändert wurden. Geraten Zellen unter Nährstoffmangel oder metabolischen Stress, wird ihre metabolische Aktivität gedrosselt. Zusätzlich werden zunächst hochkalorische Energiedepots mobilisiert (bei Metazoa Depotfette, bei Protisten Polyhydroxybutyrat) und der Energiegewinnung zugeführt. Demgegenüber wird die Verbrennung von Glucose gehemmt. Da es auch Ausgangsstoff für eine Reihe von Zellbaustoffen und anabolen Prozessen ist, ist es dann zu wertvoll, um als Brennstoff zu dienen. Reichen diese Notmaßnahmen nicht aus, wird auch bei Metazoa ein von Protisten entwickeltes Programm aktiviert. Gehen bei Protisten die Nahrungsquellen zur Neige, differenzieren sie sich in widerstandsfähigere Formen (z. B. Sporen), die in der Lage sind, die aktuelle Notsituation zu überdauern. Da Einzeller über keine ausreichenden intrazellulären Energiedepots verfügen und die Nahrungsquellen in der Umgebung erschöpft sind, wird diese Umwandlung von Brennstoffen und Bausteinen gespeist, die von toten Angehörigen der Kolonie stammen. Zwar haben Mehrzeller Gewebe entwickelt, die hochkalorische Energiequellen speichern können (Fettgewebe), trotzdem sind die anderen Gewebe unter dem Einfluss von Botenstoffen (Hormone) nicht in der Lage, diese zu verwerten und werden in der Entwicklung von differenzierten Strukturen dem dualen Differenzierungs-/Zelltod- (Apoptosis) Prozess unterworfen. Dieselben Prozesse laufen bei gewebeschädigenden Einflüssen und Reparationsvorgängen ab, die zu Dedifferenzierung/Apoptosis und Redifferenzierung/Apoptosis Gleichgewichten führen. Da eine spezialisierte Funktion von Geweben immer von ihrem Differenzierungszustand abhängt, geht dabei auch die Funktion des Gewebes verloren.Uniform, stereotyped can be found over the entire duration of evolution Recognize how cells react, their patterns by unicellular organisms (Protists) fixed and varied by multicellular organisms (metazoa) and hierarchical, but not significantly changed. Cells get under Lack of nutrients or metabolic stress, their metabolic activity is throttled. In addition, high-calorie energy deposits are initially mobilized (at Metazoa Depot greases, at protists polyhydroxybutyrate) and energy generation. In contrast, the combustion of glucose is inhibited. Since it is also raw material is too valuable for a range of cell building materials and anabolic processes, to serve as fuel. If these emergency measures are not sufficient, will also Metazoa activated a program developed by protists. Go with protists Food sources are running low, they differentiate into more resistant forms (e.g. Spores) that are able to survive the current emergency situation. Because unicellular organisms over do not have sufficient intracellular energy stores and the food sources in the environment is exhausted, this conversion of fuels and Building blocks fed by dead members of the colony. Although have Developed multi-cell tissue that can store high-calorie energy sources (Adipose tissue), nevertheless the other tissues are under the influence of messenger substances (Hormones) unable to utilize them and are in the development of differentiated structures the dual differentiation / cell death (apoptosis) process subjected. The same processes run with tissue damaging influences and Reparation processes leading to dedifferentiation / apoptosis and Redifferentiation / apoptosis lead to equilibria. Because a specialized function always depends on tissues on their differentiation state Function of the tissue lost.

Das Gehirn hat von allen Geweben den aktivsten Energie-Metabolismus und daher lassen sich diese Vorgänge bei ihm am deutlichsten erkennen. Glucose ist im reifen Gehirn fast ausschließlicher Energieträger. Nach längeren Hungerphasen oder akuten metabolischen Stresssituationen (z. B. Schlaganfall, Schädel-Hirn-Trauma) wird der Energiebedarf des Gehirns in erheblichem Umfang auch durch Ketonkörper (Hydroxybutyrat, Acetoacetat, Aceton) gedeckt, die in der Leber aus Fettsäuren entstehen. Neurotransmitter spielen bei dieser Umstellung eine wesentliche Rolle. Insbesondere das pro-glycolytische Acetylcholin wird unter diesen Umständen gehemmt und das pro-ketonolytische GABA aktiviert.The brain has the most active energy metabolism of all tissues and therefore these processes can be seen most clearly in him. Glucose is ripe Brain almost exclusively energy source. After long periods of hunger or acute metabolic stressful situations (e.g. stroke, traumatic brain injury) Significant amounts of brain energy are also required by ketone bodies (Hydroxybutyrate, acetoacetate, acetone) covered in the liver from fatty acids arise. Neurotransmitters play an important role in this change. In particular, the pro-glycolytic acetylcholine is inhibited under these circumstances and activated the pro-ketonolytic GABA.

Eine Gesamtsicht der zellulären Wirkungen von APP und seiner Metaboliten, sekretiertes APP (sAPP) und lösliches Aβ, lässt erkennen, dass, abhängig von der Menge und Zusammensetzung des Nährstoffangebots an die Zelle, APP eine zentrale Rolle bei zellulären Stressreaktionen spielt. Das sAPP/Aβ Gleichgewicht mediiert dabei in sowohl antagonistischer wie auch synergistischer Weise in einer Vielzahl von Geweben zelluläre Deprivationsanpassungen. Insbesondere Aβ spielt in der Umstellung von glycolytischem auf lipolytischen Katabolismus und im Differenzierung/Apoptose Gleichgewicht eine entscheidende Rolle und integriert somit 'mehrzellige' und 'einzellige' Stressantworten. Da ein APP-Homolog bereits bei Wirbellosen vitale Funktionen erfüllt und APP bei Säugetieren in allen Geweben exprimiert wird, kann davon ausgegangen werden, dass diese Prozesse phylogenetisch konserviert und ubiquitär sind und somit Aβ bei den unterschiedlichsten Krankheitsprozessen ähnliche Funktionen erfüllt. Zum Unterschied von einzelligen Organismen, stellt eine solche Reaktionsweise mit Hypometabolismus und Dedifferenzierung bei mehrzelligen Lebewesen einen biologischen, evolutionär aber fixierten Anachronismus dar, da in diesem internen Milieu die Zellen von ausreichend Nährstoffen umgeben sind, diese aber aufgrund der zellulären Wirkungen von Aβ nicht in die Zelle eindringen und dort verwertet werden können. Eine Blockierung des zu Aβ führenden Stoffwechselweges kann daher den bei den verschiedensten Krankheitsbildern eintretenden Funktionsverlust von Geweben und den durch das Differentierungs/Apoptosis Gleichgewicht bedingten zusätzlichen Zelltod verhindern.An overall view of the cellular effects of APP and its metabolites, secreted APP (sAPP) and soluble Aβ, indicates that, depending on the Amount and composition of the nutrient supply to the cell, APP a central Plays a role in cellular stress reactions. The sAPP / Aβ balance mediates in both antagonistic and synergistic ways in a variety of Tissue cellular deprivation adjustments. Aβ in particular plays in the transition from glycolytic to lipolytic catabolism and in differentiation / apoptosis Balance plays a crucial role and thus integrates 'multicellular' and 'unicellular' Stress responses. Because an APP homolog already fulfills vital functions in invertebrates and APP is expressed in all tissues in mammals can be assumed that these processes are phylogenetically conserved and ubiquitous and thus Aβ fulfills similar functions in the most diverse disease processes. To the Difference from unicellular organisms, provides such a reaction Hypometabolism and dedifferentiation in multicellular organisms biological, evolutionary but fixed anachronism, because in this internal milieu the cells are surrounded by sufficient nutrients, but due to the cellular effects of Aβ do not penetrate into the cell and are used there can. Blocking the metabolic pathway leading to Aβ can therefore lead to loss of function of tissues and various clinical pictures the additional cell death caused by the differentiation / apoptosis equilibrium prevent.

Die verschiedensten Zellen im Körper geraten bei praktisch allen schädigenden Prozessen jedweder Genese (z. B. traumatisch, entzündlich, ischämisch, degenerativ) wie auch bei Alterungsprozessen in metabolischen Stress und damit wird der oben beschriebene Circulus vitiosus angestossen und unterhalten. Auch eine Vorbeugung von Alterungsvorgängen oder altersbedingter Erkrankungen (z. B. Bluthochdruck, Diabetes mellitus, Arteriosklerose und ihre Folgeerscheinungen, rheumatische Erkrankungen) und ihre Behandlung ist damit zu erreichen.A wide variety of cells in the body are damaged by practically all of them Processes of any genesis (e.g. traumatic, inflammatory, ischemic, degenerative) as with aging processes in metabolic stress and with that the above initiated and entertained described vicious circle. Prevention too aging processes or age-related diseases (e.g. high blood pressure, Diabetes mellitus, arteriosclerosis and its sequelae, rheumatic Diseases) and their treatment can be achieved.

Die Erfindung betrifft daher insbesondere die Verwendung der o. g. Inhibitoren zur Herstellung von Arzneimitteln zur Behandlung von Bluthochdruck, Diabetes mellitus, Arteriosklerose, rheumatischen Erkrankungen, ischämischen Erkrankungen wie z. B. Schlaganfall oder Herzinfarkt, traumatischen Erkrankungen, entzündlichen Erkrankungen, Sepsis, Colitiden, Infektionserkrankungen, Autoimmunerkrankungen, degenerativen und altersabhängigen Erkrankungen und/oder Ulcuserkrankungen.The invention therefore relates in particular to the use of the abovementioned. Inhibitors of Manufacture of medicines to treat high blood pressure, diabetes mellitus, Arteriosclerosis, rheumatic diseases, ischemic diseases such as B. Stroke or heart attack, traumatic diseases, inflammatory Diseases, sepsis, colitis, infectious diseases, autoimmune diseases, degenerative and age-related diseases and / or ulcer diseases.

Die Verabreichung der Medikamente bei Menschen und anderen Säugetieren kann oral, sublingual, äusserlich oder parenteral geschehen. Die Menge des Mittels, die ausreicht die vorbeschriebenen Krankheiten zu behandeln, richtet sich nach den üblichen Faktoren wie Natur und Schwere der Störung und dem Gewicht des Säugetiers. Eine Einheitsdosis wird im Normalfall 1 bis 1000 mg, vorteilhaft 1 bis 500 mg betragen. Die Verabreichung der Einheitsdosis wird ein oder mehrmals täglich erfolgen.The administration of the medication to humans and other mammals can be administered orally, happen sublingually, externally or parenterally. The amount of the agent that is sufficient Treating the diseases described above depends on the usual ones Factors such as the nature and severity of the disorder and the weight of the mammal. A The unit dose will normally be 1 to 1000 mg, advantageously 1 to 500 mg. The The unit dose will be administered one or more times a day.

Die Dosis-Einheit der aktiven Verbindung wird zweckmässigerweise in Zubereitungen für orale, sublinguale, äusserliche oder parenterale Anwendung zugeführt. Als solches werden pharmazeutische Formulierungen in Form von Tabletten, Kapseln, flüssigen oralen Präparaten, Pulvern, Salben, Lotios, Pasten, Suppositorien, injizierbaren und infundierbaren Lösungen oder Suspensionen hergestellt. The dose unit of the active compound is expediently used in preparations for oral, sublingual, external or parenteral use. As such are pharmaceutical formulations in the form of tablets, capsules, liquid oral preparations, powders, ointments, lotions, pastes, suppositories, injectable and infusible solutions or suspensions.

Tabletten und Kapseln für orale und sublinguale Anwendung werden üblicherweise in einer Dosis-Einheit angeboten und können konventionelle Träger- und Hilfsstoffe wie Bindemittel, Füllstoffe, Verdünnungsmittel, Tablettierhilfen, Gleitmittel, Farbstoffe und Geschmacksstoffe enthalten.Tablets and capsules for oral and sublingual use are commonly found in offered in a dose unit and can include conventional carriers and excipients such as Binders, fillers, diluents, tabletting aids, lubricants, dyes and Contain flavorings.

Als Füllstoffe können Zellulose, Mannitol, Laktose und ähnliche Substanzen verwendet werden. Als Bindemittel können dienen Stärke, Polyvinylpyrrolidon und Stärkederivate. Als Gleitmittel kann z. B. Magnesiumstearat eingesetzt werden.Cellulose, mannitol, lactose and similar substances can be used as fillers become. Starch, polyvinylpyrrolidone and starch derivatives can serve as binders. As a lubricant z. B. magnesium stearate can be used.

Diese festen oralen Zubereitungen können durch übliche Methoden des Mischens, Füllens und Tablettierens hergestellt werden.These solid oral preparations can be mixed by conventional methods of mixing, Filling and tableting can be made.

Orale flüssige Zubereitungen können z. B. in Form von wässrigen oder öligen Suspensionen, Lösungen, Emulsionen, Sirups oder Elixieren verwendet werden oder als Trockenpulver zur Rekonstitution mit Wasser oder anderen geeigneten Trägern vor Gebrauch. Solche flüssigen Zubereitungen können übliche Additive wie Suspensionsmittel z. B. Sorbitol, Sirup, Methylzellulose, Gelatin, Hydroxyethylzellulose, Carboxymethylzellulose, Aluminiumstearat Gel oder Speisefette, emulgierende Agentien wie Lezithin, nicht-wässrige Träger wie Speiseöle auch in veresterter Form mit Glyzerin oder Äthanol und Konservierungsmittel wie Sorbinsäure enthalten.Oral liquid preparations can e.g. B. in the form of aqueous or oily Suspensions, solutions, emulsions, syrups or elixirs can be used or as Dry powder for reconstitution with water or other suitable carriers Use. Such liquid preparations can be conventional additives such as Suspension means z. B. sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, Carboxymethyl cellulose, aluminum stearate gel or edible fats, emulsifying agents such as lecithin, non-aqueous carriers such as edible oils also in esterified form with glycerin or contain ethanol and preservatives such as sorbic acid.

Orale Formulierungen können auch Retardformulierungen sein wie z. B. Coat-Core Zubereitungen und das Gastro-intestinale System (GITS).Oral formulations can also be sustained release formulations such as e.g. B. Coat core Preparations and the Gastrointestinal System (GITS).

Zur äusseren Behandlung sind Salben, Puder, Lotios, Pasten und Cremes vorgesehen. Grundlagen der Salben sind Fette, Vaselin, Emulsionen vom Typ Wasser-in-Öl und Öl- in-Wasser die auf konventionelle Weise hergestellt werden. Puder können z. B. Zinkoxid, Titanoxid, Talkum oder Stärke enthalten. Durch Mischen von Puder und Wasser werden Lotios, aus Pudern und Salben Pasten hergestellt.Ointments, powders, lotions, pastes and creams are intended for external treatment. The basis of the ointments are fats, petroleum jelly, water-in-oil and oil in water which are produced in a conventional manner. Powder can e.g. B. zinc oxide, Contain titanium oxide, talc or starch. By mixing powder and water Lotios, made from powder and ointment pastes.

Parenterale Formen enthalten aktive Substanzen und sterile Lösungsmittel. Die aktive Substanz kann entweder gelöst oder als Suspension vorliegen. Konservierungsmittel oder Puffersubstanzen können auch enthalten sein. Auch Iyophilisierte Formen sind möglich.Parenteral forms contain active substances and sterile solvents. The active one Substance can either be dissolved or in suspension. preservative or buffer substances can also be included. Iyophilized forms are also possible.

Gesonderte Zubereitungen für den Human- wie Veterinärbereich sind vorgesehen. Separate preparations for human and veterinary use are planned.

Vorzugsweise handelt es sich bei den erfindungsgemäß zu verwendenden Inhibitoren um folgende Wirkstoffe:
The inhibitors to be used according to the invention are preferably the following active ingredients:

1. Compounds which are described in patent application WO 00/24392, namely in particular compounds which are represented by the following general formula and which are suitable for treating Alzheimer's disease etc., since they have an effect on the inhibition of the Formation of β-amyloid are characterized: R 1 -Y-NH-A-CO-R 2 wherein R 1 represents an optionally substituted aryl group, an optionally substituted unsaturated heterocycle or an optionally substituted alkyl group; R 2 represents an optionally substituted amino, an optionally substituted alkoxy or hydroxy group; -Y- represents -CO-, etc .; and -A- represents a group of formula (I), etc.
wherein one of R 3 and R 4 is a hydrogen atom, a halogen, -S (O) n -X (wherein n is 0, 1 or 2 and X is an optionally substituted alkyl, optionally substituted aryl or optionally substituted unsaturated heterocycle Represents a group), represents an optionally substituted alkyl group or an optionally substituted aryl group, while the other radical of R 3 and R 4 represents an optionally substituted aryl group or an optionally substituted unsaturated heterocycle.
2. Compounds described in patent application WO 00/09119, namely in particular a compound of the general formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is suitable for inhibiting Aβ production:
wherein
R is a hydrogen atom or a (C 1 -C 6 ) alkyl group;
R 1 is a hydrogen atom,
a (C 1 -C 6 ) alkyl group;
a (C 2 -C 6 ) alkenyl group;
a phenyl group or a substituted phenyl group;
a phenyl (C 1 -C 6 ) alkyl group or a substituted phenyl (C 1 -C 6 ) alkyl group;
a phenyl (C 2 -C 6 ) alkenyl group or a substituted phenyl (C 2 -C 6 ) alkenyl group
a heterocyclyl group or a substituted heterocyclyl group;
a heterocyclyl (C 1 -C 6 ) alkyl group or a substituted heterocyclyl (C 1 -C 6 ) alkyl group;
a group BSO n A-, where n is 0, 1 or 2 and B is a hydrogen atom or a (C 1 -C 6 ) alkyl group, a phenyl group, a substituted phenyl group, a heterocyclyl group, a substituted one Heterocyclyl group, a (C 1 -C 6 ) acyl group, a phenacyl group or a substituted phenacyl group, and wherein A represents a (C 1 -C 6 ) alkylene group;
a hydroxy group or a (C 1 -C 6 ) alkoxy group;
an amino group, a protected amino group, an acylamino group, a (C 1 -C 6 ) alkylamino group or a di (C 1 -C 6 ) alkylamino group;
a mercapto or a (C 1 -C 6 ) alkylthio group;
an amino (C 1 -C 6 ) alkyl group, a (C 1 -C 6 ) alkylamino (C 1 -C 6 ) alkyl group, a di (C 1 -C 6 ) alkylamino (C 1 -C 6 ) Alkyl group, a hydroxy (C 1 -C 6 ) alkyl group, a mercapto (C 1 -C 6 ) alkyl group or a carboxy (C 1 -C 6 ) alkyl group, in which the amino, hydroxy, , Mercapto or carboxyl group optionally protected or the carboxyl group is amidated;
a short chain, carbamoyl substituted alkyl group, a mono (short chain alkyl) carbamoyl group, a di (short chain alkyl) carbamoyl group, a di (short chain alkyl) amino group, or a carboxy (short chain alkanoyl) amino group ; or is a cycloalkyl group, or
a cycloalkenyl group or a non-aromatic heterocyclic ring which contains up to 3 heteroatoms, each of which (i) can be substituted by one or more substituents selected from (C 1 -C 6 ) alkyl, (C 2 -C 6 ) Alkenyl, haiogen, cyano group (-CN), -CO 2 H, -CO 2 R, -CONH 2 , -CONHR, -CON (R) 2 , -OH, -OR, oxo-, -SH, -SR , -NHCOR, and -NHCO 2 R, wherein R is a (C 1 -C 6 ) alkyl group or a benzyl group, and / or (ii) fused to a cycloalkyl or heterocyclic ring;
R 2 is a (C 1 -C 12 ) alkyl group,
a (C 2 -C 12 ) alkenyl group,
a (C 2 -C 12 ) alkynyl group,
a phenyl (C 1 -C 6 ) alkyl group,
a heteroaryl (C 1 -C 6 ) alkyl group,
a phenyl (C 2 -C 6 ) alkenyl group,
a heteroaryl (C 2 -C 6 ) alkenyl group,
a phenyl (C 2 -C 6 ) alkynyl group,
a heteroaryl (C 2 -C 6 ) alkynyl group,
a cycloalkyl (C 1 -C 6 ) alkyl group,
a cycloalkyl (C 2 -C 6 ) alkenyl group,
a cycloalkyl (C 2 -C 6 ) alkynyl group,
a cycloalkenyl (C 1 -C 6 ) alkyl group,
a cycloalkenyl (C 2 -C 6 ) alkenyl group,
a cycloalkenyl (C 2 -C 6 ) alkynyl group,
is a phenyl (C 1 -C 6 ) alkyl) O (C 1 -C 6 ) alkyl group, or
a heteroaryl (C 1 -C 6 ) alkylO (C 1 -C 6 ) alkyl group,
each of which can be optionally substituted with
a (C 1 -C 6 ) alkyl group,
a (C 1 -C 6 ) alkoxy group,
a halogen,
a cyano group (-CN),
a phenyl or heteroaryl group, or
substituted with a phenyl or heteroaryl group
a (C 1 -C 6 ) alkyl group,
a (C 1 -C 6 ) alkoxy group,
a halogen, or with
a cyano group (-CN);
R 3 is the characterizing group of a natural or unnatural α-amino acid in which any functional group can be protected; and
R 4 is an ester or thioester group,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Mediated in another broad aspect of the invention is the use of a compound of formula (I), as defined in the immediately preceding paragraph, for the manufacture of a pharmaceutical composition for the treatment of mammals suffering from diseases related to the inhibition of the Address Aβ production.
In a further particular aspect of the invention the compound used is one of the general formula (I) above, wherein
R, R 1 and R 4 are as defined above with reference to formula (I),
R 2 is a (C 1 -C 12 ) alkyl, (C 2 -C 12 ) alkenyl, (C 2 -C 12 ) alkynyl group,
a biphenyl (C 1 -C 6 ) alkyl, phenyl heteroaryl (C 1 -C 6 ) alkyl, heteroarylphenyl (C 1 -C 6 ) alkyl group,
a biphenyl (C 2 -C 6 ) alkenyl, phenyl heteroaryl (C 2 -C 6 ) alkenyl, heteroaryl phenyl (C 2 -C 6 ) alkenyl group,
a phenyl (C 2 -C 6 ) alkynyl, heteroaryl (C 2 -C 6 ) alkynyl group,
a biphenyl (C 2 -C 6 ) alkynyl, phenyl heteroaryl (C 2 -C 6 ) alkynyl, heteroaryl phenyl (C 2 -C 6 ) alkynyl group,
is a phenyl (C 1 -C 6 ) alkylO (C 1 -C 6 ) alkyl, or a hetero aryl (C 1 -C 6 ) alkylO (C 1 -C 5 ) alkyl group,
each group on a ring carbon atom may be optionally substituted with a (C 1 -C 6 ) alkyl group, a (C 1 -C 6 ) alkoxy group, a halogen, or a cyano group (-CN); and in what
R 3 is a (C 1 -C 6 ) alkyl group, an optionally substituted benzyl group, an optionally substituted phenyl group, an optionally substituted heteroaryl group; or
the characterizing group is a natural α-amino acid in which any functional group can be protected, any amino group can be acylated and any carboxyl group present can be amidated; or
a heterocyclic (C 1 -C 6 ) alkyl group, optionally substituted in the heterocyclic ring;

und pharmazeutisch akzeptable Salze, Hydrate oder Solvate davon.
and pharmaceutically acceptable salts, hydrates or solvates thereof.

1. Compounds which are described in patent application WO 00/07995, namely in particular a compound of the formula (I):
or a pharmaceutically acceptable salt or pro-drug thereof, wherein:
Q corresponds to a radical -OR 1 or -NR 1 R 2 ;
R 1 is independently selected for each occurrence from:
H;
(C 1 -C 6 ) alkyl substituted with 0-3 R 1a ,
(C 2 -C 6 ) alkenyl substituted with 0-3 R 1a ,
(C 3 -C 10 ) carbon cycle substituted with 0-3 R 1b ,
(C 6 -C 10 ) aryl substituted with 0-3 R 1b , and
5 to 10 membered heterocycle substituted with 0-3 R 1b ;
R 1a is independently selected for each occurrence from H, (C 1 -C 6 ) alkyl, OR 14 ,
Cl, F, Br, I, = O, CN, NO 2 , NR 15 R 16 , CF 3 ,
(C 3 -C 10 ) carbon cycle substituted with 0-3 R 1b ,
(C 6 -C 10 ) aryl substituted with 0-3 R 1b , and
5 to 6-membered heterocycle substituted with 0-3 R 1b ;
R 1b is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) Alkoxy, (C 1 -C 4 ) haloalkyl, and (C 1 -C 4 ) haloalkoxy;
R 2 is independently selected from H, NH 2 , OH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, phenoxy, benzyloxy, (C 3 -C 10 ) carbon cycle, (C 6 -C 10 ) Aryl and 5 to 10 membered heterocycle;
R 3 - (CR 7 R 7a ) n -R 4 ,
- (CR 7 R 7a ) n -S- (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -O- (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -N (R 7b ) - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -S (= O) 2 - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -S (= O) 2 - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -C (= O) - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -N (R 7b ) C (= O) - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -C (= O) N (R 7b ) - (CR 7 R 7a ) m -R 4 ,
- (CR 7 R 7a ) n -N (R 7b ) S (= O) 2 - (CR 7 R 7a ) m -R 4 , or
- (CR 7 R 7a ) n -S (= O) 2 N (R 7b ) - (CR 7 R 7a ) m -R 4 ; in which
n is 0, 1, 2, or 3;
m is 0, 1, 2 or 3,
R 3a is H, OH, a (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, or (C 2 -C 4 ) alkenyloxy group;
R 4 H, OH, OR 14a ,
a (C 1 -C 6 ) alkyl group substituted with 0-3 R 4a ,
a (C 2 -C 6 ) alkenyl group substituted with 0-3 R 4a ,
a (C 2 -C 6 ) alkynyl group substituted with 0-3 R 4a ,
a (C 3 -C 10 ) carbon cycle substituted with 0-3 R 4b ,
a (C 3 -C 10 ) aryl group substituted with 0-3 R 4b , or
is a 5 to 10 membered heterocycle substituted with 0-3 R 4b ;
R 4a is independently selected for each occurrence from H, F, Cl, Br, I, CF 3 , (C 3 -C 10 ) carbon cycle substituted with 0-3 R 4b , (C 6 -C 10 ) aryl substituted with 0- 3 R 4b , or 5 to 10 membered heterocycle substituted with 0-3 R 4b ;
R 4b is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S (= O) CH 3 , S (= O) 2 CH 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, and (C 1 -C 4 ) Halogenthioalkoxy;
R 5 H, OH 14 ,
a (C 1 -C 6 ) alkyl group substituted with 0-3 R 5b ,
a (C 1 -C 6 ) alkoxy group substituted with 0-3 R 5b ,
a (C 2 -C 6 ) alkenyl group substituted with 0-3 R 5b ,
a (C 2 -C 6 ) alkynyl group substituted with 0-3 R 5b ,
a (C 3 -C 10 ) carbon cycle substituted with 0-3 R 5c ,
a (C 6 -C 10 ) aryl group substituted with 0-3 R 5c , or
is a 5 to 10 membered heterocycle substituted with 0-3 R 5c ;
R 5a is H, OH, a (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, or a (C 2 -C 4 ) alkenyloxy group ;
R 5b is independently selected for each occurrence from:
H, (C 1 -C 5 ) alkyl, CF 3 , OR 14 , Cl, F, Br, I, = O, CN, N0 2 , NR 15 R 16 ,
(C 3 -C 10 ) carbon cycle substituted with 0-3 R 5c ,
(C 6 -C 10 ) aryl substituted with 0-3 R 5c , or
5 to 10 membered heterocycle substituted with 0-3 R 5c ;
R 5c is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S (= 0) CH 3 , S (= O) 2 CH 3, (C 1 -C 6) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) haloalkyl, (C 1 -C 4) haloalkoxy, and C 1 -C 4) Halogenthioalkoxy ;
R 6 H;
a (C 1 -C 6 ) alkyl group substituted with 0-3 R 6a ,
a (C 3 -C 10 ) carbon cycle substituted with 0-3 R 6b ; or
is a (C 6 -C 10 ) aryl group substituted with 0-3 R 6b ;
R 6a is independently selected for each occurrence from H, (C 1 -C 6 ) alkyl, OR 14 , Cl, F, Br, I, = O, CN, NO 2 , NR 15 R 16 , phenyl or CF 3 ;
R 6b is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) Alkox (C 1 -C 4 ) haloalk, and (C 1 -C 4 ) haloalkoxy;
R 7 is independently selected at each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , and (C 1 -C 4 ) alkyl;
R 7a is independently selected at each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , aryl and (C 1 -C 4 ) alkyl;
R 7b is independently selected from H and (C 1 -C 4 ) alkyl;
W is a residue - (CR 8 R 8a ) p -,
p is 0, 1, 2, 3, or 4;
R 8 and R 8a are independently selected for each occurrence from H, F, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl and (C 3 -C 8 ) cycloalkyl;
X a bond,
a (C 6 -C 10 ) aryl group substituted with 0-3 R Xb ,
a (C 3 -C 10 ) carbon cycle substituted with 0-3 R Xb , or
is a 5 to 10 membered heterocycle substituted with 0-2 R Xb ;
R Xb is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 . S (= O) CH 3 , S (= O) 2 CH 3 , (C 1 -C 5 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) Haloalkoxy, and (C 1 -C 4 ) halothioalkoxy;
Y is a bond or - (CR 9 R 9a ) t -V- (CR 9 R 9a ) u -;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R 9 and R 9a are independently selected at each occurrence from H, F, (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl;
V is a bond, -C (= O) -, -O-, -S-, -S (= O) -, -S (= O) 2 -, -N (R 19 ) -, -C (= O ) NR 19b -, -NR 19b C (= O) -, -NR 19b S (= O) 2 -, -S (= O) 2 NR 19b -, NR 19b S (= O) -, -S (= O) NR 19b -, -C (= O) O-, or -OC (= O) -;
Z is a (C 1 -C 3 ) alkyl group substituted with 1-2 R 12 ,
a (C 6 -C 10 ) aryl group substituted with 0-4 R 12b ,
a (C 3 -C 10 ) carbon cycle substituted with 0-4 R 12b , or
is a 5 to 10 membered heterocycle substituted with 0-3 R 12b ;
R 12 is a (C 6 -C 10 ) aryl group substituted with 0-4 R 12b , a (C 3 -C 10 ) carbon cycle substituted with 0-4 R 12b , or a 5 to 10 membered heterocycle substituted with 0-3 R is 12b ;
R 12b is independently selected for each occurrence from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S (= O) CH 3 , S (= O) 2 CH 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, and (C 1 -C 4 ) Halogenthioalkoxy;
B is a 5 to 10-membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon atom is substituted with 0-2 R 11 ; and,
optionally, the lactam contains a heteroatom which is selected from -O-, -S-, -S (= O) -, -S (= O) 2 -, and -N (R 10 ) -;
R 10 H, C (= O) R 17 , C (= O) OR 17 , C (= O) NR 18 R 19 , S (= O) 2 NR 18 R 19 , S (= O) 2 R 17 ,
a (C 1 -C 6 ) alkyl group substituted with 0-2 R 10a ,
a (C 6 -C 10 ) aryl group substituted with 0-4 R 10b ,
a (C 3 -C 10 ) carbon cycle substituted with 0-3 R 10b , or
a 5 to 10 membered heterocycle optionally substituted with 0-3 R 10b ;
R 10a is independently selected at each occurrence from H, (C 1 -C 6 ) alkyl, OR 14 , Cl, F, Br, I, = O, CN, NO 2 , NR 15 R 16 , CF 3 , or aryl with 0-4 R 10b ;
R 10b is independently selected for each occurrence from H, OH, (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF. 3 , acetyl, SCH 3 , S (= O) CH 3 , S (= O) 2 CH 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl , (C 1 -C 4 ) haloalkoxy, and (C 1 -C 4 ) halothioalkoxy;
R 11 - is independently selected at each occurrence
(C 1 -C 4 ) alkoxy, Cl, F, Br, I, = O, CN, NO 2 , NR 18 R 19 , C (= O) R 17 , C (= O) OR 17 ,
C (= O) NR 18 R 19 , S (= O) 2 NR 18 R 19 , CF 3 ,
(C 1 -C 6 ) alkyl substituted with 0-1 R 11 a,
(C 6 -C 10 ) aryl substituted with 0-3 R 11 b,
(C 3 -C 10 ) carbon cycle substituted with 0-3 R 11b , or
5 to 10 membered heterocycle substituted with 0-3 R 11b ;
alternatively, two R 11 substituents on the same or on adjacent carbon atoms can be connected to one another to form a (C 3 -C 6 ) carbon cycle or a benzo-fused radical;
R 11a is independently selected at each occurrence from H, (C 1 -C 6 ) alkyl, OR 14 , Cl, F, Br, I, = O, CN, NO 2 , NR 15 R 16 , CF 3 , or phenyl with 0-3 R 11b ;
R 11b is independently selected for each occurrence from H, OH, Cl, F, Br, I CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S (= O) CH 3 , S (= O ) 2 CH 3 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, and (C 1 -C 4 ) halothioalkoxy ;
R 14 is independently selected at each occurrence from H, phenyl, benzyl, (C 1 -C 6 ) alkyl, or (C 2 -C 6 ) alkoxyalkyl;
R 14a is H, a phenyl group, a benzyl group, or a (C 1 -C 4 ) alkyl group;
R 15 is independently selected for each occurrence from H, (C 1 -C 6 ) alkyl, benzyl, phenethyl, -C (= O) - (C 1 -C 6 ) alkyl and -S (= O) 2 - (C 1 -C 6 ) alkyl;
R 16 is independently selected for each occurrence from H, OH, (C 1 -C 6 ) alkyl, benzyl, phenethyl, -C (= O) - (C 1 -C 6 ) alkyl and -S (= O) 2 - (C 1 -C 6 ) alkyl;
R 17 is H, an aryl, an aryl CH 2 , a (C 1 -C 6 ) alkyl, or a (C 2 -C 6 ) alkoxyalkyl group;
R 18 is independently selected for each occurrence from H, (C 1 -C 6 ) alkyl, benzyl, phenethyl, -C (= O) - (C 1 -C 6 ) alkyl and -S (= O) 2 - (C 1 -C 6 ) alkyl; and
R 19 is independently selected for each occurrence from H, OH, (C 1 -C 6 ) alkyl, phenyl, benzyl, phenethyl, -C (= O) - (C 1 -C 6 ) alkyl and -S (= O) 2 - (C 1 -C 6 ) alkyl; and
R 19b is H, a (C 1 -C 6 ) alkyl, a (C 3 -C 8 ) cycloalkyl, a phenyl, a benzyl or a phenethyl group;
2. Compounds described in patent application EP-A-0 778 266, namely in particular compounds of the formula I, their pharmaceutical formulations and their use in the inhibition of β-AP production in patients who suffer from AD or a have an increased risk of developing AD or other disorders that result from β-AP accumulation in brain tissue. The compounds of the formula I also include pharmaceutically acceptable salts which are formed with the addition of acids and / or hydrates.
In formula I, the symbols R 1 to R 4 have the following meaning.
R 1 is selected from (C 4 -C 8 ) alkyl, (C 4 -C 6 ) alkenyl, short-chain alkoxy, short-chain alkanediyl, R 5 -substituted (C 3 -C 8 ) cycloalkyl, R 5 -substituted (C 3 - C 6 ) cycloalkyl short chain alkanediyl, and Ar- (CH 2 ) n -. Ar can be R 5 -substituted phenyl and naphthyl ring, where R 5 is a hydrogen atom, a short chain alkyl or alkoxy group and n is an integer from 1 to 4. By 'short chain' is meant (C 1 -C 6 ) alkyl or alkoxy groups which can be straight or branched. (C 4 -C 8 ) Alkyl contains straight-chain and branched alkyl groups. Short chain alkoxy short chain alkanediyl means such groups as 1-methylethoxyethyl. R 5 substituted (C 3 -C 6 ) cycloalkyl would include rings from cyclopropane to cyclohexane bearing an R 5 substituent. These rings can also be attached to the nitrogen atom via a short chain alkanediyl group.
R 2 is independently selected from hydrogen atom and methyl.
R 3 is selected from short chain alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl short chain alkanediyl, (C 3 -C 6 ) alkenyl, and Ar- (CH 2 ) n -.
R 4 is selected from R 3 , short chain alkyl thio short chain alkyl, and
wherein R 6 is a short chain alkyl group.
3. Compounds described in patent application WO 95/09838, namely in particular a compound having the formula IB or the hydrate, the stereoisomer, the isoster or pharmaceutically acceptable salt thereof (which are believed to correspond to compounds of the formula IA that have not yet been disclosed):
K a -P 4 a -P 3 a -P 2 a -NH-CH (R a ) - [C (= O)] n -X a
(Peptide sequence No. 2)
IB
wherein
X a H, CHF 2 , CF 3 , CF 2 F 3 , CF 2 CH 2 NHC (= O) R 1 a , CHFCH 2 NHC (= O) R 1 a , F 2 C (= O) W a , C (= O) NHR 1 a , B (OH) 2 or C (= O) R 1 a ,
provided that,
if X a is H, R a then CH 2 Si ((C 1 -C 6 ) alkyl) 2 (C 1 -C 6 ) alkenyl, CH 2 CH (CF 3 ) 2 , CH 2 CH (CH 3 ) (CF 3 ), benzyl substituted with benzoyl, NHC (= O) R 1 a , NHC (= NH) NH 2 , halogen, or hydroxy;
if X a is CF 3 , CHF 2 , C (= O) NHR 1 a or CF 2 C (= O) NHR 1 a , then R a is not (C 1 -C 10 ) alkyl, benzyl or benzyl substituted with a hydroxy -Rest is;
if X a is CF 2 CH 2 NHC (= O) R 1 a , then R a is not (C 1 -C 10 ) alkyl, benzyl, (CH 2 ) m -naphthyl or benzyl substituted with a hydroxy radical;
if X a is CF 2 C (= O) NH-benzyl , then R a is not benzyl, t-butyl, CH 2 Si (CH 3 ) 3 , or (CH 2 ) m-naphthyl;
when X is a CF 2 C (= O) NHR 1, R a will not benzyl substituted with (C 1 - C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) Alkyoxyalkyl, benzyloxy or is -O- (CH 2 ) m -phenyl; and
if X a is C (= O) R a , then R a is not (C 1 -C 4 ) alkyl, benzyl, (C 1 - C 4 ) alkylene-O- (C 1 -C 10 ) alkyl, or (CH 2 ) m is naphthyl;
R a (C 1 -C 10 ) alkyl, benzyl, CH 2 Si ((C 1 -C 6 ) alkylkyl) 2 (Y a ), (C 1 -C 4 ) alkylene-OOR 1 a CH 2 CH (CF 3 ) 2 , CH 2 CH (CH 3 ) (CF 3 ), (CH 2 ) m -naphthyl, or a substituted benzyl, where the substitution can be carried out by 1, 2 or 3 substituents which are independently selected from the group consisting of (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkoxyalkyl, benzyloxy, hydroxy, NHC (= NH) NH 2 , NR 1 a H, NO 2 , -O- (CH 2 ) m -aryl, NHC (= O) R 1 a or halogen, wherein
m is 1 or 2;
Y a is a (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, aryl or arylalkyl group;
n is 1, unless X a is B (OH) 2 , where n is zero;
R 1 a is a hydrogen atom, a (C 1 -C 6 ) alkyl, an aryl or an arylalkyl group,
P 2 a is a bond, -HN-CH [CH 2 Si (C 1-6 alkyl) 2 (Y a )] C (= O) - or a residue from Leu, Ala, Met, Ile, Val, Nva, Nle , Phe, Asp, Ser, Pro, Hist, Cyclopentylglycine, Cyclohexylglycine, or tert Leucine;
P 3 a is a bond or a residue from Val, Leu, Ile or Met;
P 4 a is a bond or a residue from Val, Leu, Ile or Met;
K a is a hydrogen atom, a desamino group, formyl, acetyl, succinyl, benzoyl, t-butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulphonyl, 1-adamantane acetyl, 2-carboxybenzoyl, phenylacetyl, bis [(1-naphthyl) methyl] acetyl, a radical -A a -R z a , in which
and in which R z a is an aryl or arylalkyl group in which the aryl group contains 6, 10 or 12 carbon atoms which are suitably substituted with 1 to 3 radicals which are independently selected from the group consisting of fluorine, chlorine , Bromine, iodine, trifluoromethyl, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carboxy, alkylearbonylamine, where the alkyl group contains 1 to 6 carbon atoms, 5-tetrazolyl, and acylsulfonamide (ie, acylaminosulfonyl and sulfonyiaminocarbonyl) with 1 to 15 carbon atoms, provided that when the acylsulfonamide contains an aryl radical, the aryl radical may additionally be substituted by a radical selected from fluorine, chlorine, bromine, iodine and nitro; and such other terminal amine protecting groups that are functionally equivalent thereto
or
wherein Z a is N or CH, and wherein D a is a group of the formulas
wherein R ' a is a hydrogen atom or a (C 1 -C 6 ) alkyl group.
4. Compounds described in U.S. Patent 5,552,426, particularly compounds of Formula I.
wherein:
R 1 is a hydrogen atom, a (C 1 -C 12 ) alkyl group, a (C 1 -C 6 ) alkoxy group, a phenyl group, a (C 3 -C 8 ) cycloalkyl group, a naphthyl group , a heterocycle, an unsaturated heterocycle, a phenyl (C 1 -C 6 ) alkylidenyl group, a naphthyl (C 1 -C 6 ) alkylidenyl group, a heterocycle (C 1 -C 6 ) alkylidenyl group, an unsaturated heterocycle (C 1 -C 6 ) alkylidenyl group, a phenyl (C 1 -C 6 ) alkoxy group, a naphthyl (C 1 -C 6 ) alkoxy group, a heterocycle (C 1 -C 6 ) alkoxy group, or an unsaturated heterocycle (C 1 -C 6 ) alkoxy group,
each of the groups phenyl, naphthyl, heterocycle, (C 3 -C 8 ) cycloalkyl, or unsaturated heterocycle can optionally be substituted with one, two or three radicals which are independently selected from a group consisting of heterocycle (C 1 -C 6 ) Alkylidenyl, unsaturated heterocycle (C 1 -C 6 ) alkylidenyl, hydroxy, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, nitro, amino, cyano, (C 1 -C 6 ) alkylamino, and (C 1 -C 6 ) alkylthio;
R 2 is a hydrogen atom, a (C 1 -C 12 ) alkyl group, a (C 1 -C 6 ) alkoxy group, a phenyl group, a (C 3 -C 8 ) cycloalkyl group, a naphthyl group , a heterocycle, an unsaturated heterocycle, a phenyl (C 1 -C 6 ) alkylidenyl group, a naphthyl (C 1 -C 6 ) alkylidenyl group, a heterocycle (C 1 -C 6 ) alkylidenyl group, an unsaturated heterocycle (C 1 -C 6 ) alkylidenyl group, a phenyl (C 1 -C 6 ) alkoxy group, a naphthyl (C 1 -C 6 ) alkoxy group, a heterocycle (C 1 - C 6 ) alkoxy group, or an unsaturated heterocycle (C 1 -C 6 ) alkoxy group,
where each of the groups phenyl, naphthyl, heterocycle, (C 3 -C 8 ) cycloalkyl, or unsaturated heterocycle can optionally be substituted with one, two or three radicals which are independently selected from a group consisting of phenyl (C 1 -C 6 ) alkylidenyl, naphthyl (C 1 -C 6 ) alkylidenyl, heterocycle (C 1 -C 6 ) alkylidenyl, unsaturated heterocycle (C 1 -C 6 ) alkylidenyl, phenyl (C 1 -C 6 ) alkoxy, naphthyl (C 1 -C 6 ) alkoxy, heterocycle (C 1 -C 6 ) alkoxy, or unsaturated heterocycle (C 1 -C 6 ) alkoxy, hydroxy, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, nitro, amino, cyano, (C 1 -C 6 ) alkylamino, and (C 1 -C 6 ) alkylthio;
R 3 is a hydrogen atom, a nitro group, a (C 1 -C 6 ) alkanoyl group, an amino group, a (C 1 -C 6 ) alkyl group, a (C 1 -C 6 ) alkoxy group , a (C 3 -C 8 ) cycloalkyl group, a heterocycle, an unsaturated heterocycle, a halogen, a (C 1 -C 6 ) alkylthio group, a hydroxy (C 1 -C 6 ) alkylidenyl group, a Hydroxy - ((C 1 -C 6 ) alkylidenyl) amino group, an R 4 R 5 N group, an R 4 R 5 N- (C 1 -C 6 ) alkylidenyl group, an R 4 R 5 N- (C 1 -C 6 ) alkoxy group, a hydroxy (C 1 -C 6 ) alkyl group, a heterocycle (C 1 -C 6 ) alkoxy group, an amino (C 1 -C 6 ) alkylidenyl Group, or is a trifluoromethyl group,
where R 4 and R 5 are independently selected from a group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkanoyl, aryl, heterocycle, unsaturated heterocycle, aryl (C 1 -C 6 ) alkylidenyl, heterocycle (C 1 -C 6 ) alkylidenyl, unsaturated heterocycle (C 1 -C 6 ) alkylidenyl, and hydrogen, or R 4 and R 5 are linked to form a (C 3 -C 8 ) to form cycloalkyl,
where in each case the alkyl or alkoxy groups can be substituted with one or more halogens, amino groups, or nitro groups, and
where in each case the aryl groups, the unsaturated heterocyclic groups, or the heterocyclic groups can be substituted with one, two or three radicals which are independently selected from a group consisting of hydroxy, halogen, (C 1 -C 6 ) alkyl, 1 -C 6 ) alkoxy, trifluoromethyl, nitro, amino, cyano, (C 3 -C 8 ) cycloalkyl, (C 1 -C 6 ) alkylamino, and (C 1 -C 6 ) alkylthio;
with the proviso that no more than one of R 1 and R 2 is a hydrogen atom;
or a pharmaceutically acceptable salt thereof.
5. Compounds described in U.S. Patent 5,624,937, specifically a compound of the formula
in the
Is ZO or S;
R 11 is a halogen atom;
R 12 is a halogen atom or a trifluoromethyl group;
XS, SO, SO 2 , O or NH; and
R 4 is a naphthyl group, a quinolinyl group, a benzimidazolyl group, a pyridyl group, a pyridazinyl group, a benzoxazolyl group or a benzothiazolyl group, unsubstituted or substituted with one or two substituents selected from a halogen atom , (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, nitro, (C 1 -C 4 ) alkoxycarbonyl, halogen (C 1 -C 4 ) alkyl, and phenyl;
or a pharmaceutically acceptable salt thereof.
6. Compounds which are described in patent application WO 98/22433, namely in particular a compound or a mixture of compounds which are effective to inhibit the cellular release and / or synthesis of the β-amyloid peptide, said compounds being represented by formula I are represented:
wherein
R 1 is selected from the group consisting of

1. alkyl, alkenyl, alkaryl, alkcycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle, wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents, selected from the group consisting of alkyl, alkoxy, aryl, aryloxy , Halogen, nitro, thioalkoxy, and thioaryloxy;

2. a substituted phenyl group of the formula II:
wherein R is an alkylene group with 1 to 8 carbon atoms,
m is an integer from 0 to 1,
R a and R a 'are independently selected from the group consisting of hydrogen atom, hydroxy, fluorine and methyl;
R b and R b 'are independently selected from the group consisting of hydrogen atom, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halogen, heteroaryl, heteroaryloxy, heterocycle, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C ( O) R 4 , wherein R 4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; and
R c is selected from the group consisting of hydrogen atom, alkyl, aryl, cyano, halogen, nitro, and wherein R b and R c are bonded to one another to form a methylenedioxy ring with the phenyl ring; and
if R b and / or R b 'and / or R c is fluorine, chlorine, bromine and / or nitro, then R a and / or R a ' can also be chlorine; and

3. a 1- or 2-naphthyl group substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents is selected from the group consisting of alkyl, alkoxy, halogen, cyano, nitro, trihalomethyl, and thioalkoxy ;

R 2 is selected from the group consisting of hydrogen atom, alkyl having 1 to 4 carbon atoms, alkylalkoxy having 1 to 4 carbon atoms, alkylthioalkoxy having 1 to 4 carbon atoms; and
R 3 and R 3 'are independently selected from the group consisting of:

1. a hydrogen atom, with the proviso that both radicals R 3 and R 3 ' cannot be a hydrogen atom;

2. an alkyl group, provided that if R 3 is a hydrogen atom, then the R 3 'alkyl group is a linear carbon chain with a length of at least 5 carbon atoms from the nitrogen atom, the chain being optionally substituted with one or more alkyl groups and with the further proviso that if both groups R 3 and R 3 'are an alkyl group, then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms and the chain can be optionally substituted with one or more alkyl groups;

3. a group - (R 7 ) n (W) p , wherein R 7 is an alkylene group, W is selected from the group consisting of
where R 5 , R 5 ', R 9 and R 9 are independently selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group Group, an amino group, an alkylamino group, a dialkylamino group, an aryl group, an acyl group, an acylamino group, an acyloxy group, an aminoacyl group, a cy ano group, a cycloalkyl Group, a halogen, a car boxyl group, a carboxyl ester group, a heteroaryl group and a heterocycle; and
R 6 is selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an amino group, an alkylamino group, a dialkylamino group, an aryl group, an acyl -Group, an acylamino group, an acyloxy group, an alkoxy group, a substituted alkoxy group, an aminoacyl group, a cyano group, a cycloalkyl group, a halogen, a carboxyl group, a carboxyl ester - Group, a heteroaryl group, a heterocycle, and wherein R 6 and either R 5 or R 5 'are bonded together to form a 4 to 10 atom heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of oxygen , Nitrogen and sulfur;
with the proviso that when n is zero, R 9 and R 9 'correspond to a hydrogen atom;
(ii) a heteroaryl group; and
(iii) an N-heterocycle, provided that if W is an N-heterocycle then n is not zero; and
n is an integer from 0 to 1, and
p is an integer from 1 to 3, provided that if n is zero, then p is 1, and

4. a group -CH (ϕ) CH 2 C (O) OQ, where Q is selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group and a heterocycle,

X 'is a hydrogen atom, a hydroxy group or fluorine;
X '' is a hydrogen atom, a hydroxyl group or fluorine, or X ' and X '' together form an oxo group
Z is selected from the group consisting of a bond which R 1 covalently binds to -CX ' X '' -, to oxygen or to sulfur, and in which
with the proviso that when R 1 is a phenyl group, R 2 is a methyl group, X ' and X ''are hydrogen atoms, Z is a group that R 1 covalently binds to -CX ' X '' -, m is zero, R 3 is a hydrogen atom, R 3 'is a group - (R 7 ) n (W) p , where n is zero and p is one and W is a group
then (i) R 5 , R 5 ' , R 9 , R 9' 'and R 6 are not all hydrogen atoms and (ii) R 5 ,
R 5 ' , R 9 , R 9' are hydrogen atoms and R 6 is a methoxy group;
with the further proviso that when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, X ' and X ''are hydrogen atoms, Z is a group the R 1 is covalent to -CX ' X '' - binds, m is zero, R 3 is a hydrogen atom, R 3 'is a group - (R 7 ) n (W) p , where n is one and p is one, R 7 is an ethylene group and W is a group
then R 5 , R 5 ' , R 9 , R 9' and R 6 are not all hydrogen atoms; and
with the further requirement that when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, X ' and X ''are hydrogen atoms, Z is a group the R 1 is covalent to -CX ' X '' - binds and m is zero, R 3 is a hydrogen atom, R 3 'is a group - (R 7 ) n (W) p , where n is zero and p is one, W is a group
and R 5 ' , R 9 , R 9' are hydrogen atoms, then R 5 and R 6 are not fused to form a phthalimido group with the phenyl ring to which they are attached.
7. Compounds which are described in patent application WO 98122494, namely in particular a compound or a mixture of compounds which are effective in inhibiting the cellular release and / or synthesis of the β-amyloid peptide, said compounds being represented by formula I. :
wherein
R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocycle;
R 2 is selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocycle;
each R 3 is independently selected from the group consisting of hydrogen atom and methyl and R 3 may be fused together with R 4 to form a cyclic structure of 3 to 8 atoms, optionally fused to an aryl or heteroaryl group;
each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, substituted alkyl, substituted alkenyl, and substituted alkynyl;
each R 5 is selected from hydrogen atom and methyl or together with R 4 forms a cycloalkyl group with 3 to 6 carbon atoms;
X is selected from the group consisting of -C (O) Y and -C (S) Y, where Y is selected from the group consisting of

1. alkyl or cycloalkyl groups,

2. substituted alkyl groups, provided that the substitution on said substituted alkyl does not contain α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl, or α-OC (O) aryl groups,

3. alkoxy or thioalkoxy groups,

4. substituted alkoxy or substituted thioalkoxy groups;

5. hydroxyl groups,

6. aryl groups,

7. heteroaryl groups,

8. heterocyclic groups,

9. -NR ' R " , where R ' and R " are independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocycle, one of the radicals R ' or R "is a hydroxy or alkoxy group, and wherein R ' and R " together form a cyclic group having 2 to 8 carbon atoms, which optionally 1 to 2 additional heteroatoms selected from oxygen, sulfur or nitrogen, which are optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,

10. -NHSO 2 -R 8 , where R 8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocycle,

11. -NR 9 NR 10 R 10 , wherein R 9 is hydrogen atom or alkyl and each R 10 is independently selected from hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocycle, and

12. -ONR 9 [C (O) O] 2 R 10 , where z is zero or one, R 9 and R 10 are as defined above;

X can also be -CR 6 R 6 Y ', where each R 6 is independently selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocycle and Y ' is selected from the group consisting of hydroxyl, Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R 7 , -SSR 7 , -SSC (O) R 7 where R 7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, Aryl, heteroaryl and heterocycle,
X 'is a hydrogen atom, a hydroxy group, or fluorine;
X '' is a hydrogen atom, a hydroxyl group, or fluorine, or X ' and X '' together form an oxo group,
Z is selected from the group consisting of a bond that R 1 covalently binds to -CX ' X '' -, oxygen and sulfur;
n is an integer from 1 to 2; and
pharmaceutically acceptable salts, provided that:
A. when R 1 is a phenyl group or a 3-nitrophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a group -CH (OH) CH 3 , R 5 is a hydrogen atom, X ' and X ''are hydrogen atoms, Z is a bond and n is 1, then X is not -C (O) OH;
B. when R 1 is a phenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a group -CH (OH) CH 3 derived from D-threonine, R 5 is a hydrogen atom, X ' and X ''are hydrogen atoms, Z is a bond and n is 1, then X is not -C (O) OH or -C (O) OCH 3 ;
C. when R 1 is a phenyl group, R 2 is a methyl group, R 4 is a benzyl group, R 5 is a hydrogen atom, X is a methoxycarbonyl group, X ' and X ''are hydrogen atoms, Z is a bond and n is 1, then R 3 is not methyl;
D. if R 1 is an iso-propyl group, R 2 is a group -CH 2 C (O) NH 2 , R 3 is a hydrogen atom, R 4 is an iso-butyl group, R 5 is a hydrogen atom, X ' and X '' are hydrogen atoms, Z is a bond, and n is 1, then X is not -C (O) OCH 3 ;
E. when R 1 is a phenyl group, R 2 is a methyl group, R 5 is a hydrogen atom, X is a group -C (O) OCH 3 , X ' and X ''are hydrogen atoms, Z is a bond , and n is 1, then R 3 , the nitrogen atom attached to R 3 , and R4 do not form 1,2,3,4-tetrahydroisoquinolin-2-yl or pyrrolidin-2-yl;
F. when R 1 is a phenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 5 is a hydrogen atom, X is a group -C (O) OCH 3 , X ' and X ''are hydrogen atoms Z is a bond and n is 1, then R 4 is not 4-amino-n-butyl;
G. when R 1 is a 3-nitrophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a group -CH (OH) CH 3 , R 5 is a hydrogen atom, X ' and X '' Are hydrogen atoms, Z is a bond, and n is 1, then X is not -C (O) NH 2 or -CH 2 OH;
H. when R 1 is a phenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 5 is a hydrogen atom, X is a group -CH 2 OCH 3 , X ' and X ''are hydrogen atoms, Z is a bond and n is 1, then R 4 is not benzyl or ethyl;
I. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, R 3 is a methyl group, R 4 is a methyl group, R 5 is a hydrogen atom X ' and X '' Are hydrogen atoms, Z is a bond, and n is 1, then X is not -CHOHϕ;
J. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a phenyl group derived from D-phenylglycine, R 5 is a hydrogen atom, X ' and X 'are hydrogen atoms, Z is a bond, and n is 1, then X is not -CHOHϕ or -CH 2 OH;
K. when R 1 is an N- (2-pyrrolidinonyl) group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a benzyl group, R 5 is a hydrogen atom, X ' and X '' Are hydrogen atoms, Z is a bond, and n is 1, then X is not -C (O) OCH 3 ;
L. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group derived from D-alanine, R 3 is a hydrogen atom, R 4 is a phenyl group derived from D-phenylglycine, R 5 is a Is hydrogen, X ' and X ''are hydrogen, Z is a bond, and n is 1, then X is not -C (O) NH-benzyl;
M. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a hydrogen atom, X ' and X ''are hydrogen atoms, Z is a bond and n is 1, then X is not -CH 2 OH;
N. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a 4-phenylphenyl group, R 5 is a hydrogen atom, X ' and X '' Are hydrogen atoms, Z is a bond, and n is 1, then X is not -C (O) NHC (CH 3 ) 3 ; and
O. when R 1 is a 3,5-difluorophenyl group, R 2 is a methyl group, R 3 is a hydrogen atom, R 4 is a phenyl group derived from D-phenylglycine, R 5 is a hydrogen atom, X ' and X '' are hydrogen atoms, Z is a bond and n is 1, then X is not -C (O) NHCH (CH 3 ) ϕ.
8. Compounds which are described in patent application WO 00/31021, namely in particular compounds which are represented by the general formula (I),
Salts thereof or pro-drugs thereof which have an excellent effect in inhibiting the production / secretion of the β-amyloid protein, in which Ar represents an aromatic group; X and Y are each a divalent group selected from -O-, -S-, -CO-, -SO-, -SO 2 -, -NR 8 -, -CONR 8 -, -SO 2 NR 8 - and -COO- (where R 8 represents H, hydrocarbyl or acyl), or a divalent aliphatic (C 1 -C 6 ) hydrocarbyl group optionally containing one or two of these divalent groups; R 1 and R 2 each represent H or a (C 1 -C 6 ) alkyl group, or R 1 and R 2 together with the adjacent nitrogen atom can form a nitrogen-containing heterocycle, and ring A represents a monocyclic aromatic ring.
9. Compounds which are described in patent application WO 99/32453, namely in particular a compound of the formula I:
wherein
W a substituted ε-caprolactam is selected from the group consisting of
wherein
Ring A together with the atoms of the ε-caprolactam to which it is attached forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocycle;
Ring B together with the atoms of the ε-caprolactam to which it is attached forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocycle;
Ring C together with the atoms of the ε-caprolactam to which it is attached forms a heteroaryl group or a heterocyclic ring;
R 1 is selected from the group consisting of hydrogen atom and an amino blocking group;
each R 2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocycle;
R 3 is selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocycle;
each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocycle;
m is an integer from 0 to 2; n is an integer from 0 to 2;
and salts thereof.

Im folgenden wird die Erfindung anhand eines Ausführungsbeispiels erläutert:
50 mg 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one wurden unter Mitverwendung von Polysorbat, Glycerol, Sorbitol, Zellulose und Talkum als Träger- und Hilfsstoffe in bekannter Weise zu Tabletten verarbeitet.The invention is explained below using an exemplary embodiment:
50 mg of 5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one were used in a known manner using polysorbate, glycerol, sorbitol, cellulose and talc as carriers and auxiliaries processed into tablets.

Claims

1. Use of inhibitors of amyloid-β-protein formation and / or amyloid-β- Protein secretion for the manufacture of drugs for the treatment of Diseases with the exception of Alzheimer's disease, Down syndrome and cerebral hemorrhages of the Dutch type.

2. Use according to claim 1, characterized in that the inhibitors for Manufacture of medicines for the treatment of high blood pressure, diabetes mellitus, arteriosclerosis, rheumatic diseases, ischemic Diseases such as B. stroke or heart attack, traumatic Diseases, inflammatory diseases, sepsis, colitides, Infectious diseases, autoimmune diseases, degenerative and age dependent diseases and / or ulcer diseases can be used.