WO1996005189A1 - Inhibitors of the benzamidine type - Google Patents

Inhibitors of the benzamidine type Download PDF

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Publication number
WO1996005189A1
WO1996005189A1 PCT/CH1995/000174 CH9500174W WO9605189A1 WO 1996005189 A1 WO1996005189 A1 WO 1996005189A1 CH 9500174 W CH9500174 W CH 9500174W WO 9605189 A1 WO9605189 A1 WO 9605189A1
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carbon atoms
radical
straight
thrombin
compounds
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PCT/CH1995/000174
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German (de)
French (fr)
Inventor
Jörg STÜRZEBECHER
Helmut Vieweg
Peter Wikstroem
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Pentapharm Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/974—Thrombin

Definitions

  • the invention relates to new thrombin inhibitors of the amidinophenylalanine type, their preparation and their use for combating diseases. They are distinguished in particular by the fact that they carry a substituted piperazine residue in different positions of the molecule.
  • trypsin-like serine proteinases such enzymes are of particular physiological importance that trigger coagulation and fibrinolysis in the blood. Since the pathologically increased activity of the enzymes or the lack of natural inhibitors can lead to diseases, attempts are made to control these diseases by increasing the inhibitor potential. Accordingly, natural inhibitors - endogenous to the body such as antithrombin III or those from other natural sources such as hirudin - are used or prepared for the therapy.
  • inhibitors of the coagulation enzymes are being worked on particularly intensively. Extensive biochemical and (animal) experimental pharmacological studies have shown that inhibitors of throbine in particular are effective anticoagulants and antithrombotics.
  • the present invention relates to new thrombin inhibitors having a benzidine structure of the general formulas I and II
  • R 1 in the general formula I is a straight-chain alkylsulfonyl radical having 1 to 16 carbon atoms, preferably 6 to 10 carbon atoms
  • R * 2 is a straight-chain Alkylsulfonyl radical having 1 to 8 carbon atoms
  • R ⁇ in the general formula II is a straight-chain alkylsulfonyl radical having 1 to 4 carbon atoms, an alkanoyl radical having 1 to 4 carbon atoms and n is an integer of 1 or 2.
  • the inhibitor derivatives of the general formulas I and II according to the invention can be treated with a mineral acid, e.g. HC1, HBr, H2SO4 or H3PO4, or with an organic acid, e.g. Formic, acetic, oxalic or tartaric acid may be protonized.
  • a mineral acid e.g. HC1, HBr, H2SO4 or H3PO4
  • an organic acid e.g. Formic, acetic, oxalic or tartaric acid may be protonized.
  • the compounds of the general formula I are prepared by the known production process described below.
  • amidine derivatives of the formula I are prepared from these cyanphenylalanine derivatives obtained by known processes (via thioamide, thioimido ester or imido ester route).
  • the amidino derivatives of the general formula II are built up in stages in accordance with the production process known per se and described below.
  • (D) -4-cyanophenylalanine is first N-acylated with an acid-labile protective group and then the ⁇ (carboxyl group is converted to a piperidide. After the o-amino protective group has been cleaved off, the (D) - -4-cyanophenylalanine piperidide is also converted a No ⁇ - -2-naphthylsulfonyl derivative of the formula IV,
  • R ⁇ is an acid labile carboxyl protecting group, e.g. t-butyl, and n represents the number 1 or 2, implemented.
  • the compounds according to the invention can be used per se or - in combination with carriers and auxiliaries - as medicaments, and they can be administered subcutaneously, intravenously, but especially orally or rectally.
  • carriers and auxiliaries - as medicaments
  • they can be administered subcutaneously, intravenously, but especially orally or rectally.
  • the compounds according to the invention can be used in particular in test kits for determining thrombin.

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Abstract

Disclosed are thrombin inhibitors of the amidinophenylalanine type. The compounds are particular suitable for oral and rectal resorption.

Description

Neue Inhibitoren vom Benzamidintyp New inhibitors of the benzamidine type
Die Erfindung betrifft neue Thrombininhibitoren vom Amidinophenylalanin-Typ, deren Herstellung und ihr Einsatz zur Bekämpfung von Krankheiten. Sie zeichnen sich insbe¬ sondere dadurch aus, dass sie in verschiedenen Positionen des Moleküls einen substituierten Piperazin-Rest tragen.The invention relates to new thrombin inhibitors of the amidinophenylalanine type, their preparation and their use for combating diseases. They are distinguished in particular by the fact that they carry a substituted piperazine residue in different positions of the molecule.
Unter den Trypsin-ähnlichen Serinproteinasen sind solche Enzyme von besonderer physiologischer Bedeutung, die im Blut Gerinnung und Fibrinolyse auslösen. Da die patholo¬ gisch gesteigerte Aktivität der Enzyme bzw. der Mangel an natürlichen Inhibitoren zu Erkrankungen führen können, wird versucht, diese Krankheiten durch Erhöhung des Inhibitor¬ potentials zu beherrschen. Entsprechend werden natürliche Inhibitoren - körpereigene wie Antithrombin III bzw. solche aus anderen natürlichen Quellen wie Hirudin - für die The¬ rapie eingesetzt bzw. vorbereitet.Among the trypsin-like serine proteinases, such enzymes are of particular physiological importance that trigger coagulation and fibrinolysis in the blood. Since the pathologically increased activity of the enzymes or the lack of natural inhibitors can lead to diseases, attempts are made to control these diseases by increasing the inhibitor potential. Accordingly, natural inhibitors - endogenous to the body such as antithrombin III or those from other natural sources such as hirudin - are used or prepared for the therapy.
Besonders intensiv wird an der Entwicklung von Hemmstoffen der Gerinnungsenzyme gearbeitet. In umfangreichen bioche¬ mischen und (tier)experimentell-pharmakologischen Arbeiten wurde nachgewiesen, dass insbesondere Inhibitoren des Thro bins wirkungsvolle Antikoagulantien und Antithrombo- tika darstellen.The development of inhibitors of the coagulation enzymes is being worked on particularly intensively. Extensive biochemical and (animal) experimental pharmacological studies have shown that inhibitors of throbine in particular are effective anticoagulants and antithrombotics.
Die Suche nach gerinnungshemmenden Wirkstoffen aus natür¬ lichen Quellen führte zur Charakterisierung des Thrombin- Inhibitors Hirudin aus dem Blutegel. Obwohl Wirkungsstärke und Selektivität das Hirudin zum 'idealen' Antikoagulans machen, hat es den Nachteil, dass auf Grund der Protein¬ struktur nur eine parenterale Applikation möglich ist. Die Entwicklung zu einem Therapeutikum, das nach oraler Appli¬ kation resorbiert wird, ist demnach nur mit einem synthe- tischen, kleinmolekularen, selektiv wirkenden Hemmstoff möglich.The search for anticoagulant active ingredients from natural sources led to the characterization of the thrombin inhibitor hirudin from the leech. Although potency and selectivity make hirudin the 'ideal' anticoagulant, it has the disadvantage that only parenteral administration is possible due to the protein structure. The development to a therapeutic agent, which is absorbed after oral application, is therefore only possible with a synthetic tables, small molecular, selective inhibitor possible.
Als niedermolekulare Thrombin-Hemmstoffe sind bisher drei Klassen von Verbindungen beschrieben worden, nämlich a) N-ci-arylsulfonylierte ArgininamideThree classes of compounds have so far been described as low molecular weight thrombin inhibitors, namely a) N-ci-arylsulfonylated argininamides
[Okamoto et al. (Mitsubishi), US-Pat. 4,125,604] b) Verbindungen vom (D)-Phe-Pro-Arg-Typ [Kettner et al. (DuPont), US-Pat 178368] c) Benzamidin-Derivate[Okamoto et al. (Mitsubishi), U.S. Pat. 4,125,604] b) Compounds of the (D) -Phe-Pro-Arg type [Kettner et al. (DuPont), U.S. Pat. 178368] c) Benzamidine derivatives
[Wagner et al. WP C 07 D/201 898,[Wagner et al. WP C 07 D / 201 898,
Stürzebecher, Wikstroe , Vieweg, WO 92 08709, WO 94 18185Lintel cup, Wikstroe, Vieweg, WO 92 08709, WO 94 18185
Delabassee et al. (Sanofi), FR 8601398 und FR 8601399, Stüber et al. (Behring-Werke), DE 4115486, DE 4111394 undDelabassee et al. (Sanofi), FR 8601398 and FR 8601399, Stüber et al. (Behring-Werke), DE 4115486, DE 4111394 and
DE 4206858] .DE 4206858].
In allen drei Klassen wurden hochwirksame Inhibitoren ge¬ funden, die aber mit nur wenigen Ausnahmen nach oraler Verabreichung nicht resorbiert werden. Bei Benzamidinen war erstmals mit 3-Amidinophenylalanin-Derivaten eine gewisse, allerdings nicht ausreichende orale Verfügbarkeit erreicht worden (WO 92 08709).Highly effective inhibitors were found in all three classes, but with only a few exceptions they are not absorbed after oral administration. In the case of benzamidines, 3-amidinophenylalanine derivatives had, for the first time, achieved a certain, but not sufficient oral availability (WO 92 08709).
Durch Einführung eines C-terminalen Piperazids wurde die orale Verfügbarkeit weiter erhöht (WO 94 18185). Allerdings konnten nur wenige Derivate mit starker Antithrombin-Akti- vität (K^ < IOμmol/1) gefunden werden.Oral availability was further increased by introducing a C-terminal piperazide (WO 94 18185). However, only a few derivatives with strong antithrombin activity (K ^ <IOμmol / 1) could be found.
Es wurden nun überraschend Derivate des (L)-3-Amidino- phenylalanins, die Piperazin-Gruppen am C-Terminus ent¬ halten und N-terminal mit einem geradkettigen Alkyl- sulfonyl-Rest geschützt sind, mit starker Antithrombin- Aktivität gefunden. Besonders erfolgreich war die Ein¬ führung einer (L)-P2-Aminodicarbonsäure, wie (L)-Aspa- raginsäure oder (L)-Glutaminsäure in (D)-4-Amidinophenyl- alaninpiperidide, wobei die zweite Carboxylgruppe (in ß- oder Y -Position) einen substituierten Piperazin-Rest trägt. Es wurden sehr wirksame Thrombin-Inhibitoren gefunden, bei denen eine erhöhte Selektivität gegenüber Thrombin hervorzuheben ist.It has now surprisingly been found derivatives of (L) -3-amidino-phenylalanine which contain piperazine groups at the C-terminus and are protected N-terminally with a straight-chain alkylsulfonyl radical and have strong antithrombin activity. The introduction of a (L) -P2-aminodicarboxylic acid, such as (L) -asparaginic acid or (L) -glutamic acid in (D) -4-amidinophenyl- alanine piperidides, the second carboxyl group (in the β or Y position) carrying a substituted piperazine radical. Very effective thrombin inhibitors have been found, in which an increased selectivity towards thrombin is to be emphasized.
Die vorliegende Erfindung betrifft neue Thrombininhibitoren mit Benza idinstruktur der allgemeninen Formeln I und IIThe present invention relates to new thrombin inhibitors having a benzidine structure of the general formulas I and II
Figure imgf000005_0001
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0002
worin R1 in der allgemeinen Formel I ein geradkettiger Alkylsulfonylrest mit 1 bis 16 Kohlenstoffatomen, vorzugs¬ weise 6 bis 10 Kohlenstoffatomen, R*2 ein geradkettiger Alkylsulfonylrest mit 1 bis 8 Kohlenstoffatomen und R^ in der allgemeinen Formel II ein geradkettiger Alkylsulfonyl¬ rest mit 1 bis 4 Kohlenstoffatomen, ein Alkanoylrest mit 1 bis 4 Kohlenstoffatomen und n eine ganze Zahl von 1 oder 2, darstellt.wherein R 1 in the general formula I is a straight-chain alkylsulfonyl radical having 1 to 16 carbon atoms, preferably 6 to 10 carbon atoms, R * 2 is a straight-chain Alkylsulfonyl radical having 1 to 8 carbon atoms and R ^ in the general formula II is a straight-chain alkylsulfonyl radical having 1 to 4 carbon atoms, an alkanoyl radical having 1 to 4 carbon atoms and n is an integer of 1 or 2.
Die erfindungsge ässen Inhibitorderivate der allgemeinen Formeln I und II können mit einer Mineralsäure, z.B. HC1, HBr, H2SO4 oder H3PO4, oder mit einer organischen Säure, z.B. Ameisen-, Essig-, Oxal- oder Weinsäure, protonisiert sein.The inhibitor derivatives of the general formulas I and II according to the invention can be treated with a mineral acid, e.g. HC1, HBr, H2SO4 or H3PO4, or with an organic acid, e.g. Formic, acetic, oxalic or tartaric acid may be protonized.
Die Verbindungen der allgemeinen Formel I werden nach dem nachfolgend beschriebenen, an sich bekannten Herstellungs¬ verfahren dargestellt.The compounds of the general formula I are prepared by the known production process described below.
(L)-3-Cyanphenylalaninalkylester werden in einem geeigneten Lösungsmittel mit einem geradkettigen Alkylsulfonylchlorid umgesetzt und anschliessend einer Esterhydrolyse unter¬ zogen, wobei die freien Carboxylgruppen erhalten werden. Die N -alkylsulfonierten 3-(L)-Cyanphenylalaninderivate werden mit Piperazinderivaten der Formel III, worin R^ die vorstehend genannten Bedeutungen besitzt, umgesetzt:(L) -3-Cyanphenylalaninalkylester are reacted in a suitable solvent with a straight-chain alkylsulfonyl chloride and then subjected to ester hydrolysis, whereby the free carboxyl groups are obtained. The N -alkylsulfonated 3- (L) -cyanophenylalanine derivatives are reacted with piperazine derivatives of the formula III, in which R ^ has the meanings given above:
Figure imgf000006_0001
Figure imgf000006_0001
Aus diesen erhaltenen Cyanphenylalaninderivaten werden nach bekannten Verfahren (über Thioamid, Thioimidoester oder Imidoesterweg) die entsprechenden Amidinderivate der Formel I hergestellt.The corresponding amidine derivatives of the formula I are prepared from these cyanphenylalanine derivatives obtained by known processes (via thioamide, thioimido ester or imido ester route).
Die Amidinoderivate der allgemeinen Formel II werden nach dem nachfolgend beschriebenenen, an sich bekannten Her¬ stellungsverfahren stufenweise aufgebaut. (D)-4-Cyanphenylalanin wird zuerst mit einer säurelabilen Schutzgruppe N-acyliert und anschliessend wird die σ(-Carboxylgruppe zu einem Piperidid umgesetzt. Nach Ab¬ spaltung der o-Amino-Schutzgruppe wird das (D)- -4-Cyanphenylalaninpiperidid mit einem Noχ- -2-Naphthylsulfonylderivat der Formel IV,The amidino derivatives of the general formula II are built up in stages in accordance with the production process known per se and described below. (D) -4-cyanophenylalanine is first N-acylated with an acid-labile protective group and then the σ (carboxyl group is converted to a piperidide. After the o-amino protective group has been cleaved off, the (D) - -4-cyanophenylalanine piperidide is also converted a Noχ- -2-naphthylsulfonyl derivative of the formula IV,
Figure imgf000007_0001
C= 0
Figure imgf000007_0001
C = 0
worin R^ eine säurelabile Carboxylschutzgruppe, wie z.B. t-Butyl, und n die Zahl 1 oder 2 bedeutet, umgesetzt. Nach Abspaltung der säurelabilen Carboxylschutzgruppe werden diese Derivate mit freier ß-respektive V'-Carboxylgruppe mit einem Piperazinderivat der Formel V,wherein R ^ is an acid labile carboxyl protecting group, e.g. t-butyl, and n represents the number 1 or 2, implemented. After the acid-labile carboxyl protecting group has been split off, these derivatives with a free β or V ′ carboxyl group are reacted with a piperazine derivative of the formula V
Figure imgf000007_0002
Figure imgf000007_0002
worin R*** die vorstehend genannten Bedeutungen hat, umge¬ setzt und anschliessend die 4-Cyangruppe des (D) -Phenylalanins in das entsprechende 4-Amidinoderivat nach bekannten Verfahren übergeführt.in which R *** has the meanings given above, converted and then the 4-cyano group of (D) -phenylalanine converted into the corresponding 4-amidino derivative by known processes.
Die erfindungsge ässen Verbindungen können per se oder - in Verbindungen mit Trägern und Hilfsmitteln - als Arzneimit¬ tel verwendet werden, wobei sie subkutan, intravenös, ins¬ besondere aber oral oder rektal verabreicht werden können. Als mögliche Arzneimittelformen kommen insbesondere Ta¬ bletten, Dragees, Kapseln, Pellets, Suppositorien, Lö- sungen, Injektionen oder transdermale Systeme, wie Pfla¬ ster, in Frage. In der Diagnostik können die erfindungs- gemässen Verbindungen insbesondere in Testkits zur Bestim¬ mung von Thrombin verwendet werden.The compounds according to the invention can be used per se or - in combination with carriers and auxiliaries - as medicaments, and they can be administered subcutaneously, intravenously, but especially orally or rectally. In particular, tablets, coated tablets, capsules, pellets, suppositories, solvents, solutions, injections or transdermal systems such as plaster. In diagnostics, the compounds according to the invention can be used in particular in test kits for determining thrombin.
In den folgenden Beispielen wird die Erfindung näher er¬ läutert.The invention is explained in more detail in the following examples.
Beispiel 1example 1
N<Λ-(2-Naphthylsulfonyl)-ß-4-methylsulfonyl-piperazino-(L)- asρartyl-(D)-4-amidino-phenylalanin-piperidid-HydrochloridN <Λ- (2-Naphthylsulfonyl) -ß-4-methylsulfonyl-piperazino- (L) - asρartyl- (D) -4-amidino-phenylalanine-piperidide hydrochloride
Verbindung 1Connection 1
No(-(2-Naphthylsulfonyl)-ß-t-butoxycarbonyl-(L)-asparagin- säureNo ( - (2-naphthylsulfonyl) -ß-t-butoxycarbonyl- (L) -aspartic acid
6.5g ß-t-Butoxycarbonyl-(L)-asparaginsäure wurden in einer Lösung von 8g Natriumcarbonat in 120ml Wasser gelöst, mit 9.34g Naphthalin-2-sulfochlorid in 120ml Diethylether ver¬ setzt und 16 Stunden gerührt, wobei ein öliges Produkt ausfiel. Es wurde so viel Wasser zugegeben, bis 2 klare Phasen erhalten wurden. Die wässrige Phase wurde abge¬ trennt, mit 2x je 60ml Diethylether gewaschen, anschlies¬ send mit IN HCl angesäuert und 3x mit je 100ml Ethylacetat extrahiert. Nach Waschen der Ethylacetatlösung mit gesät¬ tigter Kochsalzlösung und Trocknen über Natriumsulfat wurde das Lösungsmittel abdestilliert. Es wurden 8.3g (64%) eines kristallinen Produkts erhalten.6.5 g of β-t-butoxycarbonyl- (L) -aspartic acid were dissolved in a solution of 8 g of sodium carbonate in 120 ml of water, mixed with 9.34 g of naphthalene-2-sulfochloride in 120 ml of diethyl ether and stirred for 16 hours, during which an oily product failed. So much water was added until 2 clear phases were obtained. The aqueous phase was separated, washed with 2 × 60 ml of diethyl ether, then acidified with 1N HCl and extracted 3 × with 100 ml of ethyl acetate. After washing the ethyl acetate solution with saturated sodium chloride solution and drying over sodium sulfate, the solvent was distilled off. 8.3 g (64%) of a crystalline product were obtained.
Verbindung 2Connection 2
(D)-4-cyan-phenylalanin-piperidid • Hydrochlorid(D) -4-cyanophenylalanine piperidide • Hydrochloride
4.9g Boc-(D,L)-3-cyanphenylalanin wurden in 50ml DMF ge¬ löst, mit 3.3g HOBt versetzt, auf 0 °C gekühlt und 4.2g DCC zugefügt. Nach einstündigem Rühren wurde 2.9g Piperidin zugefügt und über Nacht gerührt. Anschliessend wurde das ausgefallene Harnstoffderivat abgesaugt und das Lösungs¬ mittel unter Vakuum abdestilliert. Das anfallende Produkt wurde über KG60 (Chloroform) gereinigt. Ausbeute: 5.5g (90%) .4.9 g of Boc- (D, L) -3-cyanophenylalanine were dissolved in 50 ml of DMF, mixed with 3.3 g of HOBt, cooled to 0 ° C. and 4.2 g of DCC were added. After stirring for one hour, 2.9 g of piperidine added and stirred overnight. The precipitated urea derivative was then filtered off with suction and the solvent was distilled off under vacuum. The product obtained was purified over KG60 (chloroform). Yield: 5.5g (90%).
Dieses Produkt wurde in 50ml 2N HC1 in Ethylacetat gelöst und 2 Tage bei Raumtemperatur gerührt. Danach wurde das Lösungsmittel abdestilliert, das angefallene Produkt mit Ether trituriert, der Niederschlag abgesaugt und getrock¬ net. Ausbeute: 4.1g (90%).This product was dissolved in 50 ml of 2N HCl in ethyl acetate and stirred for 2 days at room temperature. The solvent was then distilled off, the product obtained was triturated with ether, the precipitate was filtered off with suction and dried. Yield: 4.1g (90%).
Verbindung 3Connection 3
No<-(2-Naphthylsulfonyl)-ß-t-butoxycarbonyl-(L)-aspartyl-No <- (2-naphthylsulfonyl) -ß-t-butoxycarbonyl- (L) -aspartyl-
(D)-4-cyan-phenylalanin-piperidid(D) -4-cyanophenylalanine piperidide
1.11g der Verbindung 1 wurden in 20ml DMF gelöst, 0.6g HOBt zugefügt, auf 0°C gekühlt, 0.8g DCC zugegeben und eine Stunde gerührt. Danach wurden 1.0g der Verbindung 2 sowie 0.37ml NMM zugefügt und 2 Tage gerührt. Anschliessend wurde das anfallende Harnstoffderivat abfiltriert, das Lösungs¬ mittel unter Vakuum abdestilliert und das erhaltene Roh¬ produkt über KG60 (Chloroform) gereinigt. Ausbeute: 1.5g (77%) .1.11 g of compound 1 were dissolved in 20 ml of DMF, 0.6 g of HOBt was added, the mixture was cooled to 0 ° C., 0.8 g of DCC was added and the mixture was stirred for one hour. Then 1.0 g of compound 2 and 0.37 ml of NMM were added and the mixture was stirred for 2 days. The urea derivative obtained was then filtered off, the solvent was distilled off under vacuum and the crude product obtained was purified over KG60 (chloroform). Yield: 1.5g (77%).
Verbindung 4Connection 4
Nc,-(2-Naphthylsulfonyl)-ß-carboxy-(L)-aspartyl-(D)-4- cyan-phenylalanin-piperididNc, - (2-naphthylsulfonyl) -ß-carboxy- (L) -aspartyl- (D) -4-cyanophenylalanine piperidide
1.1g der Verbindung 3 wurden in 20ml Dichlormethan und 8ml TFA gelöst, 2 Stunden bei Raumtemperatur gerührt, das Lö¬ sungsmittel abdestilliert und 2x mit Toluol codestilliert. Ausbeute: 0.95g (97%).1.1 g of compound 3 were dissolved in 20 ml dichloromethane and 8 ml TFA, stirred for 2 hours at room temperature, the solvent was distilled off and codistilled twice with toluene. Yield: 0.95g (97%).
Verbindung 5Connection 5
No(-(2-Naphthylsulfonyl)-ß-4-methylsulfonyl-piperazino-(L)- aspartyl-(D)-4-cyan-phenylalanin-piperidid 0.92g der Verbindung 4 wurden in 20ml DMF gelöst, 1.4g Komplex F zugefügt und 2 Stunden gerührt. Danach wurden 0.39g 1-Methylsulfonyl-piperazin-hydrochlorid und 0.2ml NMM in 15ml DMF zugegeben und über Nacht gerührt. Anschliessend wurde das anfallende Harnstoffderivat abfiltriert, das Lö¬ sungsmittel unter Vakuum abdestilliert und das erhaltene Rohprodukt über Kieselgel 60 (Chloroform/Methanol, 9:1) gereinigt. Ausbeute: 0.36g (31%).No (- (2-naphthylsulfonyl) -ß-4-methylsulfonyl-piperazino- (L) - aspartyl- (D) -4-cyanophenylalanine piperidide 0.92 g of compound 4 were dissolved in 20 ml of DMF, 1.4 g of complex F were added and the mixture was stirred for 2 hours. Then 0.39 g of 1-methylsulfonyl-piperazine hydrochloride and 0.2 ml of NMM in 15 ml of DMF were added and the mixture was stirred overnight. The urea derivative obtained was then filtered off, the solvent was distilled off under vacuum and the crude product obtained was purified on silica gel 60 (chloroform / methanol, 9: 1). Yield: 0.36g (31%).
Verbindung 6Connection 6
Not-(2-Naphthylsulfonyl)-ß-4-methylsulfonyl-piperazino-(L)- aspartyl-(D)-4-amidino-phenylalanin-piperidid•HydrochloridNot- (2-naphthylsulfonyl) -ß-4-methylsulfonyl-piperazino- (L) - aspartyl- (D) -4-amidino-phenylalanine-piperidide • hydrochloride
0.36g der Verbindung 5 wurden in 20ml Pyridin und 20 Trop¬ fen TEA gelöst, in die Lösung 10min. Schwefelwasserstoff eingeleitet und der Ansatz 2 Tage bei Raumtemperatur ste¬ hengelassen. Nach Abdestillieren des Lösungsmittels wurde das erhaltene Thioamid in Ethylacetat aufgenommen, mit 1 N HC1 ausgeschüttelt und nach Trocknen über Natriumsulfat das Lösungsmittel abdestilliert. Der Rückstand wurde in 30ml Aceton gelöst, die Lösung mit 2g Methyliodid versetzt, 20 Stunden bei Raumtemperatur unter Lichtschutz stehengelas¬ sen, anschliessend das Lösungsmittel abdestilliert und das Thioimidoester-hydroiodid in der erhaltenen Form zur A idinbildung eingesetzt. Dazu wurden 0.27g dieses Pro¬ duktes in 15ml Methanol gelöst, 0.1g Ammoniumacetat zuge¬ fügt und 4 Stunden im Wasserbad bei 60°C erwärmt. Danach wurde das Lösungsmittel abdestilliert und der Rückstand über KG60 (a: Chloroform, b: Chloroform/Methanol, 9:1) ge¬ reinigt. Das anfallende Hydroiodid wurde über Ionenaustau¬ scher Amberlite IRA-420 in das Hydrochlorid übergeführt. Es wurden 85mg (37% d. Theorie) erhalten.0.36 g of compound 5 were dissolved in 20 ml of pyridine and 20 drops of TEA, in the solution for 10 minutes. Hydrogen sulfide was introduced and the mixture was left to stand for 2 days at room temperature. After the solvent had been distilled off, the thioamide obtained was taken up in ethyl acetate, shaken out with 1N HCl and, after drying over sodium sulfate, the solvent was distilled off. The residue was dissolved in 30 ml of acetone, 2 g of methyl iodide was added to the solution, the mixture was left to stand under light protection for 20 hours at room temperature, then the solvent was distilled off and the thioimido ester hydroiodide in the form obtained was used for the formation of amine. For this purpose, 0.27 g of this product was dissolved in 15 ml of methanol, 0.1 g of ammonium acetate was added and the mixture was heated in a water bath at 60 ° C. for 4 hours. The solvent was then distilled off and the residue was purified over KG60 (a: chloroform, b: chloroform / methanol, 9: 1). The resulting hydroiodide was converted into the hydrochloride via Amberlite IRA-420 ion exchanger. 85 mg (37% of theory) were obtained.
Beispiel 2Example 2
Ne -Octylsulfonyl-3-amidino- ( L )-phenylalanin-4-methylsulfo- nyl-pjperazid•HydrochloridNe -octylsulfonyl-3-amidino- (L) -phenylalanine-4-methylsulfo- nyl-pyperazide • Hydrochloride
Verbindung 1 N-o<'-Octylsulfonyl-3-cyan-(L)-phenylalaninCompound 1 N-o <'- octylsulfonyl-3-cyan- (L) -phenylalanine
1.7g (L)-3-Cyan-phenylalanin-methylester-Hydrochlorid wur¬ den in 50ml Ethylacetat suspendiert, danach mit 2.0ml NMM und 2.4ml n-Octylsulfonylchlorid-Lösung versetzt und über Nacht gerührt. Nach Abfiltrieren wurde das Lösungsmittel abdestilliert. Das Rohprodukt wurde über KG60 (Chloroform) gereinigt. Ausbeute: 2.1g (79%). Der erhaltene Ester wurde in je 30ml Essigsäure und 1N Salzsäure unter Rückfluss über 2 Stunden erhitzt. Nach Extraktion mit Ethylacetat und Ab- destillieren des Lösungsmittels wurden 2.4g Produkt erhal¬ ten (74%).1.7 g of (L) -3-cyanophenylalanine methyl ester hydrochloride were suspended in 50 ml of ethyl acetate, then 2.0 ml of NMM and 2.4 ml of n-octylsulfonyl chloride solution were added and the mixture was stirred overnight. After filtering off, the solvent was distilled off. The crude product was purified over KG60 (chloroform). Yield: 2.1g (79%). The ester obtained was heated in 30 ml of acetic acid and 1N hydrochloric acid under reflux for 2 hours. After extraction with ethyl acetate and distilling off the solvent, 2.4 g of product were obtained (74%).
Verbindung 2Connection 2
Netf-Octylsulfonyl-3-cyan- ( L )-phenylalanin-4-methylsulfonyl- piperazidNetf-octylsulfonyl-3-cyan- (L) -phenylalanine-4-methylsulfonyl-piperazide
2.3g der Verbindung 1 wurden in 20ml DMF gelöst, 1.22g HOBt zugefügt, auf 0°C gekühlt, 1.56g DCC zugegeben und eine Stunde gerührt. Danach wurden 1.51g 1-Methylsulfonyl-pi- perazin-Hydrochlorid und 0.82ml NMM zugefügt und über Nacht gerührt. Anschliessend wurde das angefallene Harn¬ stoffderivat abfiltriert, das Lösungsmittel abdestilliert und das erhaltene Rohprodukt über KG60 (Chloroform : Me¬ thanol, 9:1) gereinigt. Ausbeute: 2.56g (79%).2.3 g of compound 1 were dissolved in 20 ml of DMF, 1.22 g of HOBt were added, the mixture was cooled to 0 ° C., 1.56 g of DCC were added and the mixture was stirred for one hour. Then 1.51 g of 1-methylsulfonylpiperazine hydrochloride and 0.82 ml of NMM were added and the mixture was stirred overnight. The urea derivative obtained was then filtered off, the solvent was distilled off and the crude product obtained was purified over KG60 (chloroform: methanol, 9: 1). Yield: 2.56g (79%).
Verbindung 3Connection 3
No(-Octylsulfonyl-3-amidino-(L)-phenylalanin-4-methylsul- fonyl-piperazid ■ HydrochloridNo (-Octylsulfonyl-3-amidino- (L) -phenylalanine-4-methylsulfonyl-piperazide ■ hydrochloride
2.47g der Verbindung 2 wurden in 40ml Pyridin und 20 Tropfen TEA gelöst, in die Lösung 10min. Schwefelwasser¬ stoff eingeleitet und der Ansatz 2 Tage bei Raumtemperatur stehengelassen. Nach Abdestillieren des Lösungsmittels wurde das erhaltene Thioamid in Ethylacetat aufgenommen, mit 1 N HC1 ausgeschüttelt und nach Trocknen über Natrium¬ sulfat das Lösungsmittel abdestilliert. Der Rückstand wurde in 50ml Aceton gelöst, die Lösung mit 8g Methyliodid ver¬ setzt, 20 Stunden bei Raumtemperatur unter Lichtschutz stehengelassen, anschliessend 200ml Ether zugegeben und nach einer Stunde das ausgefallene Produkt abfiltriert, mit frischem Ether gewaschen und getrocknet. 3.13g dieses Thioi idoester-hydroiodids wurden zur Amidinbildung einge¬ setzt. Es wurde in 50ml Methanol gelöst, 0.7g Ammonium- acetat zugefügt und 4 Stunden im Wasserbad bei 60°C er¬ wärmt. Danach wurde das Lösungsmittel abdestilliert und der Rückstand über KG60 (a: Chloroform, b: Chloroform/Methanol, 9:1) gereinigt. Das angefallene Hydroiodid wurde über Io¬ nenaustauscher Amberlite IRA-420 in das Hydrochlorid über¬ geführt. Es wurden 0.72g (28% d. Theorie) erhalten.2.47 g of compound 2 were dissolved in 40 ml of pyridine and 20 drops of TEA, in the solution for 10 minutes. Sulfur hydrogen initiated and the mixture left for 2 days at room temperature. After distilling off the solvent the thioamide obtained was taken up in ethyl acetate, shaken out with 1N HCl and, after drying over sodium sulfate, the solvent was distilled off. The residue was dissolved in 50 ml of acetone, the solution was mixed with 8 g of methyl iodide, left to stand under light protection for 20 hours at room temperature, then 200 ml of ether were added, and after one hour the precipitated product was filtered off, washed with fresh ether and dried. 3.13 g of this thioi idoester hydroiodide were used to form the amidine. It was dissolved in 50 ml of methanol, 0.7 g of ammonium acetate was added and the mixture was heated in a water bath at 60 ° C. for 4 hours. The solvent was then distilled off and the residue was purified on KG60 (a: chloroform, b: chloroform / methanol, 9: 1). The hydroiodide obtained was converted into the hydrochloride via Amberlite IRA-420 ion exchanger. 0.72 g (28% of theory) were obtained.
AbkürzungenAbbreviations
Boc t-ButoxycarbonylBoc t-butoxycarbonyl
DCC DicyclohexylcarbodiimidDCC dicyclohexylcarbodiimide
DMF DimethylformamidDMF dimethylformamide
HOBt HydroxybenzotriazolHOBt hydroxybenzotriazole
KG60 Kieselgel 60KG60 silica gel 60
NMM N-MethylmorpholinNMM N-methylmorpholine
TFA TrifluoressigsäureTFA trifluoroacetic acid
Komplex F (Pentafluorphenol)3 X DCC Complex F (pentafluorophenol) 3 X DCC
Tabelle 1Table 1
K^-Werte und Inhibitorkonzentration zur Verdopplung der Gerinnungszeit der Verbindungen mit der allgemeinen Formel IK ^ values and inhibitor concentration for doubling the clotting time of the compounds with the general formula I
Figure imgf000013_0001
Figure imgf000013_0001
Tabelle 2Table 2
K^-Werte und Inhibitorkonzentration zur Verdopplung der Gerinnungszeiten (Humanplasma) der Verbindungen mit der allgemeinen Formel IIK ^ values and inhibitor concentration for doubling the clotting times (human plasma) of the compounds with the general formula II
II.
Figure imgf000014_0001
Figure imgf000014_0001
Legende zu en Ta e en unLegend for en ta e en un
TT - Thrombinzeit aPTT - ThromboplastinzeitTT - thrombin time aPTT - thromboplastin time
PT - ProthrombinzeitPT - prothrombin time
FXa - Faktor Xa FX a - factor X a
Ki-Werte nach Dixon, M., Bioche . J. 55, S. 170-171 (1953). Gerinnungsdaten nach Lechner, K., 'Blutgerinnungsstörungen' , S. 157-165, Springer Verlag, Berlin, (1982). Ki values according to Dixon, M., Bioche. J. 55, pp. 170-171 (1953). Coagulation data according to Lechner, K., 'Blood coagulation disorders', pp. 157-165, Springer Verlag, Berlin, (1982).

Claims

PATENTANSPRÜCHE PATENT CLAIMS
Verbindungen der allgemeinen Formeln I und IICompounds of general formulas I and II
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0002
worin R' in der allgemeinen Formel I ein geradkettiger Alkylsulfonylrest mit 1 bis 16 Kohlenstoffatomen, vorzugs¬ weise 6 bis 10 Kohlenstoffatomen, R** ein geradkettiger Alkylsulfonylrest mit 1 bis 8 Kohlenstoffatomen und R*-*1 in der allgemeinen Formel II ein geradkettiger Alkylsulfonyl¬ rest mit 1 bis 4 Kohlenstoffatomen, ein Alkanoylrest mit 1 bis 4 Kohlenstoffatomen und n eine ganze Zahl von 1 oder 2, bedeutet, oder deren Salze. wherein R 'in the general formula I is a straight-chain alkylsulfonyl radical with 1 to 16 carbon atoms, preferably 6 to 10 carbon atoms, R ** is a straight-chain alkylsulfonyl radical with 1 to 8 carbon atoms and R * - * 1 in the general formula II is a straight-chain alkylsulfonyl ¬ radical with 1 to 4 carbon atoms, an alkanoyl radical with 1 to 4 carbon atoms and n is an integer of 1 or 2, or their salts.
2. Verwendung der Verbindungen nach Patentanspruch 1 al Thrombininhibitoren für diagnostische und pharmazeutisch Zwecke.2. Use of the compounds according to claim 1 al thrombin inhibitors for diagnostic and pharmaceutical purposes.
3. Verwendung der Verbindungen nach Patentanspruch 1 zu Herstellung von subkutan, intravenös, insbesondere ora oder rektal verabreichbaren antithrombotisch wirksame Arzneimitteln.3. Use of the compounds according to claim 1 for the production of subcutaneously, intravenously, in particular orally or rectally administrable antithrombotic drugs.
4. Subkutan, intravenös, insbesondere oral oder rekta verabreichbares antithrombotisch wirksames Arzneimitel gekennzeichnet durch eine wirksame Menge einer Verbindun gemäss Patentanspruch 1 und gegebenenfalls geeignete Träge und/oder Hilfsstoffe.4. Subcutaneously, intravenously, in particular orally or rectally administrable antithrombotic medicinal product characterized by an effective amount of a compound according to claim 1 and optionally suitable carriers and / or excipients.
5. Arzneimittel nach Patentanspruch 4 in Form von Ta bletten, Dragees, Kapseln, Pellets, Suppositorien, Lö sungen, Injektionen oder transdermalen Systemen, wie Pfla ster.5. Medicament according to claim 4 in the form of tablets, coated tablets, capsules, pellets, suppositories, solutions, injections or transdermal systems, such as plaster.
6. Verfahren zur Blutgerinnungs- resp. Thrombinhemmun bei Lebewesen, insbesondere beim Menschen, gekennzeichne durch Verabreichung einer wirksamen Menge einer Verbindun gemäss Patentanspruch 1 oder eines Arzneimittels nach eine der Patentansprüche 4 oder 5.6. Procedure for blood coagulation resp. Thrombin inhibition in living beings, in particular in humans, characterized by administration of an effective amount of a compound according to claim 1 or a medicament according to one of claims 4 or 5.
7. Testkit zur Bestimmung von Thrombin, enthaltend ein wirksame Menge einer Verbindung nach Patentanspruch 1. 7. Test kit for determining thrombin, containing an effective amount of a compound according to claim 1.
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