DE102005041613A1 - Use of octahydro-indolo-quinoline compound in the preparation of pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome - Google Patents

Use of octahydro-indolo-quinoline compound in the preparation of pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome Download PDF

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DE102005041613A1
DE102005041613A1 DE102005041613A DE102005041613A DE102005041613A1 DE 102005041613 A1 DE102005041613 A1 DE 102005041613A1 DE 102005041613 A DE102005041613 A DE 102005041613A DE 102005041613 A DE102005041613 A DE 102005041613A DE 102005041613 A1 DE102005041613 A1 DE 102005041613A1
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Rudolf Reiter
Johannes Tack
Jochen Kalbe
Reinhard Horowski
Elisabeth Sigloch
Heinz Palla
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Ergonex Pharma GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

Use of octahydro-indoloquinoline derivatives (I) is claimed in the preparation of pharmaceutical composition for treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome. Use of octahydro-indoloquinoline derivatives of formula (I) and their salts, enantiomers, diasteromers, hydrates, solvates, or racemates is claimed in the preparation of pharmaceutical composition for treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome. R1>, R4> = e.g. H, CHO, alkanoyl, cyclopropanoyl, COOH and esters, optionally substituted alkyl, C(O)NH2 or NH2, alkylsulfinyl, alkylsulfonyl, SO3H, alkoxysulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ph, benzyl, alkenyl, alkynyl, CPh3, CR11>R12>CR13>R14>R15>, CR16>R17>CR81>R19>CR20>R21>R22>, (CH2)nCR23>R24>R25>, C(O)CR26>R27>R28>, C(O)CR29>R30>CR31>R32>R33>, CR8>R9>R10>, C(O)CR34>R35>CR36>R37>CR38>R39>R40> or C(O)(CH2)nCR41>R42>R43>; R2>, R3> = 1-10C alkyl, CO(1-10C alkyl), NHC(O)1-10C alkyl, 1-10C (di)alkylureido, (hetero)aryl, (hetero)cycloalkyl, bi- or tricyclic carbocycle, bi- or tricyclic heterocycle (all optionally substituted), R6> or R7>; R5> = H, F, Cl, Br, I, CN or NO2; R6>-R45> = e.g. H, ON, OCH3, OC2H5, OC(CH3)3, OC4N9, benzyloxy, SH, SCH3, NO2, F, Cl, Br, I, N3, CN, OCN, NCO, SCN, NCS, CHO, C(O)CH3, C(O)N[CH(CH3)2]2, NH2, S(O)CH3, SO2-cyclopropyl, OCF3, ureido, NHC(O)N(cyclopropyl)2, NHC(S)NHCH3, NHC(NH)NH-cyclopropyl, OC(O)NH2, OC(O)NHCH3, OC(O)OCH3, CH2CH2I, (m)ethyl, C3H7, CH(CH3)2, C(CH3)3, C4H9, CH2CH(CH3)2, CH(CH3)C2H5, C5H11, C6H13, C7H15, C8H17, cyclopropyl, benzyl, CH=CH2, CH=CH2, CH=C(CH3)2 or CCH; a = single or double bond; and n = 1-10. Full definitions are in the Definitions: Full Definitions section. [Image] ACTIVITY : Cytostatic; Antidiarrheic; Cardiant; Immunosuppressive. MECHANISM OF ACTION : Serotonin receptor inhibitor.

Description

Die vorliegende Erfindung betrifft die Verwendung von Ergot-Derivaten bzw. Ergolinen zur Prophylaxe und Behandlung von gastrointestinalen und endokardialen Krankheiten, welche insbesondere durch neuroendokrine Fehlfunktionen unterschiedlicher Ätiologie wie beispielsweise karzinoiden Tumoren, Reizdarm oder bestimmten Autoimmunerkrankungen bedingt sind.The The present invention relates to the use of ergot derivatives or ergolines for the prophylaxis and treatment of gastrointestinal and endocardial diseases, which in particular by neuroendocrine Malfunctions of different aetiology such as carcinoid tumors, irritable bowel or certain autoimmune diseases are conditional.

Ergot-Derivate haben die Eigenschaft, an dopaminerge, α-adrenerge und serotoninerge Rezeptoren des zentralen und peripheren Nervensystems binden zu können. Die agonistische Wirkung von Ergolinderivaten am Dopamin-Rezeptor bildet die Grundlage für die therapeutische Anwendung bei Erkrankungen wie beispielsweise Morbus Parkinson, Restless Leg Syndrom und Hyperprolaktinämie.Ergot derivatives have the property of dopaminergic, α-adrenergic and serotoninergic Receptors of the central and peripheral nervous system bind can. The agonistic effect of ergoline derivatives on the dopamine receptor forms the basis for the therapeutic use in diseases such as Parkinson's disease, restless leg syndrome and hyperprolactinemia.

Aufgabe der vorliegenden Erfindung ist es, weitere Verwendungen von Ergot-Derivaten bereitzustellen.task The present invention is intended to provide further uses of ergot derivatives.

Die Aufgabe wird durch die in Patentanspruch 1 beschriebenen Indikationen gelöst. Weitere vorteilhafte Ausgestaltungen ergeben sich aus den abhängigen Ansprüchen, den Beispielen und der Beschreibung.The The object is achieved by the indications described in claim 1 solved. Further advantageous embodiments will be apparent from the dependent claims, the Examples and the description.

Überraschend wurde festgestellt, dass ausgewählte Ergot-Derivate in einem gut verträglichen Dosisbereich besonders gut für die Behandlung von Karzinoid Syndrom, gastrointestinalen Motilitätsstörungen sowie endokardialen Erkrankungen geeignet sind.Surprised was found to be selected Ergot derivatives in a well-tolerated dose range especially good for the treatment of carcinoid syndrome, gastrointestinal dysmotility as well Endocardial diseases are suitable.

Die vorliegende Erfindung betrifft somit die Verwendung der Verbindungen der allgemeinen Formel (I)

Figure 00010001
worin
R1 und R4 unabhängig voneinander bedeuten -H, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONN[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C5H11, -C6H13, -C7H15, -C8H17, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C=CH, -C≡C-CH3, -CH2-C≡CH, -CR8R9R10, -CR11R12-CR13R14R15, -CR16R17-CR81R19-CR20R21R22, -(CH2)n-CR23R24R25, -CO-CR26R27R28, -CO-CR29R30-CR31R32R33, -CO-CR34R35-CR36R37-CR38R39R40, -CO-(CH2)n-CR41R42R43;
R2 und R3 stehen unabhängig voneinander für -R6, -R7, einen linearen oder verzweigten, gesättigten oder ungesättigten Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -CO-Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -NH-CO-Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -HN-CO-NHAlkylrest oder -NH-CO-N(Dialkylrest) mit Alkylresten mit 1 – 10 Kohlenstoffatomen, die mit einem oder mehreren der Reste R8 – R43 substituiert sein können; einen Arylrest oder Cycloalkylrest oder bicyclischen oder tricyclischen Carbocyclus, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen Heteroarylrest oder Heterocyclylrest oder einen bicyclischen oder tricyclischen gesättigten oder ungesättigten Heterocyclus, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann;
R5 für einen der Reste -H, -F, -Cl, -Br, -I, -CN oder -NO2 steht;
R6 – R45 bedeuten unabhängig voneinander -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -NO2, -F, -Cl, -Br, -I, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5, -O-COOCH(CH3)2, -O-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH-cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2, -NH-CS-NHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7, -NH-CS-NH-cyclo-C3H5, -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2, -NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH3, -C2H5, -C3H7 -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C5H11, -C6H13, -C7H15, -C8H17, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -CH2-C≡CH;
X für eine Einfachbindung oder eine Doppelbindung steht;
n eine ganze Zahle von 1 bis 10 bedeutet; sowie
Salze, Enantiomere, Enantiomerengemische, Diastereomere, Diastereomerengemische, Hydrate, Solvate und Racemate der vorgenannten Verbindungen zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung und Prophylaxe von gastrointestinalen und endokardialen Erkrankungen sowie Karzinoid-Syndrom.The present invention thus relates to the use of the compounds of general formula (I)
Figure 00010001
wherein
R 1 and R 4 are independently -H, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , -COOC (CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-cyclo-C 3 H 5 , -CONN [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ], -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cycloC 3 H 5 ) 2 , -CON [CH (CH 3 ) 2] 2, -CON [C (CH 3) 3] 2, -NH 2, -NHCH 3, -NHC 2 H 5, -NHC 3 H 7, -NH-cyclo-C 3 H 5, -NHCH ( CH 3 ) 2 , -NHC (CH 3 ) 3 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N (C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [CH (CH 3 ) 2 ] 2 , -N [C (CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH (CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , - SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 - CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CPh 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH = C (CH 3 ) 2 , -C = CH, -C≡C-CH 3 , -CH 2 -C≡CH, -CR 8 R 9 R 10 , -CR 11 R 12 -CR 13 R 14 R 15 , -CR 16 R 17 -CR 81 R 19 -CR 20 R 21 R 22 , - (CH 2 ) n -CR 23 R 24 R 25 , -CO-CR 26 R 27 R 28 , -CO-CR 29 R 30 -CR 31 R 32 R 33 , -CO-CR 34 R 35 -CR 36 R 37 -CR 38 R 39 R 40 , -CO- (CH 2 ) n -CR 41 R 42 R 43 ;
R 2 and R 3 are each independently -R 6 , -R 7 , a linear or branched, saturated or unsaturated alkyl radical having 1-10 carbon atoms which may be substituted with one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -CO-alkyl radical having 1-10 carbon atoms which may be substituted by one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -NH-CO-alkyl radical having 1-10 carbon atoms which may be substituted by one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -HN-CO-NH-alkyl radical or -NH-CO-N (dialkyl radical) having alkyl radicals having 1-10 carbon atoms, the with one or more of the radicals R 8 - R 43 may be substituted; an aryl radical or cycloalkyl radical or bicyclic or tricyclic carbocycle which may be substituted by one or more of R 8 - R 43 ; a heteroaryl or heterocyclyl radical or a bicyclic or tricyclic saturated or unsaturated heterocycle which may be substituted with one or more of R 8 - R 43 ;
R 5 is one of the radicals -H, -F, -Cl, -Br, -I, -CN or -NO 2 ;
R 6 -R 45 independently represent -H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , -OCH (CH 3 ) 2 , -OC (CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH (CH 3 ) 2 , -SC (CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, - SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , -COOC (CH 3 ) 3 , -OOC -CH 3 , -OOC-C 2 H 5 , -OOC-C 3 H 7 , -OCO-cyclo-C 3 H 5 , -OCO-CH (CH 3 ) 2 , -OCO-C (CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-cyclo-C 3 H 5 , -CONH [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ], -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cycloC 3 H 5 ) 2 , -CON [CH (CH 3 ) 2] 2, -CON [C (CH 3) 3] 2, -NH 2, -NHCH 3, -NHC 2 H 5, -NHC 3 H 7, -NH-cyclo-C 3 H 5, -NHCH (CH 3 ) 2 , -NHC (CH 3 ) 3 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , - N (C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [CH (CH 3 ) 2 ] 2 , -N [C (CH 3 ) 3 ] 2 , -SOCH 3 , SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH (CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -OCF 3 , -OC 2 F 5 , -O-COOCH 3 , -O-COOC 2 H 5 , -O-COOC 3 H 7 , -O-COO-cyclo-C 3 H 5 , -O-COOCH (CH 3 ) 2 , -O-COOC (CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH -CO-NH-cyclo-C 3 H 5 , -NH-CO-NH [CH (CH 3 ) 2 ], -NH-CO-NH [C (CH 3 ) 3 ], -NH-CO-N (CH 3 ) 2 , -NH-CO-N (C 2 H 5 ) 2 , -NH-CO-N (C 3 H 7 ) 2 , -NH-CO-N (cyclo-C 3 H 5 ) 2 , -NH -CO-N [CH (CH 3 ) 2 ] 2 , -NH-CO-N [C (CH 3 ) 3 ] 2 , -NH-CS-NH 2 , -NH-CS-NHCH 3 , -NH-CS -NHC 2 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH-cyclo-C 3 H 5 , -NH-CS-NH [CH (CH 3 ) 2 ], -NH-CS- NH [C (CH 3 ) 3 ], -NH-CS-N (CH 3 ) 2 , -NH-CS-N (C 2 H 5 ) 2 , -NH -CS-N (C 3 H 7 ) 2 , -NH-CS-N (cyclo-C 3 H 5 ) 2 , -NH-CS-N [CH (CH 3 ) 2 ] 2 , -NH-CS-N [C (CH 3 ) 3 ] 2 , -NH-C (= NH) -NH 2 , -NH-C (= NH) -NHCH 3 , -NH-C (= NH) -NHC 2 H 5 , -NH -C (= NH) -NHC 3 H 7 , -NH-C (= NH) -NH-cyclo-C 3 H 5 , -NH-C (= NH) -NH [CH (CH 3 ) 2 ], NH-C (= NH) -NH [C (CH 3 ) 3 ], -NH-C (= NH) -N (CH 3 ) 2 , -NH-C (= NH) -N (C 2 H 5 ) 2 , -NH-C (= NH) -N (C 3 H 7 ) 2 , -NH-C (= NH) -N (cyclo-C 3 H 5 ) 2 , -NH-C (= NH) -N [CH (CH 3 ) 2 ] 2 , -NH-C (= NH) -N [C (CH 3 ) 3 ] 2 , -O-CO-NH 2 , -O-CO-NHCH 3 , -O-CO -NHC 2 H 5 , -O-CO-NHC 3 H 7 , -O-CO-NH-cyclo-C 3 H 5 , -O-CO-NH [CH (CH 3 ) 2 ], -O-CO- NH [C (CH 3 ) 3 ], -O-CO-N (CH 3 ) 2 , -O-CO-N (C 2 H 5 ) 2 , -O-CO-N (C 3 H 7 ) 2 , -O-CO-N (cyclo-C 3 H 5 ) 2 , -O-CO-N [CH (CH 3 ) 2 ] 2 , -O-CO-N [C (CH 3 ) 3 ] 2 , -O -CO-OCH 3 , -O-CO-OC 2 H 5 , -O-CO-OC 3 H 7 , -O-CO-O-cyclo-C 3 H 5 , -O-CO-OCH (CH 3 ) 2 , -O-CO-OC (CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, -CH 3 , -C 2 H 5 , -C 3 H 7 -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo -C 6 H 11 , -Ph, -CH 2 -Ph, -CPh 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH = C (CH 3 ) 2 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH;
X is a single bond or a double bond;
n is an integer from 1 to 10; such as
Salts, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, hydrates, solvates and racemates of the abovementioned compounds for the preparation of a pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial diseases and carcinoid syndrome.

Die Verbindungen der allgemeinen Fromel (I) sind basisch und durch Zugabe von organischen oder anorganischen Säuren können Säureadditionssalze erhalten werden. Als Säuren, welche ein Säureadditionssalz der Verbindung der Formel (I) bilden, können die folgenden genannt werden: Schwefelsäure, Sulfonsäure, Phosphorsäure, Salpetersäure, salpetrige Säure, Perchlorsäure, Bromwasserstoffsäure, Chlorwasserstoffsäure, Ameisensäure, Essigsäure, Propionsäure, Bernsteinsäure, Oxalsäure, Gluconsäure (Glycons., Dextronsäure), Milchsäure, Apfelsäure, Weinsäure, Tartronsäure (Hydroxymalonsäure, Hydroxypropandisäure), Fumarsäure, Zitronensäure, Ascorbinsäure, Maleinsäure, Malonsäure, Hydroxymaleinsäure, Brenztraubensäure, Phenylessigsäure, (o-, m-, p-) Toluylsäure, Benzoesäure, p-Aminobenzoesäure, p-Hydroxybenzoesäure, Salicylsäure, p-Aminosalicylsäure, Methansulfonsäure, Ethansulfonsäure, Hydroxyethansulfonsäure, Ethylensulfonsäure, p-Toluolsulfonsäure, Naphthylsulfonsäure, Naphthylaminsulfonsäure, Sulfanilsäure, Camphersulfonsäure, Chinasäure (Chininsäure), o-Methyl-Mandelsäure, Hydrogenbenzolsulfonsäure, Pikrinsäure (2,4,6-Trinitrophenol), Adipinsäure, d-o-Tolylweinsäure, Aminosäuren wie Methionin, Tryptophan, Arginin und insbesondere saure Aminosäuren wie Glutaminsäure oder Asparaginsäure.The Compounds of general formula (I) are basic and by addition of organic or inorganic acids, acid addition salts can be obtained become. As acids, which is an acid addition salt Compound of formula (I) may be mentioned below be: sulfuric acid, Sulfonic acid, phosphoric acid, nitric acid, nitrous Acid, perchloric acid, hydrobromic, Hydrochloric acid, formic acid, Acetic acid, propionic acid, Succinic acid, oxalic acid, gluconic (Glycons., Dextronic acid), Lactic acid, Malic acid, Tartaric acid, tartronic (Hydroxymalonic, Hydroxypropandisäure) fumaric acid, Citric acid, ascorbic acid, maleic acid, malonic, hydroxymaleic, Pyruvic acid, phenylacetic acid, (o-, m-, p-) toluic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, naphthylamine sulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic acid (quinic acid), o-methyl-mandelic acid, hydrogenbenzenesulfonic acid, picric acid (2,4,6 -Trinitrophenol) adipic acid, d-o-tolyltartaric, amino acids such as methionine, tryptophan, arginine and especially acidic amino acids such as glutamic acid or aspartic acid.

Bei dem Vorhandensein von sauren Gruppen lassen sich auch Basenadditionssalze bilden, z.B. Alkalimetallsalze sowie Salze mit Aminen. So können Alkalimetallsalze wie das Natriumsalz, das Kaliumsalz, das Lithiumsalz oder das Magnesiumsalz, das Calciumsalz, Alkylaminosalze oder Aminosäurensalze, z.B. mit basischen Aminosäuren wie Lysin gebildet werden.at the presence of acidic groups can also be added to base addition salts form, e.g. Alkali metal salts and salts with amines. So can alkali metal salts such as the sodium salt, the potassium salt, the lithium salt or the magnesium salt, the calcium salt, alkyl amino salts or amino acid salts, e.g. with basic amino acids like lysine are formed.

Die allgemeinen Formel (I) umfasst auch Stereoisomere, Enantiomere, Enantiomerengemische, Diastereomere und Diastereomerengemische, wobei beispielsweise chirale Verbindungen der folgenden Formeln (II) – (IIE) bevorzugt sind:

Figure 00050001
The general formula (I) also includes stereoisomers, enantiomers, enantiomer mixtures, Dia stereomeric and diastereomeric mixtures, wherein, for example, chiral compounds of the following formulas (II) - (IIE) are preferred:
Figure 00050001

Ferner ist bevorzugt, wenn R3 Wasserstoff bedeutet. Zudem ist bei allen hierin offenbarten Formeln bevorzugt, wenn R3 die in Formel (II), (IIA) und (IIB) gezeigte Konfiguration besitzt, d.h. aus der Ebene hervortritt und dementsprechend R2 hinter der Ebene liegt. Bevorzugt sind somit die 8-α-Ergoline. Für den Fall, dass X eine Einfachbindung bedeutet, ist die Transstellung der beiden Wasserstoffatome an C-5 und C-10 bevorzugt, wie in den allgemeinen Formeln (III) – (IIIE) dargestellt.

Figure 00050002
Figure 00060001
worin
die Reste R1 – R45 die oben angegebene Bedeutung haben.It is further preferred if R 3 is hydrogen. In addition, in all of the formulas disclosed herein, it is preferred that R 3 has the configuration shown in formulas (II), (IIA) and (IIB), ie, stands out from the plane and, accordingly, R 2 lies behind the plane. Preference is thus given to the 8-α-ergolines. In the case where X represents a single bond, the transposition of the two hydrogen atoms at C-5 and C-10 is preferable as shown in the general formulas (III) - (III).
Figure 00050002
Figure 00060001
wherein
the radicals R 1 - R 45 have the abovementioned meaning.

R1 und/oder R4 stehen vorzugsweise für Wasserstoff oder einen Alkylrest mit 1 bis 8 Kohlenstoffatomen. R3 bedeutet vorzugsweise eine Carbonylgruppe, an welche ein mono-, bi oder tricyclischer Heterocyclus gebunden ist.R 1 and / or R 4 are preferably hydrogen or an alkyl radical having 1 to 8 carbon atoms. R 3 is preferably a carbonyl group to which a mono-, bi- or tricyclic heterocycle is bonded.

Ferner ist bevorzugt, wenn R2 einen Rest -NH-CO-NH2, -NN-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH-cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2, -NH-CS-NHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7, -NH-CS-NH-cyclo-C3H5, -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2, -NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -NH-C(=NH)-N[CH(CH3)2]2 oder -NH-C(=NH)-N[C(CH3)3]2 und insbesondere einen Rest -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2 oder -NH-CO-N[CH(CH3)2]2 bedeutet. Ferner ist in diesem Fall weiter bevorzugt, wenn R3 Wasserstoff bedeutet.It is further preferred if R 2 is a radical -NH-CO-NH 2 , -NN-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO- NH-cyclo-C 3 H 5 , -NH-CO-NH [CH (CH 3 ) 2 ], -NH-CO-NH [C (CH 3 ) 3 ], -NH-CO-N (CH 3 ) 2 , -NH-CO-N (C 2 H 5 ) 2 , -NH-CO-N (C 3 H 7 ) 2 , -NH-CO-N (cyclo-C 3 H 5 ) 2 , -NH-CO- N [CH (CH 3 ) 2 ] 2 , -NH-CO-N [C (CH 3 ) 3 ] 2 , -NH-CS-NH 2 , -NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH-cyclo-C 3 H 5 , -NH-CS-NH [CH (CH 3 ) 2 ], -NH-CS-NH [C (CH 3 ) 3 ], -NH-CS-N (CH 3 ) 2 , -NH-CS-N (C 2 H 5 ) 2 , -NH-CS-N (C 3 H 7 ) 2 , -NH- CS-N (cyclo-C 3 H 5 ) 2 , -NH-CS-N [CH (CH 3 ) 2 ] 2 , -NH-CS-N [C (CH 3 ) 3 ] 2 , -NH-C ( = NH) -NH 2 , -NH-C (= NH) -NHCH 3 , -NH-C (= NH) -NHC 2 H 5 , -NH-C (= NH) -NHC 3 H 7 , -NH- C (= NH) -NH-cyclo-C 3 H 5 , -NH-C (= NH) -NH [CH (CH 3 ) 2 ], -NH-C (= NH) -NH [C (CH 3 ) 3 ], -NH-C (= NH) -N (CH 3 ) 2 , -NH-C (= NH) -N (C 2 H 5 ) 2 , -NH-C (= NH) -N (C 3 H 7 ) 2 , -NH-C (= NH) -N (cyclo-C 3 H 5 ) 2 , -NH-C (= NH) -N [CH (CH 3 ) 2 ] 2 or -NH-C ( = NH) -N [C (CH 3 ) 3 ] 2 and in particular a residue -NH- CO-N (CH 3 ) 2 , -NH-CO-N (C 2 H 5 ) 2 , -NH-CO-N (C 3 H 7 ) 2 , -NH-CO-N (cycloC 3 H 5 ) 2 or -NH-CO-N [CH (CH 3 ) 2 ] 2 . Further, in this case, further preferred is when R 3 is hydrogen.

In den Formeln (IID) und (IIID) steht R* für einen der Reste R6 – R45, welche sich an ein Stickstoffatom binden lassen. Insbesondere steht R* für eine lineare oder verzweigte, gesättigte oder ungesättigte Acylgruppe mit 1 bis 20 Kohlenstoffatomen, welche in der Kohlenstoffkette auch Kohlenstoffcyclen, Heterocyclen oder aromatische Ringe enthalten kann und deren Kohlenstoffkette des weiteren mit einem oder mehreren der Reste R6 – R45 substituiert sein kann.In formulas (IID) and (IIID), R * is one of R 6 - R 45 which can be bonded to a nitrogen atom. In particular, R * is a linear or branched, saturated or unsaturated acyl group having 1 to 20 carbon atoms, which may also contain carbon cycles, heterocycles or aromatic rings in the carbon chain and their carbon chain further substituted with one or more of R 6 - R 45 substituted can be.

R** in den Formeln (IIE) und (IIIE) steht für einen der Reste R6 – R45 und vorzugsweise für eine Aminogruppe, Alkylaminogruppe oder Dialkylaminogruppe, wobei die Alkylgruppe oder die Alkylgruppen 1 bis 20 Kohlenstoffatome umfassen, wobei die Alkylgruppen auch Carbocyclen, Heterocyclen und aromatische Systeme umfassen oder enthalten und die Alkylgruppen verzweigt oder unverzweigt sowie gesättigt oder ungesättigt und mit einem oder mehreren der Reste R6 – R45 substituiert sein können. Insbesondere bevorzugt für R** sind -CH2F, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C5H11, -C6H13, -C7H15, -C8H17, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3 und -CH2-C≡CH.R ** in formulas (IIE) and (IIIE) represents one of R 6 - R 45 and preferably an amino, alkylamino or dialkylamino group wherein the alkyl group or groups comprise from 1 to 20 carbon atoms, the alkyl groups also being carbocycles , Heterocycles and aromatic systems include or contain and the alkyl groups may be branched or unbranched and saturated or unsaturated and substituted with one or more of R 6 - R 45 . Particularly preferred for R ** are -CH 2 F, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4 H 9 , -CH 2 - CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CPh 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH = C (CH 3 ) 2 , -C≡CH, -C≡ C-CH 3 and -CH 2 -C≡CH.

Insbesondere bevorzugt sind folgende Verbindungen der Formel (I): 8-α-Ergoline, 8-α-1,6-Dimethylergoline, 8-α-1-Methylergoline, 8-α-6-Methylergoline, 8-α-10-Methoxyergoline, Lisurid (CAS-Nr.: 18016-80-3, 3-(9,10-Didehydro-6-methylergolin-8alpha-yl)-1,1-diethylharnstoff), d-Isolysergsäure, d-Isolysergsäureamid, d-Isolysergsäuredi-ethylamid, Protergurid und Tergurid ((+)-1,1-Diethyl-3-(6-methyl-8α-ergolinyl)-harnstoff). Im speziellen bevorzugt ist die Verwendung von Tergurid (trans-Dihydrolisurid) und Lisurid.Especially the following compounds of the formula (I) are preferred: 8-α-ergolines, 8-α-1,6-Dimethylergoline, 8-α-1-methyl ergoline, 8-α-6-methyl ergoline, 8-α-10-Methoxyergoline, Lisuride (CAS No .: 18016-80-3, 3- (9,10-didehydro-6-methylergoline-8alpha-yl) -1,1-diethylurea), d-isolysergic acid, d-isolysergic acid amide, d-isolysergic acid di-ethylamide, Proterguride and terguride ((+) - 1,1-diethyl-3- (6-methyl-8α-ergolinyl) urea). Especially preferred is the use of terguride (trans dihydrolisuride) and Lisurid.

Die vorgenannten Substanzen sowie die Verbindungen der allgemeinen Formeln (I) – (IIIE) eignen sich insbesondere zur Prophylaxe und Behandlung von Karzinoid-Syndrom assoziierter Diarrhoe, Bauchschmerzen, Diarrhoe-prädominanter Form von Reizdarm (irritable bowel syndrom), Chemotherapie-induzierter Diarrhoe, Flush Symptomatik, Herzklappenveränderungen und autoimmun-bedingten Herzklappenveränderungen sowie von gastrointestinalen Erkrankungen, welche durch Mobilitätsstörungen gekennzeichnet sind.The abovementioned substances and the compounds of the general formulas (I) - (IIIE) are particularly suitable for the prophylaxis and treatment of carcinoid syndrome-associated diarrhea, abdominal pain diarrhea-predominant form of irritable bowel syndrome, chemotherapy-induced diarrhea, flushing symptoms, heart valve abnormalities and autoimmune heart valve abnormalities, as well as gastrointestinal disorders characterized by mobility disorders.

In der Literatur sind verschiedene therapeutische Ansatzpunkte zur Behandlung der vorgenannten Erkrankungen diskutiert, von denen zu nennen wären:

  • a) Antagonismus am 5-HT2B Rezeptor insbesondere im Hinblick auf Herzklappenfibrosen und gastrointestinale Motilitätsstörungen,
  • b) Therapeutischer Ansatz über 5-HT1 Rezeptor Agonisten und damit Einwirkung auf den Serotonin-Tonus in Raphe Nuclei (ZNS) über die Wirkung an 5-HT1 Rezeptoren und damit Veränderung der Schmerzempfindlichkeit, welche für Karcinoid-Syndrom und IBS (Reizdarm) typisch sind,
  • c) Verwendung von a-adrenergen Inhibitoren zur Therapie einer Auslenkung des sympathischen Nervensystems durch chronischen Stress,
  • d) Einsatz von Histamin-Antagonisten, da Histamin als Mediator an Ödembildungen bei Karcinoid-Syndrom, und IBS (Reizdarm) an lokalen entzündlichen Reaktionen beteiligt ist, die Motilitätsstörungen nach sich ziehen.
The literature discusses various therapeutic approaches for the treatment of the aforementioned diseases, of which mention should be made:
  • a) antagonism at the 5-HT2B receptor, in particular with regard to heart valve fibrosis and gastrointestinal dysmotility,
  • b) Therapeutic approach via 5-HT1 receptor agonists and thus affecting the serotonin Tonus in raphe nuclei (CNS) via the action on 5-HT1 receptors and thus change in pain sensitivity, which are typical for Karcinoid syndrome and IBS (irritable bowel) .
  • c) use of a-adrenergic inhibitors for the therapy of a displacement of the sympathetic nervous system by chronic stress,
  • d) Use of histamine antagonists, as histamine acts as a mediator of edema in Karcinoid syndrome, and IBS (irritable bowel syndrome) is involved in local inflammatory reactions that cause dysmotility.

Da im Karcinoid-Syndrom die Überreaktion des sympathischen Nervensystems die Freisetzung von Serotonin durch den Tumor triggern kann, d.h. symptomatische Anfälle auslöst und das Symptomspektrum bei Carcinoid Syndrom auch bronchokonstriktive Effekte umfasst, bestehen auch Therapieansätze darin, gefäßerweiternde Stoffe einzusetzen oder durch alpha- und beta-adrenerge Blockade eine Verbesserung der Herzpumpleistung zu erzielen oder insbesondere bei Reizdarm alpha-adrenerge Substanzen zu verwenden, da bei Reizdarm (IBS) eine Überempfindlichkeit des sympatischen Nervensystems auf Stress mit der Auslösung von Diarrhoe-artigen Anfällen belegt ist. Alpha-adrenerge Substanzen entfalten hierbei ihre Wirkung nicht im gesunden Organismus, sondern nur im Krankheitsfall.There in Karcinoid syndrome, the overreaction the sympathetic nervous system through the release of serotonin can trigger the tumor, i. Symptomatic seizures triggers and the spectrum of symptoms Carcinoid syndrome also includes bronchoconstrictive effects, There are also therapeutic approaches in it, vasodilatory Use substances or by alpha and beta adrenergic blockade to achieve an improvement in cardiac pumping performance or in particular to use alpha-adrenergic substances in irritable bowel syndrome as irritable bowel (IBS) a hypersensitivity of the sympathetic nervous system on stress with the triggering of diarrhea-like seizures is occupied. Alpha-adrenergic substances develop their effect not in a healthy organism, but only in case of illness.

Aus den verschiedenen Pathomechanismen kann als wahrscheinlich abgeleitet werden, dass nur ausgewählte Patientensubgruppen auf ein definiertes Therapieprinzip ansprechen. In der Regel werden aufgrund der diversen involvierten Mechanismen Kombinationstherapien zu Einsatz kommen müssen. Die Entwicklung von Kombinationstherapien in klinischen Studien ist jedoch

  • a) sehr kostenintensiv,
  • b) nur durchführbar, wenn jedes einzelne Medikament eine bestimmte Mindeststärke, d.h. Mindestwirksamkeit als Monotherapie aufweist, und
  • c) im Hinblick auf Arzneimittelinteraktionen und Sicherheitsaspekte aller Wirkstoffe eine gute Verträglichkeit sichergestellt ist.
It can be deduced from the various pathomechanisms that only selected patient subgroups respond to a defined therapeutic principle. As a rule, combination therapies will have to be used due to the various mechanisms involved. However, the development of combination therapies in clinical trials is
  • a) very expensive,
  • (b) feasible only if each individual drug has a certain minimum strength, ie minimum efficacy as monotherapy, and
  • (c) good tolerability is ensured with regard to drug interactions and safety aspects of all active substances.

Überraschend hat sich gezeigt, dass die Verbindungen gemäss allgemeiner Formel (I) zur Therapie von Carzinoid Syndrom eignen, zumal sich mehrere Substanzen der Ergotklasse gerade als fibrosefördernd erwiesen hatten (z.B. Pergolid, Ergotamin). Herzklappenfibrosen sind als eine generelle Nebenwirkung der Ergolin Stoffklasse beschrieben und findet sich als Warnhinweisen auf den Beipackzetteln der meisten Ergolin-haltigen Medikamenten.Surprised has shown that the compounds according to general formula (I) for Therapy of carcinoid syndrome are suitable, especially as there are several substances the ergot class had just shown to promote fibrosis (e.g. Pergolide, ergotamine). Heart valve fibroses are considered a general Side effect of Ergolin class of substances described and found as warnings on the leaflets of most Ergolin-containing Medications.

Darüber hinaus haben auch gastrointestinale Nebenwirkungen wie Erbrechen aufgrund einer starken Dopamin-agonistischen Wirkung von vielen Ergolinderivaten den Fachmann davon abgehalten, Verbindungen der Formel (1) zur Prophylaxe oder Behandlung der vorgenannten Indikationen einzusetzen.Furthermore also have gastrointestinal side effects such as vomiting a strong dopamine agonistic effect of many ergoline derivatives the skilled person prevented compounds of formula (1) for prophylaxis or treatment of the aforementioned indications.

Überraschend ist darüber hinaus, dass die erfindungsgemäßen Substanzen, besonders Tergurid und Lisurid und deren Derivate, oder deren wirksame Metabolite über ein breites pharmakologisches Wirkspektrum verfügen, welches insbesondere für die vorgenannten Erkrankungen therapeutisch wertvoll ist.Surprised is about it In addition, the substances according to the invention, especially terguride and lisuride and their derivatives, or their effective ones Metabolites over have a broad pharmacological spectrum of action, which in particular for the aforementioned Diseases is therapeutically valuable.

Nach heutigem Verständnis liegt in den vorgenannten Erkrankungen eine Dysregulation der adrenergen, histaminergen sowie serotininergen Systeme vor, welche durch die Kombination von pharmakologischen Wirkungen der Verbindungen gemäß allgemeiner Formal (I) moduliert, beseitigt oder verhindert werden können. Überraschenderweise manifestieren sich diese Wirkungen in einem gemeinsamen, therapeutisch relevanten und gut verträglichen Dosisbereich und bilden die Basis für eine ganzheitliche Therapie der nachfolgend genannten Erkrankung anstelle einer Behandlung von einzelnen Symptomen.To today's understanding is in the aforementioned diseases, a dysregulation of adrenergic, histaminergic as well as serotinergic systems, which are characterized by Combination of pharmacological effects of the compounds according to more general Formally (I) can be modulated, eliminated or prevented. Surprisingly These effects manifest themselves in a common, therapeutic relevant and well tolerated Dose range and form the basis for a holistic therapy the following disease instead of treatment of individual symptoms.

Somit besteht die Überlegenheit der Verbindungen gemäß allgemeiner Formel (I) bei der Anwendung zur Behandlung und Prophylaxe von gastrointestinalen und endokardialen Erkrankungen wie beispielsweise Karzinoid-Syndrom, mit Karzinoid-Syndrom assoziierter Diarrhoe, Bauchschmerzen, Diarrhoe-prädominanter Form von Reizdarm (irritable bowel syndrom), Chemotherapie-induzierter Diarrhoe, Flush Symptomatik, Herzklappenveränderungen und autoimmun-bedingte Herzklappenveränderungen sowie von gastrointestinalen Erkrankungen, welche durch Motilitätsstörungen gekennzeichnet sind darin, dass sich ihre Wirksamkeit gegen ein breites Symptomspektrum richtet, sie eine höhere Responder-Rate von Patienten im Vergleich zu anderen Therapieprinzipien aufweisen und sie durch eine gute Verträglichkeit gekennzeichnet sind.Thus, the superiority of the compounds of general formula (I) when used for the treatment and prophylaxis of gastrointestinal and endocardial diseases such as carcinoid syndrome, associated with carcinoid syndrome diarrhea, abdominal pain, diarrhea-predominant Irritable bowel syndrome), chemotherapy-induced diarrhea, flushing symptoms, heart valve abnormalities and autoimmune heart valve abnormalities, as well as gastrointestinal disorders characterized by dysmotility in that their efficacy is directed against a broad spectrum of symptoms, they have a higher responder Rate of patients compared to other therapeutic principles and characterized by good tolerability.

In diesem Zusammenhang sind insbesondere die Abwesenheit von schweren Nebenwirkung wie Darmverschluss und ischämischer Kolitis, wie sie von bestimmten Serotonin-Antagonisten bekannt sind, auch nach Verabreichung von hohen Dosen von Lisurid oder Tergurid anzuführen. Zudem hat Tergurid als partieller Dopaminagonist kaum emetische Nebenwirkungen und ist deshalb besonders gut für die Behandlung von gastrointestinalen Motilitätsstörungen geeignet.In In this context, in particular, the absence of severe Side effects such as intestinal obstruction and ischemic colitis, such as those of certain serotonin antagonists are known, even after administration high doses of lisuride or tergurid. In addition, Tergurid has as partial dopamine agonist is hardly emetic side effects and is therefore especially good for the treatment of gastrointestinal dysmotility suitable.

Karzinoide sind sehr seltene Tumoren, die von hormonbildenden Zellen ausgehen und häufig selbst Hormone oder Botenstoffe produzieren. Sie treten bevorzugt im Magen-Darm-Trakt auf. Da die Tumoren sehr langsam wachsen, bleiben sie häufig viele Jahre unentdeckt. Karzinoide (d.h. krebsähnlich) sind Tumoren, die von sogenannten neuroendokrinen Zellen ausgehen. Neuroendokrine Zellen sind nahezu im gesamten Körper verteilt. Aus diesem Grund treten Karzinoide in verschiedenen Organen auf. Besonders häufig betroffen sind der Dünndarm, der Wurmfortsatz, die Bauchspeicheldrüse, der Magen und der Dickdarm (Gastro-Entero-Pankreatische Tumoren = Magen-Darm-Bauchspeicheldrüsen-Tumoren).carcinoid are very rare tumors that emanate from hormone-forming cells and often even produce hormones or messengers. They are preferred in the gastrointestinal tract. As the tumors grow very slowly, they remain they often undetected for many years. Carcinoids (i.e., cancerous) are tumors derived from emanating from so-called neuroendocrine cells. Neuroendocrine cells are distributed almost throughout the body. For this reason, carcinoids occur in different organs. Especially common affected are the small intestine, the appendix, the pancreas, the stomach and the colon (Gastro-entero-pancreatic Tumors = gastrointestinal pancreatic tumors).

Etwa die Hälfte aller Karzinoide produziert keine Hormone. Diese Tumoren verursachen deshalb erst dann Symptome, wenn sie durch ihr Wachstum bzw. ihre Ausbreitung im Körper benachbarte Gewebe oder Organe verdrängen. Bei großen Karzinoiden im Bauchraum treten Beschwerden wie Bauchschmerzen, Gewichtsverlust oder Gelbsucht auf. Tumoren im Brustraum können Atemnot und Hustenanfälle verursachen.Approximately the half all carcinoids do not produce hormones. These tumors cause Therefore, symptoms only when they are through their growth or their Spread in the body displace adjacent tissues or organs. For large carcinoids in the abdominal area, complaints such as abdominal pain, weight loss occur or jaundice. Tumors in the chest can cause respiratory distress and coughing fits.

Funktionell aktive Karzinoide dagegen setzen in größerer Menge Hormone in die Blutbahn frei. In Abhängigkeit davon, welche Hormone gebildet werden, treten unterschiedliche Symptome auf, z.B. leiden die Betroffenen bei überschießender Insulinproduktion an häufiger Unterzuckerung (Hypoglykämie), bei vermehrter Produktion von Gastrin an Sodbrennen und wiederholten Magen- und Dünndarmgeschwüren (Zollinger-Ellison-Syndrom) und zum Teil an chronischen Durchfällen (Verner-Morrison-Syndrom).Functional active carcinoids, on the other hand, use hormones in greater quantities Bloodstream free. Dependent on of which hormones are formed, different symptoms occur on, e.g. those affected suffer from excessive insulin production frequently Low blood sugar (hypoglycaemia), at increased production of gastrin on heartburn and repeated Gastric and small bowel ulcers (Zollinger-Ellison syndrome) and partly chronic diarrhea (Verner-Morrison syndrome).

Karzinoide, die sich im mittleren Abschnitt des Dünndarms befinden, setzen häufig Botenstoffe des Nervensystems wie Serotonin frei. Diese Tumoren führen, vor allem wenn sie bereits in die Leber oder andere Organe gestreut haben, zum so genannten Karzinoidsyndrom. Die Betroffenen leiden typischerweise unter anfallsartig auftretender Rötung des Gesichts (Flush), die sich auch auf Hals und Brustausschnitt ausdehnen kann, sowie unter Herzrasen, Schweißausbrüchen, Atembeschwerden, krampfartigen Bauchschmerzen und Durchfällen. Diese Beschwerden können durch Verabreichung mindestens einer Verbindung gemäß allgemeiner Formel (I) in Einzeldosen von 0,1 – 10 mg wirksam verhindert und/oder behandelt werden.carcinoid, which are located in the middle section of the small intestine, often set messengers of the nervous system such as serotonin free. These tumors lead to, before especially if they are already scattered in the liver or other organs have, to the so-called carcinoid syndrome. The sufferers suffer typically under attack-like redness of the face (flush), which can also extend to the neck and neckline, as well tachycardia, sweating, respiratory problems, spasmodic abdominal pain and diarrhea. These complaints can be due Administration of at least one compound according to general formula (I) in Single doses of 0.1 - 10 mg are effectively prevented and / or treated.

Wie bereits ausgeführt ist sind die Verbindungen gemäß Formel (I) mit oder ohne zusätzlichem antiproliferativen, antimigratorischen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff zur Behandlung von Carcinoid Patienten geeignet.As already executed is the compounds according to formula (I) with or without additional antiproliferative, antimigrative, antiinflammatory, antiangiogenic, anti-inflammatory, cytostatic and / or cytotoxic agent suitable for the treatment of carcinoid patients.

Bei einer bevorzugten Ausführungsform wird mindestens eine Verbindung gemäß einer oder mehrerer der Formeln (I) – (IIIE) zusammen mit einem antiproliferativen, antimigrativen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff verabreicht. Somit ist die vorliegende Erfindung auch auf Wirkstoffkombinationen aus mindestens einer Verbindung gemäß Formel (I) (oder einer der anderen Formeln (II) – (IIIE)) und einem antiproliferativen, antimigrativen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff.at a preferred embodiment is at least one compound according to one or more of the formulas (I) - (IIIE) together with an anti-proliferative, anti-inflammatory, antiinflammatory, antiangiogenic, antiinflammatory, cytostatic and / or cytotoxic Drug administered. Thus, the present invention is also on active compound combinations of at least one compound according to formula (I) (or one of the other formulas (II) - (IIIE)) and an antiproliferative, anti-inflammatory, anti-inflammatory, anti-angiogenic, anti-inflammatory, cytostatic and / or cytotoxic agent.

Als antiproliferative, antimigrative, antiphlogistische, antiangiogene, antiinflammatorische, cytostatische und/oder cytotoxische Wirkstoffe eignen sich Alkylierungsmittel, Antibiotika mit zytostatischen Eigenschaften, Antimetabolite, Mikrotubuli-Inhibitoren, Topoisomerase-Inhibitoren, Platin-enthaltende, Alkaloide, Podophyllotoxine, Taxane, Hormone, Immunmodulatoren, monoklonale Antikörper, Zytokine, Sirolimus (Rapamycin), Everolimus, Somatostatin, Tacrolimus, Roxithromycin, Dunaimycin, Ascomycin, Bafilomycin, Erythromycin, Midecamycin, Josamycin, Concanamycin, Clarithromycin, Troleandomycin, Folimycin, Cerivastatin, Simvastatin, Lovastatin, Fluvastatin, Rosuvastatin, Atorvastatin, Pravastatin, Pitavastatin, Vinblastin, Vincristin, Vindesin, Vinorelbin, Etobosid, Teniposid, Nimustin, Carmustin, Lomustin, Cyclophosphamid, C-Type Natriuretic Peptide (CNP), 4-Hydroxycyclophosphamid, Estramustin, Melphalan, Ifosfamid, Tropfosfamid, Chlorambucil, Bendamustin, Dacarbazin, Busulfan, Procarbazin, Treosulfan, Tremozolomid, Thiotepa, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Mitoxantron, Idarubicin, Bleomycin, Mitomycin, Dactinomycin, Methotrexat, Fludarabin, Fludarabin-5'-dihydrogenphosphat, Cladribin, Mercaptopurin, Thioguanin, Cytarabin, Fluorouracil, Gemcitabin, Capecitabin, Docetaxel, Carboplatin, Cisplatin, Cryptophycine, Anginex, Oxaliplatin, Amsacrin, Irinotecan, Topotecan, Hydroxycarbamid, Miltefosin, Pentostatin, Aldesleukin, Tretinoin, Asparaginase, Pegasparase, Anastrozol, Exemestan, Letrozol, Formestan, Aminoglutethemid, Adriamycin, Azithromycin, Spiramycin, Cepharantin, SMC-Proliferation-Inhibitor-2w, Epothilone A und B, Mitoxanthrone, Azathioprin, Mycophenolatmofetil, c-myc-Antisense, b-myc-Antisense, Betulinsäure, Camptothecin, Lapachol, β-Lapachon, Podophyllotoxin, Betulin, Podophyllsäure-2-ethylhydrazid, Molgramostim (rhuGM-CSF), Peginterferon α-2b, Lanograstim (r-HuG-CSF), Filgrastim, Macrogol, Anginex, Na-Uretic-Peptide, Dacarbazin, Basiliximab, Daclizumab, Selectin (Cytokinantagonist), Chryptophycine, CETP-Inhibitor, Cadherine, Cytokininhibitoren, COX-2-Inhibitor, AE-941 (Neovastat®), NFkB, Angiopeptin, Ciprofloxacin, Camptothecin, Fluroblastin, monoklonale Antikörper, die die Muskelzellproliferation hemmen, bFGF-Antagonisten, Probucol, Prostaglandine, Ac-YVAD-CMK, 1,11-Dimethoxycanthin-6-on, 1-Hydroxy-11-Methoxycanthin-6-on, Scopolectin, Colchicin, NO-Donoren wie Pentaerythrityltetranitrat und Syndnoeimine, S-Nitrosoderivate, Tamoxifen, Staurosporin, β-Estradiol, α-Estradiol, Estriol, Estron, Ethinylestradiol, Fosfestrol, Medroxyprogesteron, Estradiolcypionate, Estradiolbenzoate, Tranilast, Kamebakaurin und andere Terpenoide, die in der Krebstherapie eingesetzt werden, Verapamil, Tyrosin-Kinase-Inhibitoren (Tyrphostine), Cyclosporin A, Paclitaxel und dessen Derivate wie 6-α-Hydroxy-Paclitaxel, Baccatin, Taxotere u.a., synthetisch hergestellte als auch aus nativen Quellen gewo nnene macrocyclische Oligomere des Kohlensuboxids (MCS) und seine Derivate, Mofebutazon, Acemetacin, Diclofenac, Lonazolac, Dapson, o-Carbamoylphenoxyessigsäure, Lidocain, Ketoprofen, Mefenaminsäure, Piroxicam, Meloxicam, Chloroquinphosphat, Penicillamin, Hydroxychloroquin, Auranofin, Natriumaurothiomalat, Oxaceprol, Celecoxib, β-Sitosterin, Ademetionin, Myrtecain, Polidocanol, Nonivamid, Levomenthol, Benzocain, Aescin, Ellipticin, D-24851 (Calbiochem), Colcemid, Cytochalasin A-E, Indanocine, Nocadazole, S 100 Protein, Bacitracin, Vitronectin-Rezeptor Antagonisten, Azelastin, Guanidylcyclase-Stimulator Gewebsinhibitor der Metallproteinase-1 und 2, freie Nukleinsäuren, Nukleinsäuren in Virenüberträger inkorporiert, DNA- und RNA-Fragmente, Plaminogen-Aktivator Inhibitor-1, Plasminogen-Aktivator Inhibitor-2, Antisense Oligonucleotide, VEGF-Inhibitoren, IGF-1, Wirkstoffe aus der Gruppe der Antibiotika wie Cefadroxil, Cefazolin, Cefaclor, Cefotixin Tobramycin, Gentamycin, Penicilline wie Dicloxacillin, Oxacillin, Sulfonamide, Metronidazol, Antithrombotika wie Argatroban, Aspirin, Abciximab, synthetisches Antithrombin, Bivalirudin, Coumadin, Enoxoparin, desulfatiertes und N-reacetyliertes Heparin (Hemoparin®), Gewebe-Plasminogen-Aktivator, GpIIb/IIIa-Plättchenmembranrezeptor, Faktor Xa-Inhibitor Antikörper, Heparin, Hirudin, r-Hirudin, PPACK, Protamin, Prourokinase, Streptokinase, Warfarin, Urokinase, Vasodilatoren wie Dipyramidol, Triazolopyrimidine (Trapidil®), Nitroprusside, PDGF-Antagonisten wie Triazolopyrimidin und Seramin, ACE-Inhibitoren wie Captopril, Cilazapril, Lisinopril, Enalapril, Losartan, Thioproteaseinhibitoren, Prostacyclin, Vapiprost, Interferon α, β und γ, Apoptoseinhibitoren, Apoptoseregulatoren wie p65, NF-kB oder Bcl-xL-Antisense-Oligonukleotiden, Halofuginon, Nifedipin, Tocopherol Tranilast, Molsidomin, Teepolyphenole, Epicatechingallat, Epigallocatechingallat, Boswellinsäuren und ihre Derivate, Leflunomid, Anakinra, Etanercept, Sulfasalazin, Etoposid, Dicloxacyllin, Tetracyclin, Triamcinolon, Mutamycin, Procainimid, Retinolsäure, Quinidin, Disopyrimid, Flecainid, Propafenon, Sotolol, Amidoron., natürliche und synthetisch hergestellte Steroide wie Bryophyllin A, Inotodiol, Maquirosid A, Ghalakinosid, Mansonin, Streblosid, Hydrocortison, Betamethason, Dexamethason, nichtsteroidale Substanzen (NSAIDS) wie Fenoporfen, Ibuprofen, Indomethacin, Naproxen, Phenylbutazon und andere antivirale Agentien wie Acyclovir, Ganciclovir und Zidovudin, Antimykotika wie Clotrimazol, Flucytosin, Griseofulvin, Ketoconazol, Miconazol, Nystatin, Terbinafin, antiprozoale Agentien wie Chloroquin, Mefloquin, Quinin, des weiteren natürliche Terpenoide wie Hippocaesculin, Barringtogenol-C21-angelat, 14-Dehydroagrostistachin, Agroskerin, Agrostistachin, 17-Hydroxyagrostistachin, Ovatodiolide, 4,7-Oxycycloanisomelsäure, Baccharinoide B1, B2, B3 und B7, Tubeimosid, Bruceanole A, B und C, Bruceantinoside C, Yadanzioside N, und P, Isodeoxyelephantopin, Tomenphantopin A und B, Coronarin A, B, C und D, Ursolsäure, Hyptatsäure A, Zeorin, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A und B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A und B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A und B, Regenilol, Triptolid, des weiteren Cymarin, Apocymarin, Aristolochsäure, Anopterin, Hydroxyanopterin, Anemonin, Protoanemonin, Berberin, Cheliburinchlorid, Cictoxin, Sinococulin, Bombrestatin A und B, Cudraisoflavon A, Curcumin, Dihydronitidin, Nitidinchlorid, 12-beta-Hydroxypregnadien 3,20-dion, Bilobol, Ginkgol, Ginkgolsäure, Helenalin, Indicin, Indicin-N-oxid, Lasiocarpin, Inotodiol, Glykosid 1a, Podophyllotoxin, Justicidin A und B, Larreatin, Malloterin, Mallotochromanol, Isobutyrylmallotochromanol, Maquirosid A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidin, Oxoushinsunin, Aristolactam-AII, Bisparthenolidin, Periplocosid A, Ghalakinosid, Ursolsäure, Deoxypsorospermin, Psycorubin, Ricin A, Sanguinarin, Manwuweizsäure, Methylsorbifolin, Sphatheliachromen, Stizophyllin, Mansonin, Streblosid, Akagerin, Dihydrousambaraensin, Hydroxyusambarin, Strychnopentamin, Strychnophyllin, Usambarin, Usambarensin, Berberin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Umbelliferon, Afromoson, Acetylvismion B, Desacetylvismion A, Vismion A und B.As antiproliferative, antimigrative, anti-inflammatory, anti-angiogenic, anti-inflammatory, cytostatic and / or cytotoxic agents are alkylating agents, antibiotics with cytostatic properties, antimetabolites, microtubule inhibitors, topoisomerase inhibitors, platinum-containing, alkaloids, podophyllotoxins, taxanes, hormones, immunomodulators, monoclonal antibodies, cytokines, sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, Pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, C-type natriuretic peptides (CNP), 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, tropfosfamide, chlorambucil, bendamustine, dacarbazine , Busulfan, Procarb azin, treosulfan, tremozolomide, thiotepa, daunorubi cin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine 5'-dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, cryptophycins , Anginex, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegasparase, anastrozole, exemestane, letrozole, formestane, aminoglutethemide, adriamycin, azithromycin, spiramycin, cepharantin, SMC proliferation inhibitor 2w , Epothilones A and B, mitoxanthrones, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense, betulinic acid, camptothecin, lapachol, β-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF) , Peginterferon α-2b, lanograstim (r -HuG-CSF), filgrastim, macrogol, anginex, Na-uretic peptides, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist), Chr yptophycine, CETP inhibitor, cadherins, cytokine inhibitors, COX-2 inhibitor, AE-941 (Neovastat ®), NFkB, angiopeptin, ciprofloxacin, camptothecin, Fluroblastin, monoclonal antibody, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, Ac-YVAD-CMK, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β- Estradiol, α-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), cyclosporin A, paclitaxel and its derivatives such as 6-α-hydroxy-paclitaxel, baccatin, taxotere, etc., synthetically prepared as well as native-sourced macrocyclic oligomers of carbon suboxide (MCS) and its derivatives, mofebutazone, Acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, β-sitosterol, ademetionin, myrtainaine, polidocanol, nonivamide, levomenthol, Benzocaine, aescin, ellipticin, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocadazole, S100 protein, bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator, tissue protector 1 and 2, free nucleic acids, nucleic acids incorporated into virus carriers, DNA and RNA fragments, Plaminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2, Antisense Oligonucleotides, VEGF inhibitors, IGF-1, drugs from the group of antibiotics such as Cefadroxil, Cefazolin, Cefaclor, Cefotixin Tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, Aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, Enoxoparin, desulphated and N-reacetylated heparin (hemoparin ®), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factor X a inhibitor antibody, heparin, hirudin, r-hirudin , PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidol, triazolopyrimidines (Trapidil ® ), nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin , Vapiprost, interferon α, β and γ, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechingallate, epigallocatechin gallate, boswellic acids and their derivatives, leflunomide, Anakinra, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide , Retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol, amidorone, natural and synthetically produced steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS) such as fenoporfen, Ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antifungals such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, and natural terpenoids such as hippocaesculin; Barringtogenol-C21-angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolide, 4,7-oxycycloanisomic acid, bucerinoids B1, B2, B3 and B7, tubeimoside, bruceanols A, B and C, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronary A, B, C and D, ursolic acid, hyptate acid e A, Zeorin, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Apocymarin, Aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburine chloride, cictoxin, sinococulin, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene 3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline , Indicin, Indicin N-oxide, Lasiocarpine, Inotodiol, Glycoside 1a, Podophyllotoxin, Justicidin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin , Aristolactam AII, bis-parthenolidine, periplocoside A, ghalacinoside, ursolic acid, deoxypypsorospermine, psycorubin, ricin A, sanguinarine, manuwic acid, methylsorbifolin, sphatheliachromes, Stizo phyllin, mansonine, strebloside, akagerin, dihydrousambaraensin, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin, usambarensin, berberine, liriodenin, oxoushinsunin, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromosone, acetylvismion B, deacetylvismion A, vismion A and B.

Ferner betrifft die vorliegende Erfindung pharmazeutische Zusammensetzungen, welche unter Verwendung mindestens einer Verbindung gemäß Formel (I) oder eines Salzes davon hergestellt wurden.Further the present invention relates to pharmaceutical compositions, which using at least one compound according to formula (I) or a salt thereof.

Diese pharmazeutischen Zusammensetzung enthalten mindestens eine Verbindung der allgemeinen Formel (I) in einer aktiven Wirkstoffkonzentration von 0,1 – 10 mg pro Einzeldosis zusammen mit mindestens einem pharmakologisch verträglichen Träger, Hilfsstoff oder Lösungsmittel.These Pharmaceutical composition contain at least one compound of the general formula (I) in an active ingredient concentration from 0.1-10 mg per single dose together with at least one pharmacological acceptable Carrier, Excipient or solvent.

Zusätzlich zu der mindestens einen Verbindung gemäß Formel (I) kann die pharmazeutische Zusammensetzung vorzugsweise mindestens einen antiproliferativen, antimigrativen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff enthalten. Geeignete antiproliferative, antimigrative, antiphlogistische, antiangiogene, antiinflammatorische, cytostatische und/oder cytotoxische Wirkstoffe wurden bereits oben genannt.In addition to the at least one compound according to formula (I) may be the pharmaceutical Composition preferably at least one antiproliferative, anti-inflammatory, anti-inflammatory, anti-angiogenic, anti-inflammatory, contain cytostatic and / or cytotoxic agent. suitable antiproliferative, antimigrative, antiinflammatory, antiangiogenic, anti-inflammatory, cytostatic and / or cytotoxic agents have already been mentioned above.

Die pharmazeutischen Zusammensetzung werden bevorzugt in Form von Tabletten, Schichttabletten, Pillen, Kapseln, Mikrokapseln, Retard-Oralia, transdermalen Systemen, Implantaten, Suppositorien, Mikroformulierungen, Nanoformulierungen, liposomalen Formulierungen, Tropfen, Ampullen, Lösungen, Emulsionen, Dispersionen, Pulvern, Inhalationspulvern, mikrokristallinen Formulierungen oder Inhalationssprays bereit gestellt und sind insbesondere zur oralen, sublingualen, parenteralen, buccalen, kutanen oder perkutanen Verabreichung geeignet.The pharmaceutical compositions are preferably in the form of tablets, Coated tablets, pills, capsules, microcapsules, sustained-release oralia, transdermal systems, implants, suppositories, microformulations, Nanoformulations, liposomal formulations, drops, ampoules, Solutions, Emulsions, dispersions, powders, inhalation powders, microcrystalline Formulations or inhalation sprays are provided and are in particular for oral, sublingual, parenteral, buccal, cutaneous or percutaneous Suitable administration.

Als pharmakologisch verträgliche Träger können beispielsweise Lactose, Stärke, Sorbitol, Sucrose, Cellulose, Magnesiumstearat, Dicalciumphosphat, Calciumsulfat, Talk, Mannitol, Ethylalkohol und dergleichen eingesetzt werden. Puder als auch Tabletten können zu 5 bis 95% aus einem derartigen Träger bestehen.When pharmacologically acceptable carrier can for example, lactose, starch, Sorbitol, sucrose, cellulose, magnesium stearate, dicalcium phosphate, Calcium sulfate, talc, mannitol, ethyl alcohol and the like become. Powder as well as tablets can be 5 to 95% of one such carrier consist.

Als Bindemittel können zudem Stärke, Gelatine, natürliche Zucker, sowohl natürliche als auch synthetische Gummis wie beispielsweise Akaziengummi oder Guar-Gummi, Natriumalginat, Carboxymethyl-Cellulose, Polyethylenglycol und Wachse eingesetzt werden. Als Gleitmittel können Borsäure, Natriumbenzoat, Natriumacetat, Natriumchlorid, und dergleichen dienen.When Binders can also strength, Gelatin, natural Sugar, both natural as well as synthetic gums such as gum acacia or Guar gum, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes are used. Boric acid, sodium benzoate, sodium acetate, Sodium chloride, and the like.

Ferner können den pharmazeutischen Zusammensetzungen noch Sprengmittel, Farbstoffe, Geschmacksstoffe und/oder Bindemittel zugesetzt werden.Further can the pharmaceutical compositions nor disintegrants, dyes, Flavors and / or binders are added.

Flüssige Formulierungen umfassen Lösungen, Suspensionen, Sprays und Emulsionen. Beispielsweise Injektionslösungen auf Wasserbasis oder Wasser-Propylenglycol-Basis für parenterale Injektionen.Liquid formulations include solutions, Suspensions, sprays and emulsions. For example, injection solutions on Water-based or water-propylene glycol base for parenteral Injections.

Für die Zubereitung von Suppositorien werden bevorzugt niedrigschmelzende Wachse, Fettsäureester und Glyceride eingesetzt.For the preparation Suppositories are preferably low-melting waxes, fatty acid esters and glycerides used.

Kapseln werden beispielsweise aus Methylcellulose, Polyvinylalkohole oder denaturierte Gelatine oder Stärke hergestellt.capsules For example, methylcellulose, polyvinyl alcohols or denatured gelatin or starch produced.

Als Sprengmittel können Stärke, Natrium-Carboxymethylstärke, natürliche und synthetische Gummis wie beispielsweise Johannisbrotkernmehl, Karaya, Guar, Tragacanth und Agar sowie Cellulosederivate wie Methylcellulose, Natrium-Carboxymethylcellulose, microkristalline Cellulose sowie Alginate, Tonerden und Bentonite verwendet werden. Diese Bestandteile können in Mengen von 2 bis 30 Gew.-% eingesetzt werden.When Explosives can Strength, Sodium carboxymethyl starch, natural and synthetic gums such as locust bean gum, Karaya, guar, tragacanth and agar, as well as cellulose derivatives such as methylcellulose, Sodium carboxymethylcellulose, microcrystalline cellulose and alginates, clays and bentonites be used. These ingredients can be used in quantities of 2 to 30 % By weight.

Als Bindemittel können Zucker, Stärke aus Korn, Reis oder Kartoffeln, natürliche Gummis wie Akaziengummi, Gelatine, Tragacanth, Alginsäure, Natriumalginat, Ammonium-Calcium-Alginat, Methylcellulose, Natrium-Carboxymethylcellulose, Hydroxypropyl-methylcellulose, Polyvinylpyrrolidon sowie anorganische Verbindungen wie Magnesium-Aluminum-Silicate zugesetzt werden. Die Bindemittel könne in Mengen von 1 bis 30 Gew.-% zugesetzt werden.When Binders can Sugar, starch made of grain, rice or potatoes, natural gums like acacia gum, Gelatin, tragacanth, alginic acid, Sodium alginate, ammonium calcium alginate, methyl cellulose, sodium carboxymethyl cellulose, Hydroxypropyl-methylcellulose, polyvinylpyrrolidone and inorganic compounds as magnesium aluminum silicates are added. The binders could in Amounts of 1 to 30 wt .-% are added.

Als Gleitmittel können Stearate wie Magnesiumstearat, Calciumstearat, Kaliumstearat, Stearinsäure, hochschmelzende Wachse als auch wasserlösliche Gleitmittel wie Natriumchlorid, Natriumbenzoat, Natriumacetat, Natriumoleat, Polyethylenglycol und Aminosäuren wie Leucin eingesetzt werden. Derartige Gleitmittel können in Mengen von 0,05 bis 15 Gew.-% verwendet werden.When Lubricants can Stearates such as magnesium stearate, calcium stearate, potassium stearate, stearic acid, high melting point Waxes as well as water-soluble Lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, Polyethylene glycol and amino acids like leucine are used. Such lubricants can in Quantities of 0.05 to 15 wt .-% are used.

Beispiel 1:Example 1:

Hemmung der Längsmuskulatur im Dünndarm der Ratte durch Tergurid/Lisurid:Inhibition of the longitudinal muscles in the small intestine rat by Tergurid / Lisurid:

Männliche Wistar Ratten (Charles River) mit einem Gewicht zwischen 200g und 300g wurden verwendet. 24 Stunden vor Versuchsbeginn wurde das Futter abgesetzt, die Tiere hatten aber weiterhin freien Zugang zu Trinkwasser.male Wistar Rats (Charles River) weighing between 200g and 300g were used. 24 hours before the start of the experiment was the feed but the animals still had free access to drinking water.

Die Ratten wurden durch intraperitoneale Injektion von Na-Phenobarbital (NarcorenR) eingeschläfert, der Dünndarm wurde sofort entnommen, in oxygenierte, eiskalte Krebs-Ringer-Bicarbonat-Lösung überführt und 20 cm des terminalen Ileums präpariert und in fünf bis sechs ca. 1 cm lange Streifen in longitudinaler Richtung präpariert.The Rats were identified by intraperitoneal injection of Na-phenobarbital (NarcorenR) eclipsed the small intestine was immediately removed, transferred to oxygenated, ice-cold Krebs-Ringer bicarbonate solution and 20 cm of the terminal ileum prepared and in five to six approximately 1 cm long strips prepared in the longitudinal direction.

An den beiden Enden jedes Streifens wurde jeweils eine zirkuläre Ligatur angebracht, von denen man die aborale an einem Haken eines Elektrodenhalters befestigt. Der Elektrodenhalter besteht aus einem Fixationshaken und zwei Platinringelektroden (Abstand voneinander ca. 5 mm), durch die der Muskelstreifen geführt wurde. Der Elektrodenhalter mit den Organstreifen wurde in ein doppelwandiges Bad mit Krebs-Ringer-Bicarbonat-Lösung (Krebs-Ringer-Solution, KRS) eingebracht. Das Organbad wurde durch einen umgebenden Heizkreislauf auf 37°C gehalten und der Puffer mit Carbogen (95% O2, 5% CO2) begast.At each end of each strip, a circular ligature was attached, of which the aboral is attached to a hook of an electrode holder. The electrode holder consists of a fixation hook and two platinum ring electrodes (distance of approx. 5 mm), through which the muscle strip was guided. The electrode holder with the organ strips was placed in a double-walled bath with Krebs-Ringer-bicarbonate solution (Krebs-Ringer-Solution, KRS). The organ bath was maintained at 37 ° C by a surrounding heating circuit and the buffer gassed with carbogen (95% O 2 , 5% CO 2 ).

Das orale Ende der Organsegmente war mit einem isometrischen Kraftaufnehmer verbunden (Swegma Force Displacement Transducer SG 4-500, Swegma, Schweden). Die Segmente wurden derart fixiert, dass entstehende Kräfte in Richtung der longitudinalen Muskulatur registriert wurden. Über den Kraftaufnehmer wurden die isometrischen Kontraktionen in elektrische Spannungsänderungen umgewandelt, verstärkt und registriert. Bei einer Vorspannung von ca. 40 mN wurde das System 30 min. lang equilibriert. Danach wurde das Organbad mehrmals mit KRS gespült und das jeweilige Experiment wurde mit frischem Puffer gestartet.The The oral end of the organ segments was with an isometric force transducer (Swegma Force Displacement Transducers SG 4-500, Swegma, Sweden). The segments were fixed in such a way that resulting personnel were registered in the direction of the longitudinal musculature. On the Force transducers were the isometric contractions into electrical voltage changes transformed, amplified and registered. At a preload of about 40 mN the system became 30 min. long equilibrated. Thereafter, the organ bath was with several times KRS flushed and the respective experiment was started with fresh buffer.

Serotonin wurde kumulativ in Endkonzentrationen von 10–9 – 10–4 zur KRS zugegeben. 1 – 1,5 Minuten nach der jeweiligen Zugabe von Serotonin wurde ein Kontraktionsplateau erreicht. Nach 3 minütiger Stimulation wurde dann die nächsthöhere Konzentration von Serotonin zugesetzt.Serotonin was cumulatively added to the KRS at final concentrations of 10 -9 -10 -4 . A contraction plateau was reached 1 to 1.5 minutes after the respective addition of serotonin. After 3 minutes of stimulation, the next higher concentration of serotonin was then added.

Im Anschluss an diesen Arbeitsschritt wurde das Inkubationsmedium gegen frische KRS ausgetaucht und über 60-Minuten äquilibriert. Anschliessend wurde die oben beschriebene Inkubation mit Serotonin in Abwesenheit (Kontrolle) oder in Gegenwart von Prüfsubstanz, die über 30 Minuten vorinkubiert wurde, wiederholt. Als Prüfsubstanz wurde Tergurid und Lisurid in Endkonzentrationen von 10–8 und 10–6 mol/l eingesetzt.Following this step, the incubation medium was replaced with fresh KRS and equilibrated for 60 minutes. Subsequently, the above-described incubation with serotonin was repeated in the absence (control) or in the presence of test substance, which was preincubated for 30 minutes. The test substance used was terguride and lisuride in final concentrations of 10 -8 and 10 -6 mol / l.

Zu Ende jedes Experimentes wurde durch 30 μmol/l Acetylcholin die maximal induzierbare Kontraktion bestimmt und die Antwort auf Serotonin als % dieser Maximalkontraktion ausgedrückt. Die Versuche wurden in Triplikaten durchgeführt und Daten als Mittelwert angegeben und graphisch dargestellt (s. 1 und 2).At the end of each experiment, the maximum inducible contraction was determined by 30 μmol / L acetylcholine and the response to serotonin expressed as% of this maximal contraction. The experiments were carried out in triplicates and data were given as an average and plotted (s. 1 and 2 ).

Figurenbeschreibung:Brief Description:

1 zeigt die Serotonin-induzierte Kontraktion des vermessenen Muskelstreifens ohne Anwesenheit einer Verbindung gemäß Formel (I) sowie bei Anwesenehit von 10–8 bzw. 10–6 mol/l Tergurid als ein repräsentatives Beispiel für eine Verbindung gemäß Formel (I). 1 Figure 7 shows the serotonin-induced contraction of the measured muscle strip without the presence of a compound according to formula (I) as well as at 10 -8 and 10 -6 mol / l terguride, respectively, as a representative example of a compound according to formula (I).

2 zeigt die Serotonin-induzierte Kontraktion des vermessenen Muskelstreifens ohne Anwesenheit einer Verbindung gemäß Formel (I) sowie bei Anwesenehit von 10–8 bzw. 10–6 mol/l Lisurid als ein repräsentatives Beispiel für eine Verbindung gemäß Formel (I). 2 Figure 4 shows the serotonin-induced contraction of the measured muscle strip without the presence of a compound according to formula (I) as well as in the presence of 10 -8 and 10 -6 mol / l lisuride, respectively, as a representative example of a compound according to formula (I).

Durch die genannten Substanzen wird die Serotonin-induzierte Kontraktion der Längsmuskulatur des Dünndarmpräparats im Organbad gehemmt. Aus dieser Hemmwirkung kann eine Verlangsamung der Darmmotilität und Verlängerung der Transitzeit im Dünndarm in vivo abgeleitet werden. Diese Wirkung ist therapeutisch bei Diarrhoe-prädominanten Motilitätsstörungen des Darmes therapeutisch erwünscht.By The substances mentioned will be the serotonin-induced contraction of the longitudinal muscles of the small intestine preparation in the Organ bath inhibited. From this inhibitory effect can slow down the gut motility and extension the transit time in the small intestine be derived in vivo. This effect is therapeutic in diarrhea-predominant Motility disorders of the Darmes therapeutically desired.

Claims (12)

Verwendung der Verbindungen der allgemeinen Formel (I)
Figure 00180001
worin R1 und R4 unabhängig voneinander bedeuten -H, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3N7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -CH2F, -CHF2, -CF3, -CH2Cl -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH3, -C2H5, -C3H7 -CH(CH3)2, -C(CH3)3, -C4H5, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C2H11, -C6H13, -C7H15, -C8H17, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -CR11R12-CR13R14R15, -CR16R17-CR81R19-CR20R21R22, -(CH2)n-CR23R24R25, -CO-CR26R27R28, -CO-CR29R30-CR31R32R33, -CR8R9R10, -CO-CR34R35-CR36R37-CR38R39R40, -CO-(CH2)n-CR41R42R43; R2 und R3 stehen unabhängig voneinander für -R6, -R7, einen linearen oder verzweigten, gesättigten oder ungesättigten Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -CO-Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -NH-CO-Alkylrest mit 1 – 10 Kohlenstoffatomen, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen linearen oder verzweigten, gesättigten oder ungesättigten -NH-CO-NHAlkylrest oder -NH-CO-N(Dialkylrest) mit Alkylresten mit 1 – 10 Kohlenstoffatomen, die mit einem oder mehreren der Reste R8 – R43 substituiert sein können; einen Arylrest oder Cycloalkylrest oder bicyclischen oder tricyclischen Carbocyclus, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; einen Heteroarylrest oder Heterocyclylrest oder einen bicyclischen oder tricyclischen gesättigten oder ungesättigten Heterocyclus, der mit einem oder mehreren der Reste R8 – R43 substituiert sein kann; R5 für einen der Reste -H, -F, -Cl, -Br, -I, -CN oder -NO2 steht; R6 – R45 bedeuten unabhängig voneinander -H, -ON, -OCH3, -OC2H5, -OC3H7 -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4N9, -OPh, -OCH2-Ph, -OCPh3, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -NO2, -F, -Cl, -Br, -I, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5, -O-COOCH(CH3)2, -O-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH-cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2, -NH-CS-NHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7, -NH-CS-NH-cyclo-C3H5, -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2, -NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH5)-C2H5, -C5H11, -C6H13, -C7H15, -C8H17, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -CH2-C≡CH; X für eine Einfachbindung oder eine Doppelbindung steht; n eine ganze Zahle von 1 bis 10 bedeutet; sowie Salze, Enantiomere, Enantiomerengemische, Diastereomere, Diastereomerengemische, Hydrate, Solvate und Racemate der vorgenannten Verbindungen zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung und Prophylaxe von gastrointestinalen und endokardialen Erkrankungen sowie Karzinoid-Syndrom.Use of the compounds of general formula (I)
Figure 00180001
in which R 1 and R 4 independently of one another represent -H, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , - COC (CH 3 ) 3 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , -COOC (CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-cyclo-C 3 H 5 , -CONH [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ], -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cycloC 3 H 5 ) 2 , -CON [CH (CH 3 ) 2 ] 2 , -CON [C (CH 3 ) 3 ] 2 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-cyclo-C 3 H 5 , -NHCH (CH 3 ) 2 , -NHC (CH 3 ) 3 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N (C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [CH (CH 3 ) 2 ] 2 , -N [C (CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH (CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 N 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, -CH 3 , -C 2 H 5 , -C 3 H 7 -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4 H 5 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C 2 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CPh 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH = C (CH 3 ) 2 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -CR 11 R 12 -CR 13 R 14 R 15 , -CR 16 R 17 -CR 81 R 19 -CR 20 R 21 R 22 , - (CH 2 ) n -CR 23 R 24 R 25 , -CO-CR 26 R 27 R 28 , -CO-CR 29 R 30 -CR 31 R 32 R 33 , -CR 8 R 9 R 10 , -CO-CR 34 R 35 -CR 36 R 37 -CR 38 R 39 R 40 , -CO- (CH 2 ) n -CR 41 R 42 R 43 ; R 2 and R 3 are each independently -R 6 , -R 7 , a linear or branched, saturated or unsaturated alkyl radical having 1-10 carbon atoms which may be substituted with one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -CO-alkyl radical having 1-10 carbon atoms which may be substituted by one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -NH-CO-alkyl radical having 1-10 carbon atoms which may be substituted by one or more of R 8 - R 43 ; a linear or branched, saturated or unsaturated -NH-CO-NHalkyl radical or -NH-CO-N (dialkyl radical) with alkyl radicals having 1-10 carbon atoms which may be substituted by one or more of the radicals R 8 - R 43 ; an aryl radical or cycloalkyl radical or bicyclic or tricyclic carbocycle which may be substituted by one or more of R 8 - R 43 ; a heteroaryl or heterocyclyl radical or a bicyclic or tricyclic saturated or unsaturated heterocycle which may be substituted with one or more of R 8 - R 43 ; R 5 is one of the radicals -H, -F, -Cl, -Br, -I, -CN or -NO 2 ; R 6 -R 45 are independently -H, -ON, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 -O-cyclo-C 3 H 5 , -OCH (CH 3 ) 2 , -OC ( CH 3 ) 3 , -OC 4 N 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH (CH 3 ) 2 , -SC (CH 3 ) 3 , -NO 2 , -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN , -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , - COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , -COOC (CH 3 ) 3 , -OOC- CH 3 , -OOC-C 2 H 5 , -OOC-C 3 H 7 , -OCO-cyclo-C 3 H 5 , -OCO-CH (CH 3 ) 2 , -OCO-C (CH 3 ) 3 , CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH-cyclo-C 3 H 5 , -CONH [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ] , -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cycloC 3 H 5 ) 2 , -CON [CH (CH 3 ) 2 ] 2 , -CON [C (CH 3 ) 3 ] 2 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-cyclo-C 3 H 5 , -NHCH (CH 3 ) 2 , -NHC (CH 3 ) 3 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N ( C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [CH (CH 3 ) 2 ] 2 , -N [C (CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH (CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , - SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -OCF 3 , -OC 2 F 5 , -O-COOCH 3 , -O-COOC 2 H 5 , -O-COOC 3 H 7 , -O-COO-cyclo-C 3 H 5 , -O-COOCH (CH 3 ) 2 , -O-COOC (CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO -NH-cyclo-C 3 H 5 , -NH-CO-NH [CH (CH 3 ) 2 ], -NH-CO-NH [C (CH 3 ) 3 ], -NH-CO-N (CH 3 ) 2 , -NH-CO-N (C 2 H 5 ) 2 , -NH-CO-N (C 3 H 7 ) 2 , -NH-CO-N (cyclo-C 3 H 5 ) 2 , -NH-CO -N [CH (CH 3 ) 2 ] 2 , -NH-CO-N [C (CH 3 ) 3 ] 2 , -NH-CS-NH 2 , -NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH-cyclo-C 3 H 5 , -NH-CS-NH [CH (CH 3 ) 2 ], -NH-CS-NH [ C (CH 3 ) 3 ], -NH-CS-N (CH 3 ) 2 , -NH-CS-N (C 2 H 5 ) 2 , -NH-C S-N (C 3 H 7 ) 2 , -NH-CS-N (cycloC 3 H 5 ) 2 , -NH-CS-N [CH (CH 3 ) 2 ] 2 , -NH-CS-N [C ( CH 3 ) 3 ] 2 , -NH-C (= NH) -NH 2 , -NH-C (= NH) -NHCH 3 , -NH-C (= NH) -NHC 2 H 5 , -NH-C ( = NH) -NHC 3 H 7 , -NH-C (= NH) -NH-cyclo-C 3 H 5 , -NH-C (= NH) -NH [CH (CH 3 ) 2 ], -NH-C (= NH) -NH [C (CH 3 ) 3 ], -NH-C (= NH) -N (CH 3 ) 2 , -NH-C (= NH) -N (C 2 H 5 ) 2 , - NH-C (= NH) -N (C 3 H 7 ) 2 , -NH-C (= NH) -N (cyclo-C 3 H 5 ) 2 , -NH-C (= NH) -N [CH ( CH 3 ) 2 ] 2 , -NH-C (= NH) -N [C (CH 3 ) 3 ] 2 , -O-CO-NH 2 , -O-CO-NHCH 3 , -O-CO-NHC 2 H 5 , -O-CO-NHC 3 H 7 , -O-CO-NH-cyclo-C 3 H 5 , -O-CO-NH [CH (CH 3 ) 2 ], -O-CO-NH [C (CH 3 ) 3 ], -O-CO-N (CH 3 ) 2 , -O-CO-N (C 2 H 5 ) 2 , -O-CO-N (C 3 H 7 ) 2 , -O-CO-N (cyclo-C 3 H 5 ) 2 , -O-CO-N [CH (CH 3 ) 2 ] 2 , -O-CO-N [C (CH 3 ) 3 ] 2 , -O-CO-OCH 3 , -O-CO-OC 2 H 5 , -O-CO-OC 3 H 7 , -O-CO-O-cyclo-C 3 H 5 , -O-CO-OCH (CH 3 ) 2 , -O-CO -OC (CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 5 ) -C 2 H 5 , -C 5 H 11 , - C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , Ph, -CH 2 -Ph, -CPh 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH = C (CH 3 ) 2 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH; X is a single bond or a double bond; n is an integer from 1 to 10; and salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates of the abovementioned compounds for the preparation of a pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial diseases and carcinoid syndrome. Verwendung gemäß Anspruch 1, wobei es sich bei den Verbindungen der allgemeinen Formel (I) um 8-α-Ergoline, 8-α-1,6-Dimethylergoline, 8-α-1-Methylergoline, 8-α-6-Methylergoline, 8-α-10-Methoxyergoline, Lisurid, d-Isolysergsäure, d-Isolysergsäureamid, d-Isolysergsäuredi-ethylamid, Protergurid oder Tergurid handelt.Use according to claim 1, wherein the compounds of the general formula (I) around 8-α-ergolines, 8-α-1,6-Dimethylergoline, 8-α-1-methylergolines, 8-α-6-methylergolines, 8-α-10-methoxyergoline, lisuride, d-isolysergic acid, d-isolysergic acid amide, d-Isolysergsäuredi ethylamide, Proterguride or Tergurid acts. Verwendung gemäß Anspruch 2, wobei es sich bei den Verbindungen der allgemeinen Formel (I) um Lisurid oder Tergurid handelt.Use according to claim 2, wherein the compounds of the general formula (I) is about Lisurid or Tergurid. Verwendung gemäß Anspruch 1, 2 oder 3 zur Prophylaxe und Behandlung von Karzinoid-Syndrom assoziierter Diarrhoe, Bauchschmerzen, Diarrhoeprädominanter Form von Reizdarm, Chemotherapie-induzierter Diarrhoe, Flush Symptomatik, Herzklappenveränderungen, mit Autoimmunerkrankungen assoziierten Herzklappenveränderungen.Use according to claim 1, 2 or 3 for the prophylaxis and treatment of carcinoid syndrome associated diarrhea, abdominal pain, diarrhea predominant Form of irritable bowel, chemotherapy-induced diarrhea, flushing symptoms, Cardiac valve disorders, Cardiac valve changes associated with autoimmune diseases. Verwendung gemäß Anspruch 1, 2 oder 3, wobei die gastrointestinalen Erkrankungen durch Motilitätsstörungen gekennzeichnet sind.Use according to claim 1, 2 or 3, wherein the gastrointestinal disorders characterized by dysmotility are. Verwendung gemäß eines der vorherigen Ansprüche, wobei die mindestens eine Verbindung der allgemeinen Formel (I) in Kombination mit mindestens einem antiproliferativen, antimigrativen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff verabreicht wird.Use according to a the previous claims, where the at least one compound of the general formula (I) in combination with at least one antiproliferative, antimigrative, antiinflammatory, antiangiogenic, antiinflammatory, cytostatic and / or cytotoxic agent. Verwendung gemäß Anspruch 6, wobei der mindestens eine antiproliferative, antimigrative, antiphlogistische, antiangiogene, antiinflammatorische, cytostatische und/oder cytotoxische Wirkstoff aus der Gruppe ausgewählt wird, umfassend: Alkylierungsmittel, Antibiotika mit zytostatischen Eigenschaften, Antimetabolite, Mikrotubuli-Inhibitoren, Topoisomerase-Inhibitoren, Platin-enthaltende, Alkaloide, Podophyllotoxine, Taxane, Hormone, Immunmodulatoren, monoklonale Antikörper, Zytokine, Sirolimus (Rapamycin), Everolimus, Somatostatin, Tacrolimus, Roxithromycin, Dunaimycin, Ascomycin, Bafilomycin, Erythromycin, Midecamycin, Josamycin, Concanamycin, Clarithromycin, Troleandomycin, Folimycin, Cerivastatin, Simvastatin, Lovastatin, Fluvastatin, Rosuvastatin, Atorvastatin, Pravastatin, Pitavastatin, Vinblastin, Vincristin, Vindesin, Vinorelbin, Etobosid, Teniposid, Nimustin, Carmustin, Lomustin, Cyclophosphamid, C-Type Natriuretic Peptide (CNP), 4-Hydroxycyclophosphamid, Estramustin, Melphalan, Ifosfamid, Tropfosfamid, Chlorambucil, Bendamustin, Dacarbazin, Busulfan, Procarbazin, Treosulfan, Tremozolomid, Thiotepa, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Mitoxantron, Idarubicin, Bleomycin, Mitomycin, Dactinomycin, Methotrexat, Fludarabin, Fludarabin-5'-dihydrogenphosphat, Cladribin, Mercaptopurin, Thioguanin, Cytarabin, Fluorouracil, Gemcitabin, Capecitabin, Docetaxel, Carboplatin, Cisplatin, Cryptophycine, Anginex, Oxaliplatin, Amsacrin, Irinotecan, Topotecan, Hydroxycarbamid, Miltefosin, Pentostatin, Aldesleukin, Tretinoin, Asparaginase, Pegasparase, Anastrozol, Exemestan, Letrozol, Formestan, Aminoglutethemid, Adriamycin, Azithromycin, Spiramycin, Cepharantin, SMC-Proliferation-Inhibitor-2w, Epothilone A und B, Mitoxanthrone, Azathioprin, Mycophenolatmofetil, c-myc-Antisense, b-myc-Antisense, Betulinsäure, Camptothecin, Lapachol, β-Lapachon, Podophyllotoxin, Betulin, Podophyllsäure-2-ethylhydrazid, Molgramostim (rhuGM-CSF), Peginterferon α-2b, Lanograstim (r-HuG-CSF), Filgrastim, Macrogol, Anginex, Na-Uretic-Peptide, Dacarbazin, Basiliximab, Daclizumab, Selectin (Cytokinantagonist), Chryptophycine, CETP-Inhibitor, Cadherine, Cytokininhibitoren, COX-2-Inhibitor, AE-941 (Neovastat®), NFkB, Angiopeptin, Ciprofloxacin, Camptothecin, Fluroblastin, monoklonale Antikörper, die die Muskelzellproliferation hemmen, bFGF-Antagonisten, Probucol, Prostaglandine, Ac-YVAD-CMK, 1,11-Dimethoxycanthin-6-on, 1-Hydroxy-11-Methoxycanthin-6-on, Scopolectin, Colchicin, NO-Donoren wie Pentaerythrityltetranitrat und Syndnoeimine, S-Nitrosoderivate, Tamoxifen, Staurosporin, β-Estradiol, α-Estradiol, Estriol, Estron, Ethinylestradiol, Fosfestrol, Medroxyprogesteron, Estradiolcypionate, Estradiolbenzoate, Tranilast, Kamebakaurin und andere Terpenoide, die in der Krebstherapie eingesetzt werden, Verapamil, Tyrosin-Kinase-Inhibitoren (Tyrphostine), Cyclosporin A, Paclitaxel und dessen Derivate wie 6-α-Hydroxy-Paclitaxel, Baccatin, Taxotere u.a., synthetisch hergestellte als auch aus nativen Quellen gewonnene macrocyclische Oligomere des Kohlensuboxids (MCS) und seine Derivate, Mofebutazon, Acemetacin, Diclofenac, Lonazolac, Dapson, o-Carbamoylphenoxyessigsäure, Lidocain, Ketoprofen, Mefenaminsäure, Piroxicam, Meloxicam, Chloroquinphosphat, Penicillamin, Hydroxychloroquin, Auranofin, Natriumaurothiomalat, Oxaceprol, Celecoxib, β-Sitosterin, Ademetionin, Myrtecain, Polidocanol, Nonivamid, Levomenthol, Benzocain, Aescin, Ellipticin, D-24851 (Calbiochem), Colcemid, Cytochalasin A-E, Indanocine, Nocadazole, S 100 Protein, Bacitracin, Vitronectin-Rezeptor Antagonisten, Azelastin, Guanidylcyclase-Stimulator Gewebsinhibitor der Metallproteinase-1 und 2, freie Nukleinsäuren, Nukleinsäuren in Virenüberträger inkorporiert, DNA- und RNA-Fragmente, Plaminogen-Aktivator Inhibitor-1, Plasminogen-Aktivator Inhibitor-2, Antisense Oligonucleotide, VEGF-Inhibitoren, IGF-1, Wirkstoffe aus der Gruppe der Antibiotika wie Cefadroxil, Cefazolin, Cefaclor, Cefotixin Tobramycin, Gentamycin, Penicilline wie Dicloxacillin, Oxacillin, Sulfonamide, Metronidazol, Antithrombotika wie Argatroban, Aspirin, Abciximab, synthetisches Antithrombin, Bivalirudin, Coumadin, Enoxoparin, desulfatiertes und N-reacetyliertes Heparin (Hemoparin®), Gewebe-Plasminogen-Aktivator, GpIIb/IIIa-Plättchenmembranrezeptor, Faktor Xa-Inhibitor Antikörper, Heparin, Hirudin, r-Hirudin, PPACK, Protamin, Prourokinase, Streptokinase, Warfarin, Urokinase, Vasodilatoren wie Dipyramidol, Triazolopyrimidine (Trapidil®), Nitroprusside, PDGF-Antagonisten wie Triazolopyrimidin und Seramin, ACE-Inhibitoren wie Captopril, Cilazapril, Lisinopril, Enalapril, Losartan, Thioproteaseinhibitoren, Prostacyclin, Vapiprost, Interferon α, β und γ, Apoptoseinhibitoren, Apoptoseregulatoren wie p65, NF-kB oder Bcl-xL-Antisense-Oligonukleotiden, Halofuginon, Nifedipin, Tocopherol Tranilast, Molsidomin, Teepolyphenole, Epicatechingallat, Epigallocatechingallat, Boswellinsäuren und ihre Derivate, Leflunomid, Anakinra, Etanercept, Sulfasalazin, Etoposid, Dicloxacyllin, Tetracyclin, Triamcinolon, Mutamycin, Procainimid, Retinolsäure, Quinidin, Disopyrimid, Flecainid, Propafenon, Sotolol, Amidoron., natürliche und synthetisch hergestellte Steroide wie Bryophyllin A, Inotodiol, Maquirosid A, Ghalakinosid, Mansonin, Streblosid, Hydrocortison, Betamethason, Dexamethason, nichtsteroidale Substanzen (NSAIDS) wie Fenoporfen, Ibuprofen, Indomethacin, Naproxen, Phenylbutazon und andere antivirale Agentien wie Acyclovir, Ganciclovir und Zidovudin, Antimykotika wie Clotrimazol, Flucytosin, Griseofulvin, Ketoconazol, Miconazol, Nystatin, Terbinafin, antiprozoale Agentien wie Chloroquin, Mefloquin, Quinin, des weiteren natürliche Terpenoide wie Hippocaesculin, Barringtogenol-C21-angelat, 14-Dehydroagrostistachin, Agroskerin, Agrostistachin, 17-Hydroxyagrostistachin, Ovatodiolide, 4,7-Oxycycloanisomelsäure, Baccharinoide B1, B2, B3 und B7, Tubeimosid, Bruceanole A, B und C, Bruceantinoside C, Yadanzioside N, und P, Isodeoxyelephantopin, Tomenphantopin A und B, Coronarin A, B, C und D, Ursolsäure, Hyptatsäure A, Zeorin, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A und B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A und B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A und B, Regenilol, Triptolid, des weiteren Cymarin, Apocymarin, Aristolochsäure, Anopterin, Hydroxyanopterin, Anemonin, Protoanemonin, Berberin, Cheliburinchlorid, Cictoxin, Sinococulin, Bombrestatin A und B, Cudraisoflavon A, Curcumin, Dihydronitidin, Nitidinchlorid, 12-beta-Hydroxypregnadien 3,20-dion, Bilobol, Ginkgol, Ginkgolsäure, Helenalin, Indicin, Indicin-N-oxid, Lasiocarpin, Inotodiol, Glykosid 1a, Podophyllotoxin, Justicidin A und B, Larreatin, Malloterin, Mallotochromanol, Isobutyrylmallotochromanol, Maquirosid A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidin, Oxoushinsunin, Aristolactam-AII, Bisparthenolidin, Periplocosid A, Ghalakinosid, Ursolsäure, Deoxypsorospermin, Psycorubin, Ricin A, Sanguinarin, Manwuweizsäure, Methylsorbifolin, Sphatheliachromen, Stizophyllin, Mansonin, Streblosid, Akagerin, Dihydrousambaraensin, Hydroxyusambarin, Strychnopentamin, Strychnophyllin, Usambarin, Usambarensin, Berberin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Umbelliferon, Afromoson, Acetylvismion B, Desacetylvismion A, Vismion A und B.Use according to claim 6, wherein said at least one antiproliferative, antimigrative, anti-inflammatory, antiangiogenic, anti-inflammatory, cytostatic and / or cytotoxic agent is selected from the group comprising: alkylating agents, antibiotics having cytostatic properties, antimetabolites, microtubule inhibitors, topoisomerase inhibitors, Platinum-containing alkaloids, podophyllotoxins, taxanes, hormones, immunomodulators, monoclonal antibodies, cytokines, sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, Folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, C-type natriuretic peptides (CNP), 4-hydroxycyclophosphamide , Estramustin, Melphala n, ifosfamide, tropfosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, tremol, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine 5'-dihydrogen phosphate , Cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, cryptophycins, anginex, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegasparase, anastrozole, exemestane , Letrozole, formestane, aminoglutethemide, adriamycin, azithromycin, spiramycin, cepharantin, SMC proliferation inhibitor 2w, epothilones A and B, mitoxanthrones, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense, betulinic acid, camptothecin, Lapachol, β-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon α-2b, Lanograsti m (r -HuG-CSF), filgrastim, macrogol, anginex, Na-uretic peptides, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist), chryptophycins, CETP inhibitor, cadherins, cytokine inhibitors, COX-2 inhibitor, AE- 941 (Neovastat ®), NFkB, angiopeptin, ciprofloxacin, camptothecin, Fluroblastin, monoclonal antibodies, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, Ac-YVAD-CMK, 1,11-Dimethoxycanthin-6-one, 1- Hydroxy-11-methoxycanthin-6-one, scopolectin, colchicine, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, Ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), cyclosporin A, paclitaxel and its derivatives such as 6-α-hydroxy paclitaxel , Baccatin, Taxotere and others, synthetically prepared and naturally derived macrocyclic oligomers of carbon suboxide (MCS) and its derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate , Penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, β-sitosterol, ademetionin, myrtainaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticin, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocadazole, S 100 protein, bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator Tissue inhibitor of metalloproteinase-1 and 2, free nucleic acids, nucleic acids incorporated into virus carriers, DNA and RNA fragments, plaminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, drugs the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotixine tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxoparin, desulfated and N-reacetylated heparin ( hemoparin ®), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factor X a inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyridamole, triazolopyrimidine (Trapidil ® ), nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, Li sinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechingallate, Epigallocatechin gallate, boswellic acids and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol, amidorone, natural and synthetically produced steroids such as bryophyllin A , Inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antifungals such as clotrimazole, flucytosine, Griseofulvin, Ketoconazole, Miconazole, Nystatin, Te rbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, further natural terpenoids such as hippocaesculin, barringtogenol C21-angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolides, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7, tubeimoside, brucoleols A, B and C, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronary A, B, C and D, ursolic acid, hyptate acid A, zeorin, iso-iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Apocymarin, Aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburine chloride, cictoxin, sinococulin, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene 3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline , Indicin, Indicin N-oxide, Lasiocarpine, Inotodiol, Glycoside 1a, Podophyllotoxin, Justicidin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin , Aristolactam AII, bis-parthenolidine, periplocoside A, ghalacinoside, ursolic acid, deoxypypsorospermine, psycorubin, ricin A, sanguinarine, manuwic acid, methylsorbifolin, sphatheliachromes, Stizo phyllin, mansonine, strebloside, akagerin, dihydrousambaraensin, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin, usambarensin, berberine, liriodenin, oxoushinsunin, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromosone, acetylvismion B, deacetylvismion A, vismion A and B. Pharmazeutische Zusammensetzung enthaltend mindestens eine Verbindung der allgemeinen Formel (I) in einer aktiven Wirkstoffkonzentration von 0,1 – 10 mg pro Einzeldosis zusammen mit pharmakologisch verträglichen Trägern, Hilfsstoffen und/oder Lösungsmitteln.Pharmaceutical composition containing at least a compound of the general formula (I) in an active ingredient concentration from 0.1-10 mg per single dose together with pharmacologically acceptable carriers, Auxiliaries and / or solvents. Pharmazeutische Zusammensetzung gemäß Anspruch 8, wobei die pharmazeutische Zusammensetzung zur oralen, sublingualen, parenteralen, buccalen, kutanen oder perkutanen Verabreichung geeignet ist.Pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for oral, sublingual, parenteral, buccal, cutaneous or percutaneous administration is. Pharmazeutische Zusammensetzung gemäß Anspruch 8 oder 9 in Form von Tabletten, Schichttabletten, Kapseln, Retard-Oralia, transdermalen Systemen, Implantaten, Suppositorien, Mikroformulierungen, Nanoformulierungen, liposomalen Formulierungen, Tropfen, Ampullen, Lösungen, Emulsionen, Dispersionen, Pulvern, Inhalationspulvern, mikrokristallinen Formulierungen, Inhalationssprays.Pharmaceutical composition according to claim 8 or 9 in the form of tablets, coated tablets, capsules, sustained-release oralia, transdermal systems, implants, suppositories, microformulations, Nanoformulations, liposomal formulations, drops, ampoules, Solutions, Emulsions, dispersions, powders, inhalation powders, microcrystalline Formulations, inhalation sprays. Pharmazeutische Zusammensetzung gemäß Anspruch 8, 9 oder 10 des weiteren umfassend mindestens einem antiproliferativen, antimigrativen, antiphlogistischen, antiangiogenen, antiinflammatorischen, cytostatischen und/oder cytotoxischen Wirkstoff.A pharmaceutical composition according to claim 8, 9 or 10 further comprising at least one antiproliferative, anti-inflammatory, anti-inflammatory, anti-angiogenic, anti-inflammatory, cyto static and / or cytotoxic agent. Pharmazeutische Zusammensetzung gemäß Anspruch 11, wobei der mindestens eine antiproliferative, antimigrative, antiphlogistische, antiangiogene, antiinflammatorische, cytostatische und/oder cytotoxische Wirkstoff aus der Gruppe ausgewählt wird, umfassend: Alkylierungsmittel, Antibiotika mit zytostatischen Eigenschaften, Antimetabolite, Mikrotubuli-Inhibitoren, Topoisomerase-Inhibitoren, Platin-enthaltende, Alkaloide, Podophyllotoxine, Taxane, Hormone, Immunmodulatoren, monoklonale Antikörper, Zytokine, Sirolimus (Rapamycin), Everolimus, Somatostatin, Tacrolimus, Roxithromycin, Dunaimycin, Ascomycin, Bafilomycin, Erythromycin, Midecamycin, Josamycin, Concanamycin, Clarithromycin, Troleandomycin, Folimycin, Cerivastatin, Simvastatin, Lovastatin, Fluvastatin, Rosuvastatin, Atorvastatin, Pravastatin, Pitavastatin, Vinblastin, Vincristin, Vindesin, Vinorelbin, Etobosid, Teniposid, Nimustin, Carmustin, Lomustin, Cyclophosphamid, C-Type Natriuretic Peptide (CNP), 4-Hydroxycyclophosphamid, Estramustin, Melphalan, Ifosfamid, Tropfosfamid, Chlorambucil, Bendamustin, Dacarbazin, Busulfan, Procarbazin, Treosulfan, Tremozolomid, Thiotepa, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Mitoxantron, Idarubicin, Bleomycin, Mitomycin, Dactinomycin, Methotrexat, Fludarabin, Fludarabin-5'-dihydrogenphosphat, Cladribin, Mercaptopurin, Thioguanin, Cytarabin, Fluorouracil, Gemcitabin, Capecitabin, Docetaxel, Carboplatin, Cisplatin, Cryptophycine, Anginex, Oxaliplatin, Amsacrin, Irinotecan, Topotecan, Hydroxycarbamid, Miltefosin, Pentostatin, Aldesleukin, Tretinoin, Asparaginase, Pegasparase, Anastrozol, Exemestan, Letrozol, Formestan, Aminoglutethemid, Adriamycin, Azithromycin, Spiramycin, Cepharantin, SMC-Proliferation-Inhibitor-2w, Epothilone A und B, Mitoxanthrone, Azathioprin, Mycophenolatmofetil, c-myc-Antisense, b-myc-Antisense, Betulinsäure, Camptothecin, Lapachol, β-Lapachon, Podophyllotoxin, Betulin, Podophyllsäure-2-ethylhydrazid, Molgramostim (rhuGM-CSF), Peginterferon α-2b, Lanograstim (r-HuG-CSF), Filgrastim, Macrogol, Anginex, Na-Uretic-Peptide, Dacarbazin, Basiliximab, Daclizumab, Selectin (Cytokinantagonist), Chryptophycine, CETP-Inhibitor, Cadherine, Cytokininhibitoren, COX-2-Inhibitor, AE-941 (Neovastat®), NFkB, Angiopeptin, Ciprofloxacin, Camptothecin, Fluroblastin, monoklonale Antikörper, die die Muskelzellproliferation hemmen, bFGF-Antagonisten, Probucol, Prostaglandine, Ac-YVAD-CMK, 1,11-Dimethoxycanthin-6-on, 1-Hydroxy-11-Methoxycanthin-6-on, Scopolectin, Colchicin, NO-Donoren wie Pentaerythrityltetranitrat und Syndnoeimine, S-Nitrosoderivate, Tamoxifen, Staurosporin, β-Estradiol, α-Estradiol, Estriol, Estron, Ethinylestradiol, Fosfestrol, Medroxyprogesteron, Estradiolcypionate, Estradiolbenzoate, Tranilast, Kamebakaurin und andere Terpenoide, die in der Krebstherapie eingesetzt werden, Verapamil, Tyrosin-Kinase-Inhibitoren (Tyrphostine), Cyclosporin A, Paclitaxel und dessen Derivate wie 6-α-Hydroxy-Paclitaxel, Baccatin, Taxotere u.a., synthetisch hergestellte als auch aus nativen Quellen gewonnene macrocyclische Oligomere des Kohlensuboxids (MCS) und seine Derivate, Mofebutazon, Acemetacin, Diclofenac, Lonazolac, Dapson, o-Carbamoylphenoxyessigsäure, Lidocain, Ketoprofen, Mefenaminsäure, Piroxicam, Meloxicam, Chloroquinphosphat, Penicillamin, Hydroxychloroquin, Auranofin, Natriumaurothiomalat, Oxaceprol, Celecoxib, β-Sitosterin, Ademetionin, Myrtecain, Polidocanol, Nonivamid, Levomenthol, Benzocain, Aescin, Ellipticin, D-24851 (Calbiochem), Colcemid, Cytochalasin A-E, Indanocine, Nocadazole, S 100 Protein, Bacitracin, Vitronectin-Rezeptor Antagonisten, Azelastin, Guanidylcyclase-Stimulator Gewebsinhibitor der Metallproteinase-1 und 2, freie Nukleinsäuren, Nukleinsäuren in Virenüberträger inkorporiert, DNA- und RNA-Fragmente, Plaminogen-Aktivator Inhibitor-1, Plasminogen-Aktivator Inhibitor-2, Antisense Oligonucleotide, VEGF-Inhibitoren, IGF-1, Wirkstoffe aus der Gruppe der Antibiotika wie Cefadroxil, Cefazolin, Cefaclor, Cefotixin Tobramycin, Gentamycin, Penicilline wie Dicloxacillin, Oxacillin, Sulfonamide, Metronidazol, Antithrombotika wie Argatroban, Aspirin, Abciximab, synthetisches Antithrombin, Bivalirudin, Coumadin, Enoxoparin, desulfatiertes und N-reacetyliertes Heparin (Hemoparin®), Gewebe-Plasminogen-Aktivator, GpIIb/IIIa-Plättchenmembranrezeptor, Faktor Xa-Inhibitor Antikörper, Heparin, Hirudin, r-Hirudin, PPACK, Protamin, Prourokinase, Streptokinase, Warfarin, Urokinase, Vasodilatoren wie Dipyramidol, Triazolopyrimidine (Trapidil®), Nitroprusside, PDGF-Antagonisten wie Triazolopyrimidin und Seramin, ACE-Inhibitoren wie Captopril, Cilazapril, Lisinopril, Enalapril, Losartan, Thioproteaseinhibitoren, Prostacyclin, Vapiprost, Interferon α, β und γ, Apoptoseinhibitoren, Apoptoseregulatoren wie p65, NF-kB oder Bcl-xL-Antisense-Oligonukleotiden, Halofuginon, Nifedipin, Tocopherol Tranilast, Molsidomin, Teepolyphenole, Epicatechingallat, Epigallocatechingallat, Boswellinsäuren und ihre Derivate, Leflunomid, Anakinra, Etanercept, Sulfasalazin, Etoposid, Dicloxacyllin, Tetracyclin, Triamcinolon, Mutamycin, Procainimid, Retinolsäure, Quinidin, Disopyrimid, Flecainid, Propafenon, Sotolol, Amidoron., natürliche und synthetisch hergestellte Steroide wie Bryophyllin A, Inotodiol, Maquirosid A, Ghalakinosid, Mansonin, Streblosid, Hydrocortison, Betamethason, Dexamethason, nichtsteroidale Substanzen (NSAIDS) wie Fenoporfen, Ibuprofen, Indomethacin, Naproxen, Phenylbutazon und andere antivirale Agentien wie Acyclovir, Ganciclovir und Zidovudin, Antimykotika wie Clotrimazol, Flucytosin, Griseofulvin, Ketoconazol, Miconazol, Nystatin, Terbinafin, antiprozoale Agentien wie Chloroquin, Mefloquin, Quinin, des weiteren natürliche Terpenoide wie Hippocaesculin, Barringtogenol-C21-angelat, 14-Dehydroagrostistachin, Agroskerin, Agrostistachin, 17-Hydroxyagrostistachin, Ovatodiolide, 4,7-Oxycycloanisomelsäure, Baccharinoide B1, B2, B3 und B7, Tubeimosid, Bruceanole A, B und C, Bruceantinoside C, Yadanzioside N, und P, Isodeoxyelephantopin, Tomenphantopin A und B, Coronarin A, B, C und D, Ursolsäure, Hyptatsäure A, Zeorin, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A und B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A und B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A und B, Regenilol, Triptolid, des weiteren Cymarin, Apocymarin, Aristolochsäure, Anopterin, Hydroxyanopterin, Anemonin, Protoanemonin, Berberin, Cheliburinchlorid, Cictoxin, Sinococulin, Bombrestatin A und B, Cudraisoflavon A, Curcumin, Dihydronitidin, Nitidinchlorid, 12-beta-Hydroxypregnadien 3,20-dion, Bilobol, Ginkgol, Ginkgolsäure, Helenalin, Indicin, Indicin-N-oxid, Lasiocarpin, Inotodiol, Glykosid 1a, Podophyllotoxin, Justicidin A und B, Larreatin, Malloterin, Mallotochromanol, Isobutyrylmallotochromanol, Maquirosid A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidin, Oxoushinsunin, Aristolactam-AII, Bisparthenolidin, Periplocosid A, Ghalakinosid, Ursolsäure, Deoxypsorospermin, Psycorubin, Ricin A, Sanguinarin, Manwuweizsäure, Methylsorbifolin, Sphatheliachromen, Stizophyllin, Mansonin, Streblosid, Akagerin, Dihydrousambaraensin, Hydroxyusambarin, Strychnopentamin, Strychnophyllin, Usambarin, Usambarensin, Berberin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Umbelliferon, Afromoson, Acetylvismion B, Desacetylvismion A, Vismion A und B.The pharmaceutical composition according to claim 11, wherein said at least one antiproliferative, antimigrative, anti-inflammatory, anti-angiogenic, anti-inflammatory, cytostatic and / or cytotoxic agent is selected from the group comprising: alkylating agents, antibiotics having cytostatic properties, antimetabolites, microtubule inhibitors, topoisomerase inhibitors , Platinum-containing, alkaloids, podophyllotoxins, taxanes, hormones, immunomodulators, monoclonal antibodies, cytokines, sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin , Folimycin, Cerivastatin, Simvastatin, Lovastatin, Fluvastatin, Rosuvastatin, Atorvastatin, Pravastatin, Pitavastatin, Vinblastine, Vincristine, Vindesine, Vinorelbine, Etoboside, Teniposide, Nimustine, Carmustine, Lomustine, Cyclophosphamide, C-Type Natriuretic Peptide (CNP), 4- hydroxycyclophosphamide, Estramustine, Melphalan, Ifosfamide, Tropfosfamide, Chlorambucil, Bendamustine, Dacarbazine, Busulfan, Procarbazine, Treosulfan, Tremozolomide, Thiotepa, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Mitoxantrone, Idarubicin, Bleomycin, Mitomycin, Dactinomycin, Methotrexate, Fludarabine, Fludarabine-5 ' dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, cryptophycins, anginex, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegasparase, anastrozole , Exemestane, letrozole, formestane, aminoglutethemide, adriamycin, azithromycin, spiramycin, cepharantin, SMC proliferation inhibitor 2w, epothilones A and B, mitoxanthrones, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense, betulinic acid, Camptothecin, lapachol, β-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterf eron α-2b, lanograstim (r -HuG-CSF), filgrastim, macrogol, anginex, Na-uretic peptides, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist), chryptophycins, CETP inhibitor, cadherins, cytokine inhibitors, COX-2 inhibitor, AE-941 (Neovastat ®), NFkB, angiopeptin, ciprofloxacin, camptothecin, Fluroblastin, monoclonal antibodies, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, Ac-YVAD-CMK, 1,11-Dimethoxycanthin-6 -on, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, colchicine, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, Fosfestrol , Medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), cyclosporin A, paclitaxel and its derivatives such as 6-α-hydroxy-paclitaxel, baccatin, Taxo and other synthetically prepared and naturally derived macrocyclic oligomers of carbon suboxide (MCS) and its derivatives, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, Hydroxychloroquine, Auranofin, Sodium Aurothiomalate, Oxaceprol, Celecoxib, β-Sitosterol, Ademetionin, Myrtecain, Polidocanol, Nonivamide, Levomenthol, Benzocaine, Aescin, Ellipticin, D-24851 (Calbiochem), Colcemid, Cytochalasin AE, Indanocine, Nocadazole, S 100 Protein, Bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, metalloproteinase 1 and 2 tissue inhibitor, free nucleic acids, nucleic acids incorporated into virus carriers, DNA and RNA fragments, plaminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense Oligonucleotides, VEGF inhibitors, IGF-1, drugs from the group of antibiotics such as cefadroxil, Cefazolin, cefaclor, Cefotixin tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, Enoxoparin, desulphated and N-reacetylated heparin (hemoparin ®), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, factor X a inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyridamole, triazolopyrimidine (Trapidil ®), nitroprusside, PDGF Antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides , Halofuginone, Nifedipine, Tocopherol Tranilast, Molsidomine, Teepolyphenols, Epicatechin gallate, Epigallocatechin gallate, Bo swellinsäuren and their derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacyllin, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotolol, amidoron, natural and synthetically produced steroids such as bryophyllin A, inotodiol , Maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal drugs (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antifungals such as clotrimazole, flucytosine, griseofulvin, Ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, and also natural terpenoids such as hippocaesculin, barringtogenol C21 angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolide, 4,7-oxycycloanisomic acid, Baccharinoids B1, B2, B3 and B7, Tubeimoside, Bruc eanole A, B and C, bruceantinoside C, yadanzioside N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptate acid A, zeorin, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Apocymarin, Aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburine chloride, cictoxin, sinococulin, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene 3,20-dione, bilobol, ginkgol, ginkgolic acid, helenaline , Indicin, Indicin N-oxide, Lasiocarpine, Inotodiol, Glycoside 1a, Podophyllotoxin, Justicidin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin , Aristolactam AII, bis-parthenolidine, periplocoside A, ghalacinoside, ursolic acid, deoxypypsorospermine, psycorubin, ricin A, sanguinarine, manuwic acid, methylsorbifolin, sphatheliachromes, Stizo phyllin, mansonine, strebloside, akagerin, dihydrousambaraensin, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin, usambarensin, berberine, liriodenin, oxoushinsunin, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromosone, acetylvismion B, deacetylvismion A, vismion A and B.
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