DE102004019492A1 - Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals - Google Patents

Abstract

The present invention relates to the CGRP antagonists of the general formula DOLLAR F1 in which A, X, Q and R · 1 · to R · 3 · are defined as in claim 1, DOLLAR A their tautomers, their diastereomers, their enantiomers, their Hydrate, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids, pharmaceutical compositions containing these compounds, their use and processes for their preparation.

Description

deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, sowie diejenigen Verbindungen der allgemeinen Formel I, in denen ein oder mehrere Wasserstoffatome durch Deuterium ausgetauscht sind, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.The present invention relates to the CGRP antagonists of the general formula

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, and those compounds of general formula I in which one or more hydrogen atoms substituted by deuterium, medicaments containing these compounds, their use and processes for their preparation.

in der
Y¹ das Kohlenstoffatom oder, wenn R⁵ ein freies Elektronenpaar darstellt, auch das Stickstoffatom,
q und r, wenn Y¹ das Kohlenstoffatom darstellt, die Zahlen 0, 1 oder 2, oder
q und r, wenn Y¹ das Stickstoffatom darstellt, die Zahlen 1 oder 2,
R⁴ das Wasserstoffatom, eine Amino-, C_1–4-Alkyl-amino-, Di-(C_1–4-Alkyl)-alkylamino-, C_1–6-Alkyl-, Cyclo-C_3–7-alkyl-, Cyclo-C_3–7-alkenyl-, Amino-C_2–7-alkyl-, C_1–4-Alkyl-amino-C_2–7-alkyl-, Di-(C_1–4-amino)-C_2–7-alkyl-, Aminoiminomethyl-, Aminocarbonylamino-, C_1–4-Alkyl-aminocarbonylamino-, Di-(C_1–4-alkyl)- aminocarbonylamino-, C_1–4-Alkyl-aminocarbonyl-C_1–4-amino-, Di-(C_1–4-alkyl)-aminocarbonyl-C_1–4-amino-, Phenylaminocarbonylamino-, Aminocarbonyl-, C_1–4-Alkyl-aminocarbonyl-, Di-(C_1–4-alkyl)-aminocarbonyl-, Aminocarbonyl-C_1–3-alkyl-, C_1–4-Alkyl-aminocarbonyl-C_1–3-alkyl-, Di-(C_1–4-alkyl)-aminocarbonyl-C_1–3-alkyl-, Aminocarbonylamino-C_1–3-alkyl-, C_1–6-Alkoxycarbonyl-, C₃_₆-Alkenoxycarbonyl-, C₃_₆-Alkinoxycarbonyl-, C_1–6-Alkoxycarbonyl-C_1–3-alkyl-, C_1–6-Alkenoxycarbonyl-C_1–3-alkyl-, C_1–6-Alkinoxycarbonyl-C_1–3-alkyl- oder Hydroxycarbonyl-C_1–3-alkylgruppe,
eine Phenyl-, Pyridinyl-, Diazinyl-, 1-Naphthyl-, 2-Naphthyl-, Pyridinylcarbonyl- oder Phenylcarbonylgruppe, die jeweils im Kohlenstoffgerüst durch Halogen, durch C_1–3-Alkyl-, C₂_₃-Alkenyl-, C₂_₃-Alkinyl-, C_1–3-Alkoxy-, Hydroxy-, Amino-, C_1–4-Alkylamino-, Di-(C_1–4-alkyl)-amino-, Amino-C_1–3-alkyl-, C_1–4-Alkyl-amino-C_1–3-alkyl-, Di-(C_1–4-alkyl)-amino-C_1–3-alkyl-, C_1–4-Alkylcarbonylamino-, C_1–4-Alkylcarbonylamino-C₁_₃-alkyl-, Aminocarbonyl-, C_1–4-Alkyl-aminocarbonyl-, Di-(C_1–4-Alkyl)-aminocarbonyl-, Cyano-, Aminosulfonyl-, C_1–4-Alkyl-aminosulfonyl-, Di-(C_1–4-Alkyl)-aminosulfonyl-, C_1–4-Alkyl-thio-, C_1–4-Alkyl-sulfinyl-, oder C_1–4-Alkylsulfonyl- mono-, di- oder trisubstituiert und die Substituenten gleich oder verschieden sein können,
ein Heterocyclus ausgewählt aus einer 4- bis 10-gliedrigen Azacycloalkylgruppe, einer 6- bis 10-gliedrige Oxaza-, Thiaza- und Diazacycloalkylgruppe sowie einer 6- bis 10-gliedrige Azabicycloalkylgruppe,
eine 1-Alkyl-4-piperidinylcarbonyl- oder 4-Alkyl-1-piperazinylcarbonylgruppe,
wobei die vorstehend genannten mono- und bicyclischen Heterocyclen über ein Stickstoff- oder ein Kohlenstoffatom an Y¹ in Formel (II) gebunden sind,
in den vorstehend genannten mono- und bicyclischen Heterocyclen eine nicht direkt mit einem Stickstoff-, Sauerstoff- oder Schwefelatom verknüpfte Methingruppe durch ein Fluoratom sowie eine nicht direkt mit einem Stickstoff-, Sauerstoff- oder Schwefelatom verknüpfte Methylengruppe durch ein oder zwei Fluoratome substituiert sein kann, die vorstehend genannten mono- und bicyclischen Heterocyclen sowie die 1-(C_1–6-Alkyl)-4-piperidinylcarbonyl- und 4-(C_1–6-Alkyl)-1-piperazinylcarbonylgruppe im Ring ein- bis vierfach durch C₁_₆-Alkylgruppen, oder, gegebenenfalls zusätzlich, einfach durch eine Cyclo-C_3–7-alkyl-, Cyclo-C_3–7-alkenyl-, Cyclo-C_3–7-alkyl-C_1–3-alkyl-, Phenyl-C_1–3-alkyl-, Pyridyl-C_1–3-alkyl-, C_1–6-Alkylcarbonyl-, Hydroxy-, C_1–6-Alkoxy-, Amino-, C_1–4-Alkylamino-, Di-(C_1–4-alkyl)amino-, Phenylcarbonyl-, Pyridinylcarbonyl-, Hydroxycarbonyl-, Hydroxycarbonyl-C_1–3-alkyl-, C_1–6-Alkoxycarbonyl-, C_1–6-Alkoxycarbonyl-C_1–3-alkyl, Aminocarbonyl-, C_1–4-Alkylaminocarbonyl-, Di-(C_1–4-alkyl)aminocarbonyl- oder C_1–3-Alkylsulfonyl-gruppe, durch eine im Ring gegebenenfalls C_1–3alkylsubstituierte Cyclo-C_3–7-alkyl-carbonyl-, Azacyclo-C_4–7-alkyl-carbonyl-, Diazacyclo-C_5–7-alkyl-carbonyl- oder Oxazacyclo-C_5–7-alkyl-carbonylgruppe substituiert sein können, wobei die Substituenten gleich oder verschieden und an ein Ring-Kohlenstoff- oder Ring-Stickstoffatom gebunden sein können,
wobei die in den für R⁴ vorstehend definierten Resten enthaltenen Phenyl- und Pyridinyl-Reste ihrerseits durch Halogenatome, durch C_1–3-Alkyl-, C₂_₃-Alkenyl-, C₂_₃-Alkinyl-, C_1–3-Alkoxy-, Hydroxy-, Amino-, C_1–4-Alkylamino-, Di-(C_1–4-alkyl)-amino-, Amino-C_1–3-alkyl-, C_1–4-Alkylamino-C_1–3-alkyl-, Di-(C_1–4-alkyl)-amino-C_1–3-alkyl-, C_1–4-Alkylcarbonylamino-, C_1–4-Alkylcarbonylamino-C_1–3-alkyl-, Aminocarbonyl-, C_1–3-Alkylaminocarbonyl-, Di-C_1–4-Alkyl-aminocarbonyl-, Cyano-, Aminosulfonyl-, C_1–4-Alkyl-aminosulfonyl-, Di-(C_1–4-Alkyl)-aminosulfonyl-, C_1–3-Alkyl-thio-, C_1–3-Alkyl-sulfinyl-, oder C_1–3-Alkyl-sulfonyl- mono-, di- oder trisubstituiert sein können, wobei die Substituenten gleich oder verschieden sein können,
oder auch, wenn Y¹ das Kohlenstoffatom darstellt, die Hydroxycarbonyl-, Aminomethyl-, C_1–4-Alkyl-aminomethyl- oder Di-(C_1–4-Alkyl)-aminomethylgruppe,
R⁵ ein Wasserstoffatom,
einen C_1–4-Alkylrest, wobei ein unverzweigter Alkylrest in ω-Stellung durch eine Phenyl-, Pyridinyl-, Diazinyl-, Amino-, C_1–4-Alkylamino-, Di-(C_1–4-alkyl)-amino-, 4-C_1–4-Alkyl-1-piperazinyl- oder 4-Morpholinyl-gruppe substituiert sein kann,
eine C_1–6-Alkoxycarbonyl-, Cyano- oder Aminocarbonylgruppe oder auch, wenn Y¹ ein Stickstoffatom darstellt, ein freies Elektronenpaar,
oder, wenn Y¹ das Kohlenstoffatom darstellt, auch das Fluoratom, oder
R⁴ zusammen mit R⁵ und Y¹ einen 4- bis 7-gliedrigen cycloaliphatischen Ring, in dem eine Methylengruppe durch eine Gruppe -NH-, -N(C_1–4-Alkyl)-, -N(C_3–4-Alkenyl)-, -N(C_3–4-Alkinyl)-, -N(Cyclo-C_3–7-alkyl)- oder -N(C_3–7-Cycloalkyl-C_1–3-alkyl)- ersetzt sein kann,
wobei ein an ein Stickstoffatom in einer der für R⁴ vorstehend definierten Gruppen gebundenes Wasserstoffatom durch einen Schutzrest ersetzt sein kann,
R⁶ und R⁷, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom, eine C_1–4-Alkylgruppe oder auch, wenn Y¹ ein Kohlenstoffatom darstellt, das Fluoratom, eine C_1–4-Alkylamino- oder Di-(C_1–4-alkyl)-aminogruppe, wobei die beiden C_1–4-Alkylgruppen unter Ausbildung eines Ringes miteinander verbunden sein können und
R⁸ und R⁹, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom oder eine C_1–3-Alkylgruppe darstellen,
wobei
R^a ein Wasserstoffatom, eine lineare oder verzweigte C_1–6-Alkyl-, C₃_₆-Alkenyl-, C₃_₆-Alkinyl- oder Cyclo-C_3–7-alkylgruppe, in der jedes Wasserstoffatom, sofern es sich nicht in α-Position zu einem Stickstoffatom befindet, durch Fluor ersetzt sein kann, bedeutet,
R^b ein Halogenatom, eine eine lineare oder verzweigte C_1–6-Alkyl-, C₂_₆-Alkenyl-, C₂_₆-Alkinyl-, Cyclo-C_3–7-alkyl-, Cyano-, Hydroxy-, Hydroxy-C_1–6-alkyl-, C_1–6-Alkoxy-, C_1–6-Alkoxy-C_1–6-alkyl-, Amino-, C_1–6-Alkyl-amino- oder Di-C_1–6-Alkyl-aminogruppe bedeutet, in der jedes Wasserstoffatom, sofern es sich nicht in α-Position zu einem Stickstoffatom befindet, durch Fluor ersetzt sein kann und die beiden Alkylgruppen der Di-C_1–6-Alkyl-amino-Substituenten unter Ausbildung eines 4- bis 8-gliedrigen Ringes miteinander verknüpft sein können,
eine Methylengruppe in α-Position zu einem durch die Gruppe R^a substituierten, gesättigten Stickstoffatom, einem Sauerstoff- oder Schwefelatom als Ringglied des Heterocyclus der Gruppe Q nicht durch Hydroxy-, C_1–6-Alkoxy-, Amino-, C_1–6-Alkylamino- oder Di-C_1–6-Alkyl-aminogruppe substituiert ist,
die Doppel- und Dreifachbindungen der in den für R^a, R^b, und R¹ vorstehend definierten Gruppen enthaltenen C₃_₆-Alkenyl- oder C_3–6-Alkinyl-gruppen von in diesen Gruppen gegebenenfalls ebenfalls enthaltenen Heteroatomen isoliert sind,
und, soweit nichts anderes erwähnt wurde, alle in den vorstehend definierten Resten erwähnten oder enthaltenen Alkyl-, Alkenyl- und Alkinylgruppen geradkettig oder verzweigt sein können, jede in den vorstehend definierten Resten enthaltene Methingruppe mit einem Fluoratom, jede Methylengruppe mit bis zu 2 Fluoratomen und jede Methylgruppe mit bis zu 3 Fluoratomen substituiert sein kann sowie zwei an ein Stickstoffatom gebundene Alkyl- und Alkenylgruppen unter Ausbildung eines 4-bis 7-gliedrigen, gesättigten oder ungesättigten heterocyclischen Ringes miteinander verbunden sein können,
alle in den vorstehend definierten Resten erwähnten oder enthaltenen aromatischen und heteroaromatischen Reste zusätzlich durch Halogen, durch Cyano- oder Hydroxygruppen mono-, di- oder trisubstituiert und die Substituenten gleich oder verschieden sein können und
unter den in den vor- und nachstehenden Definitionen genannten Schutzresten die aus der Peptidchemie geläufigen Schutzgruppen zur verstehen sind, insbesondere eine im Phenylkern gegebenenfalls durch ein Halogenatom, durch eine Nitro- oder Phenylgruppe, durch eine oder zwei Methoxygruppen substituierte Phenylalkoxycarbonylgruppe mit 1 bis 3 Kohlenstoffatomen im Alkoxyteil,
beispielsweise die Benzyloxycarbonyl-, 2-Nitro-benzyloxycarbonyl-, 4-Nitrobenzyloxycarbonyl-, 4-Methoxy-benzyloxycarbonyl-, 2-Chlor-benzyloxycarbonyl-, 3-Chlor-benzyloxycarbonyl-, 4-Chlor-benzyloxycarbonyl-, 4-Biphenylyl-α,α-dimethyl-benzyloxycarbonyl- oder 3,5-Dimethoxy-α,α-dimethyl-benzyloxycarbonylgruppe,
eine Alkoxycarbonylgruppe mit insgesamt 1 bis 5 Kohlenstoffatomen im Alkylteil,
beispielsweise die Methoxycarbonyl-, Ethoxycarbonyl-, n-Propoxycarbonyl-, Isopropoxycarbonyl-, n-Butoxycarbonyl-, 1-Methylpropoxycarbonyl-, 2-Methylpropoxy-carbonyl- oder tert.Butyloxycarbonylgruppe,
die Allyloxycarbonyl-, 2,2,2-Trichlor-(1,1-dimethylethoxy)carbonyl- oder 9-Fluorenylmethoxycarbonyl-Gruppe oder
die Formyl-, Acetyl- oder Trifluoracetylgruppe.In the above general formula (I), in a first embodiment
A is an oxygen or sulfur atom,
X is an oxygen or sulfur atom,
Q is a heterocycle bonded via a carbon or nitrogen atom and consisting of two or three, each 4- to 8-membered, independently saturated, partially unsaturated or completely unsaturated, condensed rings,
wherein the heterocycle has a total of one to five heteroatoms independently of one another selected from the group O, N and S,
may contain one or two carbonyl groups as ring members and
each saturated nitrogen atom as a ring member of the heterocycle may be substituted by the group R ^a and one or two carbon atoms as ring members of the heterocycle may be substituted by the group R ^b ,
R ^{1 represents} a saturated, mono- or diunsaturated, 5- to 7-membered aza-, diaza-, triaza-, oxaza-, thiaza-, thiadiaza- or S, S-dioxo-thiadiaza heterocycle,
wherein the above-mentioned heterocycles are linked via a carbon or nitrogen atom with the piperidine ring in formula I or
via two carbon atoms, via a carbon and a nitrogen atom, via a carbon and an oxygen atom, or via a carbon and a sulfur atom, are spirocyclically linked to the piperidine ring in formula I,
contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom,
at one of the nitrogen atoms by a C _1-6 alkyl, C ₃ _ ₆ alkenyl, or C _3-6 alkenyl group may be substituted,
at one or two carbon atoms by a C _1-6 alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl , Furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1- (C _1-3 -alkyl) -pyrazolyl, imidazolyl or 1- ( C _1-3 alkyl) -imidazolyl may be substituted, wherein the substituents may be the same or different, and
an olefinic double bond of one of the aforementioned unsaturated heterocycles with a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, NC _1-3 alkyl pyrrole - or quinoline ring, with a on the nitrogen atom is optionally substituted by a C _1-6 alkyl, C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkynyl group substituted 1H-quinolin-2-one ring or with an imidazole or NC _1-3 -alkyl-imidazole ring may be condensed or else two olefinic double bonds of one of the abovementioned unsaturated heterocycles may each be condensed with a phenyl or pyridine ring,
wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-C _1-3 contained in R ¹ Alkyl-pyrazolyl, imidazolyl or C ₁ -C 3 -alkyl-imidazolyl groups and benzo, thieno, pyrido and diazinocondensed heterocycles in the carbon skeleton additionally by halogen atoms, C _1-6 -alkyl-, C ₂ _ ₆ - alkenyl, C ₂ _ ₆ alkynyl, cyclo-C _3-7 -alkyl, cyclo-C _3-7 -alkenyl, cyano, hydroxy, hydroxy-C _1-6 alkyl-, hydroxy-C ₃ _ ₆ alkenyl, hydroxy-C ₃ _ ₆ alkynyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _{3- 6} alkenyl, C _1-6 alkoxy-C ₃ _ ₆ alkynyl, C ₃ _ ₆ -alkenoxy-C _1-6 alkyl, C _3-6 -alkenoxy-C _3-6 alkenyl, C _3-6 -alkenoxy-C _3-6 -alkynyl, C ₃ _ ₆ alkynoxy-C _1-6 alkyl, C _3-6 alkynoxy-C _3-6 alkenyl, C _3-6 - alkynoxy-C ₃ _ ₆ alkynyl, Thiohydroxy-, C _1-6 alkylthio, C ₃ _ ₆ -Alkenylthio-, C ₃ _ ₆ -Alkinylthio-, amino, C _1-6 alkyl-amino- , C alkenyl _amino-3 _ _6, C ₃ _ ₆ alkynyl amino, di- (C _1-6 alkyl) amino, di- (C ₃ _ ₆ alkenyl) amino, di - (C ₃ _ ₆ alkynyl) -amino, amino-C _1-6 alkyl, C _1-3 alkyl-amino-C _1-6 -alkyl, di- (C _1-3 alkyl) amino-C _1-6 alkyl, amino-C ₃ _ ₆ alkenyl, C alkenyl _1-3 alkyl-amino-C ₃ _ _6, di (C _1-3 alkyl) amino C ₃ _ ₆ alkenyl, amino-C ₃ _ ₆ alkynyl, C _1-3 -alkyl-amino-C ₃ _ ₆ alkynyl, di- (C _1-3 -alkyl) -amino-C ₃ _ ₆ alkynyl, hydroxycarbonyl, phenylcarbonyl, pyridylcarbonyl, C _1-6 alkyl-carbonyl, C ₂ _ ₆ -Alke nyl-carbonyl, C ₂ _ ₆ -Alkinylcarbonyl-, formyl, C _1-6 alkoxy-carbonyl, C ₃ _ ₆ -alkenoxy-carbonyl, C ₃ _ ₆ alkynoxy-carbonyl, aminocarbonyl, C _1-6 alkyl-aminocarbonyl, C ₃ _ ₆ alkenyl-aminocarbonyl, aminocarbonyl C ₃ _ ₆ alkynyl, di (C _1-6 alkyl) aminocarbonyl, di- (C ₃ _ ₆ alkenyl) -aminocarbonyl, di- (C ₃ _ ₆ alkynyl) -aminocarbonyl, formylamino, _C1-6 alkyl-carbonylamino, C ₂ _ ₆ -Alkenylcarbonylamino-, C ₂ _ ₆ alkynyl-carbonylamino -, formyl-C _1-6 -alkyl-amino, formyl-C ₃ _ ₆ -alkenyl-amino, formyl-C ₃ _ ₆ -alkynyl-amino, C _1-6 -alkyl-carbonyl-C _{1- 6} alkyl-amino, C ₂ _ ₆ alkenyl-carbonyl-C _1-6 -alkyl-amino, C ₂ _ ₆ alkynylcarbonyl-C _1-6 alkyl amino, C _1-6 alkyl carbonyl C _3-6 alkenylamino, C _2-6 alkenylcarbonyl C _3-6 alkenylamino, C _2-6 alkynylcarbonyl C _3-6 alkenylamino, C _{1 -6-} alkyl-carbonyl-C _3-6 -alkynyl-amino, C _2-6 -alkenyl-carbonyl-C _3-6 -alkynyl-amino, C ₂ _ ₆ -alkynyl-carbonyl-C ₃ _ ₆ - alkiny l-amino-, C _1-6 alkylsulphonyl, C ₂ _ ₆ alkenyl-sulfonyl, C ₂ _ ₆ alkynyl-sulfonyl, _C1-6 alkyl sulfinyl-, C _2-6 alkenyl sulfinyl, C _2-6 alkynylsulfinyl, C _1-6 alkylsulfonylamino, C _2-6 alkenylsulfonylamino, C _2-6 alkynylsulfonylamino, C _1-6 alkyl sulfonyl C _1-6 alkylamino, C _1-6 alkylsulfonyl C _3-6 alkenylamino, C _1-6 alkylsulfonyl C _3-6 alkynylamino, C _2-6 alkenyl -sulfonyl-C _1-6 -alkylamino, C _2-6 -alkenylsulfonyl-C _3-6 -alkenylamino, C _2-6 -alkenyl-sulfonyl-C _3-6 -alkynylamino, C _2-6 -alkynyl- sulfonyl C _1-6 alkylamino, C _2-6 alkynylsulfonyl C _3-6 alkenylamino, C _2-6 alkynylsulfonyl C _3-6 alkynylamino, aminosulfonyl, C _{1 6-} Alkylaminosulphonyl, di (C _1-6 alkyl) -aminosulphonyl, C _3-6 alkenylaminosulphonyl, di- (C _3-6 alkenyl) -aminosulphonyl, C _3-6 alkynylaminosulphonyl, di - (C _3-6 alkynyl) -aminosulfonyl groups mono-, di- or may be trisubstituted, wherein the substituent may be the same or different,
R ^{2 is} the hydrogen atom,
a phenylmethyl group or a C _2-7 -alkyl group which is in the ω-position by a cyclo-C _3-7 -alkyl, cyclo-C _3-7 -akenyl, phenyl, pyridinyl, diazinyl, hydroxy, Amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _3-6 alkenylamino, di (C _3-6 alkenyl) amino, C _3-6 Alkynylamino, di (C _3-6 alkynyl) amino, hydroxycarbonyl, C _1-6 alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, C _1-6 alkylcarbonylamino, C _2-6 alkenylcarbonylamino, C _2-6 alkynecarbonylamino, 4-morpholinyl, [bis (2-hydroxyethyl)] amino, 4- (C _1-6 alkyl) -1-piperazinyl or 4- (ω-hydroxy-C _{2 -7-} alkyl) -1-piperazinyl group may be substituted,
a phenyl or pyridinyl group,
in which the phenyl, pyridinyl and diazinyl groups mentioned in the groups defined above for R ² or as substituents are additionally represented in the carbon skeleton by halogen, by C _1-3 -alkyl, C ₂ _ ₃ -alkenyl, C ₂ _ ₃ - Alkynyl, C _1-3 alkoxy, hydroxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylaminoC _1-3 alkyl, di (C _1-3 alkyl) aminoC _1-3 alkyl, C _1-3 alkylcarbonylamino, C _1-3 Alkylcarbonylamino-C _1-3 -alkyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di (C _1-3 -alkyl) -aminocarbonyl, cyano, aminosulfonyl, C _1-3 -alkyl- aminosulfonyl, di (C _1-3 alkyl) aminosulfonyl, C _1-3 alkylthio, C _1-3 alkylsulfinyl, or C _1-3 alkylsulfonyl mono-, di- or trisubstituted and the substituents may be the same or different,
R ^{3 is} the hydrogen atom or a C _1-3 -alkyl group substituted by a phenyl or pyridinyl group,
wherein the C _1-3 alkyl group is bonded to an alkyl group contained in R ² or a phenyl or pyridyl ring contained in R ² , including the nitrogen atom to which R ² and R ^{3 are} bonded to form a 4-7 membered ring can be,
or
R ² and R ³ together with the enclosed nitrogen atom is a radical of the general formula

in the
Y ^{1 represents} the carbon atom or, if R ^{5 represents} a free electron pair, also the nitrogen atom,
q and r, when Y ^{1 represents} the carbon atom, the numbers 0, 1 or 2, or
q and r when Y ^{1 represents} the nitrogen atom, the numbers 1 or 2,
R ^{4 is} the hydrogen atom, an amino, C _1-4 alkylamino, di (C _1-4 alkyl) alkylamino, C _1-6 alkyl, cycloC _3-7 alkyl , Cyclo-C _3-7 -alkenyl, amino-C _2-7 -alkyl, C _1-4 -alkyl-amino-C _2-7 -alkyl-, di- (C _1-4 -amino) -C _2-7 alkyl, aminoiminomethyl, aminocarbonylamino, C _1-4 alkylaminocarbonylamino, di (C _1-4 alkyl) aminocarbonylamino, C _1-4 alkylaminocarbonylC _1-4 amino, di (C _1-4 alkyl) aminocarbonylC _1-4 amino, phenylaminocarbonylamino, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-4 alkyl ) -aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-4 -alkylaminocarbonyl-C _1-3 -alkyl, di- (C _1-4 -alkyl) -aminocarbonyl-C _1-3 - alkyl, aminocarbonylamino C _1-3 alkyl, C _1-6 alkoxycarbonyl, C ₃ _ ₆ -Alkenoxycarbonyl-, C ₃ _ ₆ -Alkinoxycarbonyl-, C _1-6 alkoxycarbonyl-C _1-3 alkyl C _1-6 alkenoxycarbonyl C _1-3 alkyl, C _1-6 alkynoxycarbonyl C _1-3 alkyl or hydroxycarbonyl C _1-3 alkyl group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group, each in the carbon skeleton by halogen, by C _1-3 alkyl, C ₂ _ ₃ alkenyl, C ₂ _ ₃ alkynyl, C _1-3 alkoxy, hydroxy, amino, C _1-4 Alkylamino, di (C _1-4 alkyl) amino, amino C _1-3 alkyl, C _1-4 alkylamino C _1-3 alkyl, di (C _{1 -4} alkyl) amino-C _1-3 alkyl, C _1-4 alkylcarbonylamino, C _1-4 alkylcarbonylamino-C ₁ _ ₃ alkyl, aminocarbonyl, C _1-4 -alkyl-aminocarbonyl , Di (C _1-4 alkyl) aminocarbonyl, cyano, aminosulfonyl, C _1-4 alkyl aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, C _1-4 -Alkyl-thio, C _1-4 -alkyl-sulfinyl-, or C _1-4 -alkylsulfonyl mono-, di- or trisubstituted and the substituents may be identical or different,
a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered oxaza-, thiaza- and diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl group,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
the abovementioned mono- and bicyclic heterocycles being bonded to Y ¹ in formula (II) via a nitrogen or a carbon atom,
in the abovementioned mono- and bicyclic heterocycles, a methine group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms and a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms, the abovementioned mono- and bicyclic heterocycles and the 1- (C _1-6 -alkyl) -4-piperidinylcarbonyl and 4- (C _1-6 -alkyl) -1-piperazinylcarbonyl group in the ring one to four times by C ₁ _ ₆ alkyl groups, or, optionally additionally, simple alkyl by a cyclo-C _3-7 -alkyl, cyclo-C _3-7 -alkenyl, cyclo-C _3-7 alkyl-C _1-3, phenyl C _1-3 alkyl, pyridyl C _1-3 alkyl, C _1-6 alkylcarbonyl, hydroxy, C _1-6 alkoxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, phenylcarbonyl, pyridinylcarbonyl, hydroxycarbonyl, hydroxycarbonylC _1-3 -alkyl, C _1-6 -alkoxycarbonyl, C _1-6 -alkoxycarbonyl-C _{1- 3-} alkyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-4 alkyl) aminocarbonyl or C _1-3 alkylsulfonyl group, by an optionally in the ring C _1-3 alkyl-substituted cyclo-C _3-7- alkyl-carbonyl, azacyclo-C _4-7 -alkyl-carbonyl, diazacyclo-C _5-7 -alkyl-carbonyl or oxazacyclo-C _5-7- alkyl-carbonyl group may be substituted, wherein the substituents may be the same or different and bonded to a ring carbon or ring nitrogen atom,
in which the phenyl and pyridinyl radicals contained in the radicals defined above for R ⁴ are in turn replaced by halogen atoms, by C _1-3 -alkyl, C ₂ _ ₃ -alkenyl, C ₂ _ ₃ -alkynyl, C _1-3 Alkoxy, hydroxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, amino C _1-3 alkyl, C _1-4 alkylamino C _1-3 -alkyl, di- (C _1-4 -alkyl) -amino-C _1-3 -alkyl, C _1-4 -alkylcarbonylamino, C _1-4 -alkylcarbonylamino-C _1-3 -alkyl- , Aminocarbonyl, C _1-3 -alkylaminocarbonyl, di-C _1-4 -alkylaminocarbonyl, cyano, aminosulfonyl, C _1-4 -alkyl-aminosulfonyl, di- (C _1-4 -alkyl) -amino-sulfonyl, C _1-3 -alkyl-thio, C _1-3 -alkyl-sulfinyl-, or C _1-3 -alkyl-sulfonyl-mono-, di- or trisubstituted, wherein the substituents are identical or different could be,
or also, when Y ^{1 represents} the carbon atom, the hydroxycarbonyl, aminomethyl, C _1-4 alkylaminomethyl or di (C _1-4 alkyl) aminomethyl group,
R ^{5 is} a hydrogen atom,
a C _1-4 alkyl radical, wherein an unbranched alkyl radical in the ω position by a phenyl, pyridinyl, diazinyl, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino , 4-C _1-4 -alkyl-1-piperazinyl or 4-morpholinyl group may be substituted,
a C _1-6 alkoxycarbonyl, cyano or aminocarbonyl group or also, when Y ^{1 represents} a nitrogen atom, a lone pair of electrons,
or, when Y ^{1 represents} the carbon atom, also the fluorine atom, or
R ⁴ together with R ⁵ and Y ¹ denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group is represented by a group -NH-, -N (C _1-4 -alkyl) -, -N (C _3-4 -) Alkenyl), -N (C _3-4 -alkynyl) -, -N (cyclo-C _3-7 -alkyl) - or -N (C _3-7 -cycloalkyl-C _1-3 -alkyl) - be replaced can
wherein a hydrogen atom bonded to a nitrogen atom in one of the groups defined above for R ⁴ may be replaced by a protecting group,
R ⁶ and R ⁷ , which may be the same or different, each represents a hydrogen atom, a C _1-4 alkyl group or, when Y ^{1 represents} a carbon atom, the fluorine atom, a C _1-4 alkylamino or di (C _1-4 alkyl) amino group, wherein the two C _1-4 alkyl groups may be connected together to form a ring and
R ⁸ and R ⁹ , which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group,
in which
R ^a is a hydrogen atom, a linear or branched C _1-6 alkyl, C ₃ _ ₆ alkenyl, C ₃ _ ₆ alkyl alkynyl or cyclo-C _3-7, in which each hydrogen atom, provided that it not in α-position to a nitrogen atom, may be replaced by fluorine, means
R ^b is a halogen atom, a linear or branched C _1-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, cyclo C _3-7 alkyl, cyano, hydroxy, HydroxyC _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, amino, C _1-6 alkylamino or diC _{1 -6-} Alkyl-amino group in which each hydrogen atom, unless it is in α-position to a nitrogen atom, may be replaced by fluorine and the two alkyl groups of the di-C _1-6 -alkyl-amino substituents with formation a 4- to 8-membered ring can be linked together,
a methylene group in α-position to a saturated nitrogen atom substituted by the group R ^a , an oxygen or sulfur atom as ring member of the heterocycle of the group Q not by hydroxy, C _1-6 alkoxy, amino, C _1-6 -Alkylamino or di-C _1-6 -alkylamino group is substituted,
^b, the double and triple bonds in the definitions of R ^a, R and R ¹ groups defined above contained C ₃ _ ₆ alkenyl or C _3-6 alkynyl groups in these groups may optionally also heteroatoms contained are isolated,
and, unless otherwise stated, all of the alkyl, alkenyl and alkynyl groups mentioned or included in the above defined radicals may be straight chain or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms and two alkyl and alkenyl groups bonded to a nitrogen atom may be linked together to form a 4 to 7 membered, saturated or unsaturated heterocyclic ring,
all in the above defined radicals mentioned or contained aromatic and heteroaromatic radicals additionally by halogen, by cyano or hydroxy groups mono-, di- or trisubstituted and the substituents may be the same or different and
the protective groups mentioned in the definitions above and below are to be understood as meaning the protective groups known from peptide chemistry, in particular a phenylalkoxycarbonyl group having 1 to 3 carbon atoms in the phenyl nucleus, optionally substituted by a halogen atom, by a nitro or phenyl group, by one or two methoxy groups alkoxy,
for example, the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-α , α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α, α-dimethyl-benzyloxycarbonyl group,
an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl part,
for example, the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert-butyloxycarbonyl group,
the allyloxycarbonyl, 2,2,2-trichloro (1,1-dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl group or
the formyl, acetyl or trifluoroacetyl group.

In the above and following definitions, among a group substituted in ω-position is a terminally substituted group,
under a halogen atom, a fluorine, chlorine, bromine or iodine atom and
under a double or triple bond isolated from a heteroatom to understand a double or triple bond which is linked via at least one saturated carbon atom to a heteroatom.

A second embodiment of the present invention consists in the compounds of the above general formula (I) in which
A, X, Q, R ² and R ³ as mentioned above under the first embodiment
are defined and
R ^{1 represents} a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza or thiaza heterocycle,
wherein the above-mentioned heterocycles are linked via a carbon or nitrogen atom, or
are linked spirocyclically via a carbon and a nitrogen atom, via a carbon and an oxygen atom or via a carbon and a sulfur atom,
contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted on a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1- (C _1-4 alkyl) pyrazolyl group and
wherein an olefinic double bond of one of the aforementioned unsaturated heterocycles is condensed with a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline ring or with an optionally substituted on the nitrogen atom by a methyl group substituted 1H-quinolin-2-one ring can be,
where the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1- (C _1-4 -alkyl) -pyrazolyl groups present in R ¹ and the benzoic , pyrido and diazinokondensierten heterocycles in the carbon skeleton additionally by halogen, by C _1-6 -alkyl, cyclo-C _3-7 -alkyl, cyclo-C _3-7 -alkenyl, C _1-6 alkoxy, cyano -, hydroxy, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkylcarbonylamino or C _1-4 alkylcarbonyl groups mono-, di- or trisubstituted can, where the substituents may be the same or different,
Unless otherwise stated, all of the alkyl, alkenyl and alkynyl groups mentioned or contained in the radicals defined above under R ¹ may be straight-chain or branched, any methine group having one fluorine atom contained in the above-defined radicals, each methylene group having up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms and two to a stick carbon-atom-bonded alkyl and alkenyl groups to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring may be joined together, and
all aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above under R ¹ may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxyl groups and the substituents may be identical or different,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A third embodiment of the present invention consists in the compounds of the above general formula (I) in which
A, X, Q, R ² and R ^{3 are defined} as mentioned above under the first embodiment, and
R ^{1 represents} a monounsaturated 5- to 7-membered diaza or triaza heterocycle,
wherein the above-mentioned heterocycles are linked via a nitrogen atom or
are spirocyclically linked via a carbon and a nitrogen atom or via a carbon and an oxygen atom,
contain a carbonyl group adjacent to a nitrogen atom,
in addition to a carbon atom may be substituted by a phenyl group and
wherein an olefinic double bond of one of the aforementioned unsaturated heterocycles may be condensed with a phenyl, thienyl or quinoline ring,
wherein the phenyl groups contained in R ¹ and benzo-fused heterocycles in the carbon skeleton additionally by halogen, by methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl, amino, acetylamino, acetyl, cyano-difluoromethoxy or trifluoromethoxy groups may be mono-, di- or trisubstituted, where the substituents may be identical or different, but preferably unsubstituted or denoted by a halogen atom, by a methyl or methoxy group are monosubstituted,
Unless otherwise stated, all of the alkyl groups mentioned or included in the radicals defined above under R ¹ may be straight-chain or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and any methyl group be substituted by up to 3 fluorine atoms,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A fourth embodiment of the present invention consists in the compounds of the above general formula (I) in which
A, X, Q, R ² and R ^{3 are defined} as mentioned above under the first embodiment, and
R ^{1 is} a 1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one-3-yl, 3,4-dihydro-1H-quinazolin-2-on-3-yl, 5-phenyl 2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-dihydroimidazo [4,5-c] quinolin-2-one-3-yl, 1 , 3-Dihydro-naphth [1,2-d] imidazol-2-one-3-yl, 1,3-dihydro-benzimidazol-2-one-3-yl, 4-phenyl-1,3-dihydro -imidazol-2-one-1-yl, 3,4-dihydro-1H-thieno [3,2-d] pyrimidin-2-one-3-yl or 3,4-dihydro-1H-thieno [3 , 4-d] pyrimidin-2-on-3-yl group or, together with the piperidine ring in formula (I), the 1 ', 2'-dihydro-2'-oxospiro-4H-3', 1-benzoxazine '4,4'-piperidin-1-yl group means
wherein the heterocycles mentioned above under R ¹ in the carbon skeleton may additionally be monosubstituted by a methoxy group,
all the aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above under R ¹ may additionally be mono-, di- or trisubstituted by halogen atoms, by cyano or hydroxyl groups and the substituents may be identical or different,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

• (i) die Gruppe Q insgesamt nicht mehr als fünf Heteroatome als Ringglieder enthält,
• (ii) die Gruppe Q insgesamt nicht mehr als zwei Carbonylgruppen als Ringglieder enthält und
• (iii) eine an ein gesättigtes Kohlenstoffatom in α-Position zu einem durch die Gruppe R^a substituierten, gesättigten Stickstoffatom, einem Sauerstoff- oder Schwefelatom als Ringglied eines bi- oder tricyclischen Heterocyclus der Gruppe Q gebundene Gruppe R^b nicht die Bedeutungen einer Hydroxy-, C_1–6-Alkoxy-, Amino-, C_1–6-Alkyl-amino- oder Di-C_1–6-Alkyl-aminogruppe annimmt,

deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren.A fifth embodiment of the present invention consists in the compounds of the above general formula (I) in which
A, X, R ¹ , R ² and R ^{3 are defined} as mentioned above under the first, second, third or fourth embodiment, and
Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom to the ring A, the rings A and B being selected independently of one another are made
a 4-membered, saturated or monounsaturated carbocycle in which a ring member may be replaced by a> NR ^a group, an oxygen or sulfur atom or, in the case of an unsaturated ring member, by a nitrogen atom,
a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members are independently of each other replaced by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a nitrogen atom can, wherein in each case two or three oxygen or sulfur atoms can not be directly linked, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three ring members independently of one another by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a In each case, two or three oxygen or sulfur atoms can not be directly linked to each other, and optionally in addition a fourth, unsaturated ring member may be replaced by a nitrogen atom, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two, three or four ring members are each independently represented by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, can be replaced by a nitrogen atom, wherein in each case two or three oxygen or sulfur atoms can not be directly linked together, or
an 8-membered, saturated, mono-, di-, tri- or tetra-unsaturated carbocycle in which one, two, three or four ring members independently of one another by a> NR ^a group, an oxygen or sulfur atom or, in the case unsaturated ring members, may be replaced by a nitrogen atom, wherein in each case two or three oxygen or sulfur atoms can not be directly linked to each other,
wherein at least one of the fused rings A and B contains at least one heteroatom as a ring member,
a methylene group as a ring member in the 4-membered rings A and B may each be independently replaced by a carbonyl group,
one or two methylene groups as ring members in the 5- to 8-membered rings A and B may each be independently replaced by carbonyl groups,
one or two carbon atoms may be substituted as ring members of rings A and B by R ^b , where the substituents may be the same or different,
two on adjacent carbon or nitrogen atoms or a carbon and an adjacent nitrogen atom as ring members of rings A or B-bonded hydrogen atoms may be replaced by a C ₃ _ ₆ n-alkylene and thus form a tricyclic compound, or
a hydrogen atom bonded to a carbon or nitrogen atom as the ring member of the ring A and another hydrogen atom bonded to a carbon or nitrogen atom as a ring member of the ring B, said ring members being separated by two bonds, by a C ₂ _ ₅ -n- Alkylene bridge can be replaced to form a tricycle,
wherein in the aforementioned C _3-6 n -alkylene bridges and C _2-5 n -alkylene bridges a methylene group may be replaced by a carbonyl group and / or one or two methylene groups independently with the proviso that two oxygen and two sulfur atoms are not directly linked to each other, in each case by a> NR ^a group, an oxygen or sulfur atom may be replaced or / and a carbon atom may be substituted by R ^b ,
R ^a is a hydrogen atom, a linear or branched C _1-6 alkyl, C ₃ _ ₆ alkenyl, C ₃ _ ₆ alkynyl or is cyclo-C _3-7 alkyl in which each hydrogen atom, provided that is not in the α-position to a nitrogen atom, may be replaced by fluorine,
R ^b is a halogen atom, a linear or branched C _1-6 alkyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, cyclo C _3-7 alkyl, cyano, hydroxy, HydroxyC _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, amino, C _1-6 alkylamino or diC _{1 -6-} Alkyl-amino group in which each hydrogen atom, unless it is in α-position to a nitrogen atom, may be replaced by fluorine and the two alkyl groups of the di-C _1-6 -alkyl-amino substituents with formation a 4- to 8-membered ring can be linked together,
with the stipulations that

• (i) the group Q contains a total of no more than five heteroatoms as ring members,
• (ii) the group Q contains a total of not more than two carbonyl groups as ring members, and
• (iii) a group R ^b bound to a saturated carbon atom in the α position relative to a saturated nitrogen atom substituted by the group R ^a , an oxygen or sulfur atom as ring member of a bi- or tricyclic heterocycle of the group Q does not have the meanings of a hydroxyl group. , C _1-6 alkoxy, amino, C _1-6 alkylamino or diC _1-6 alkylamino group,

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids.

• (i) die Gruppe Q insgesamt nicht mehr als drei Heteroatome als Ringglieder enthält,
• (ii) die Gruppe Q insgesamt nicht mehr als zwei Carbonylgruppen als Ringglieder enthält und
• (iii) eine an ein gesättigtes Kohlenstoffatom in α-Position zu einem durch die Gruppe R^a substituierten, gesättigten Stickstoffatom, einem Sauerstoff- oder Schwefelatom als Ringglied eines bi- oder tricyclischen Heterocyclus der Gruppe Q gebundene Gruppe R^b nicht die Bedeutungen einer Hydroxy-, C_1–3-Alkoxy-, Amino-, C_1–3-Alkyl-amino- oder Di-C_1–3-Alkyl-aminogruppe annimmt,

deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren.A sixth embodiment of the present invention is the compounds of the above general formula (I) in which
A, X, R ¹ , R ² and R ^{3 are defined} as mentioned above under the first, second, third fourth or fifth embodiment, and
Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom to the ring A, the rings A and B being selected independently of one another are made
a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members are independently of each other replaced by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a nitrogen atom can, wherein a maximum of two ring members represent oxygen or sulfur atoms and they can not be directly linked, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three ring members independently of one another by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a Nitrogen atom can be replaced, wherein a maximum of two ring members represent oxygen or sulfur atoms and these can not be directly linked together, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three ring members are each independently represented by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by Nitrogen atom can be replaced, wherein a maximum of two ring members represent oxygen or sulfur atoms and these can not be directly linked together, or
wherein at least one of the fused rings A and B contains at least one heteroatom as a ring member,
one or two methylene groups as ring members in the 5- to 7-membered rings A and B may each be independently replaced by carbonyl groups,
one or two carbon atoms may be substituted as ring members of rings A and B by R ^b , where the substituents may be the same or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or a carbon and an adjacent nitrogen atom as ring members of rings A or B may be replaced by a C ₃ _ ₅ -n-alkylene bridge to form a tricycle, or US Pat
a hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring A and another hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring B, said ring members being separated from each other by two bonds, represented by a C _2-4 -n- Alkylene bridge can be replaced to form a tricycle,
wherein in the aforementioned C _3-5 -n -alkylene bridges and C _2-4 -n-alkylene bridges, one or two methylene groups independently, provided that two oxygen atoms are not directly linked, each through a> NR ^a group or one may be replaced by an oxygen atom and / or a carbon atom may be substituted by R ^b ,
R ^a is a hydrogen atom, a linear or branched C _1-3 alkyl, C ₃ alkenyl, C ₃ alkynyl or cyclo C ₃ _ ₆ alkyl group means, in which each hydrogen atom, unless it is in α Position to a nitrogen atom, may be replaced by fluorine,
R ^b is a halogen atom, a linear or branched C _1-3 alkyl, C ₂ _ ₃ alkenyl, C ₂ _ ₃ alkynyl, cyclo-C ₃ _ ₆ alkyl, cyano, hydroxy, HydroxyC _1-3 -alkyl, C _1-3 -alkoxy, C _1-3 -alkoxy-C _1-3 -alkyl, amino, C _1-3 -alkylamino or di-C _{1 3} alkyl-amino group in which each hydrogen atom, unless it is in α-position to a nitrogen atom, may be replaced by fluorine and the two alkyl groups of the di-C _1-3 alkyl-amino substituents with formation a 5- to 7-membered ring may be linked together,
with the stipulations that

• (i) the group Q contains in total not more than three heteroatoms as ring members,
• (ii) the group Q contains a total of not more than two carbonyl groups as ring members, and
• (iii) a group R ^b bound to a saturated carbon atom in the α position relative to a saturated nitrogen atom substituted by the group R ^a , an oxygen or sulfur atom as ring member of a bi- or tricyclic heterocycle of the group Q does not have the meanings of a hydroxyl group. , C _1-3 alkoxy, amino, C _1-3 alkylamino or diC _1-3 alkylamino group,

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids.

• (i) die Gruppe Q insgesamt nicht mehr als drei Heteroatome als Ringglieder enthält,
• (ii) die Gruppe Q insgesamt nicht mehr als zwei Carbonylgruppen als Ringglieder enthält und

deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren.A seventh embodiment of the present invention consists in the compounds of the above general formula (I) in which
A, X, R ¹ , R ² and R ³ as above under the first, second, third fourth or fifth embodiment he mentions are defined and
Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom with the ring A, wherein the rings A and B with the proviso in that A is a 5- or 6-membered ring and B is a 6- or 7-membered ring selected from
a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members are independently of each other replaced by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a nitrogen atom can represent, wherein a maximum of two ring members oxygen atom, which can not be directly linked together, represent and a maximum of one ring member is a sulfur atom, or
a 6-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three ring members independently of one another by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a Nitrogen atom can be replaced, wherein a maximum of two ring members oxygen atom, which can not be directly linked to each other, represent and a maximum of one ring member is a sulfur atom, or
a 7-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three ring members are each independently represented by a> NR ^a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by Nitrogen atom can be replaced, wherein a maximum of two ring members represent oxygen or sulfur atoms and these can not be directly linked together, or
wherein at least one of the fused rings A and B contains at least one heteroatom as a ring member,
one or two methylene groups as ring members in the 5- to 7-membered rings A and B may each be independently replaced by carbonyl groups,
one or two carbon atoms may be substituted as ring members of rings A and B by R ^b , where the substituents may be the same or different,
two hydrogen atoms bound to adjacent carbon or nitrogen atoms or a carbon and an adjacent nitrogen atom as ring members of rings A or B may be replaced by a C _3-4 -n-alkylene bridge to form a tricycle, or
a hydrogen atom bound to a carbon or nitrogen atom as the ring member of ring A and another hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring B, said ring members being separated by two bonds, by a C ₂ _ ₃ -n- Alkylene bridge can be replaced to form a tricycle,
wherein in the aforementioned C _3-4 -n-alkylene bridges and C _2-3 -n-alkylene bridges one or two methylene groups may independently of one another be substituted by R ^b ,
R ^{a represents} a hydrogen atom or a linear or branched C _1-3 alkyl group in which each hydrogen atom may be replaced by fluorine, if it is not in the α-position to a nitrogen atom,
R ^{b represents} a halogen atom or a linear or branched C _1-3 alkyl group in which each hydrogen atom may be replaced by fluorine, if it is not in the α-position to a nitrogen atom,
with the stipulations that

• (i) the group Q contains in total not more than three heteroatoms as ring members,
• (ii) the group Q contains a total of not more than two carbonyl groups as ring members, and

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids.

in der
Y¹ das Kohlenstoffatom oder, wenn R⁵ ein freies Elektronenpaar darstellt, auch das Stickstoffatom,
q und r, wenn Y¹ das Kohlenstoffatom darstellt, die Zahlen 0 oder 1 oder
q und r, wenn Y¹ das Stickstoffatom darstellt, die Zahlen 1 oder 2,
R⁴ das Wasserstoffatom, eine Amino-, C_1–4-Alkyl-amino-, Di-(C_1–4-Alkyl)-alkylamino-, C_1–6-Alkyl-, Cyclo-C_3–7-alkyl-, Cyclo-C_3–7-alkenyl-, Amino-C_2–7-alkyl-, C_1–4-Alkyl-amino-C_2–7-alkyl-, Di-(C_1–4-Amino)-C_2–7-alkyl-, C_1–4-Alkyl-aminocarbonyl-, Di-(C_1–4-Alkyl)-aminocarbonyl-, Aminocarbonyl-C_1–3-alkyl-, C_1–4-Alkyl-aminocarbonyl-C_1–3-alkyl-, Di-(C_1–4-Alkyl)-aminocarbonyl-C_1–3-alkyl-, Aminocarbonylamino-C_1–3-alkyl-, C_1–6-Alkoxycarbonyl-, C_1–6-Alkoxycarbonyl-C_1–3-alkyl- oder Hydroxycarbonyl-C_1–3-alkylgruppe,
eine Phenyl-, Pyridinyl- oder Diazinylgruppe, die jeweils durch ein Halogen, durch eine C_1–3-Alkyl-, C_1–3-Alkoxy-, Hydroxy-, Amino-, C_1–4-Alkyl-amino-, Di-(C_1–4-Alkyl)-amino- Amino-C_1–3-alkyl-, C_1–4-Alkyl-amino-C_1–3-alkyl-, Di-(C_1–4-Alkyl)-amino-C_1–3-alkyl-gruppe substituiert sein können,
ein Heterocyclus ausgewählt aus einer 4- bis 7-gliedrigen Azacycloalkylgruppe, einer 6- bis 7-gliedrigen Oxaza- oder Diazacycloalkylgruppe und einer 7- bis 9-gliedrigen Azabicycloalkylgruppe,
wobei die vorstehend genannten mono- und bicyclischen Heterocyclen über ein Stickstoff- oder ein Kohlenstoffatom an Y¹ in Formel (II) gebunden sind,
in den vorstehend genannten mono- und bicyclischen Heterocyclen eine nicht direkt mit einem Stickstoff-, Sauerstoff- oder Schwefelatom verknüpfte Methylengruppe durch ein oder zwei Fluoratome substituiert sein kann und
die vorstehend genannten mono- und bicyclischen Heterocyclen ein- oder mehrfach, beispielsweise ein- bis dreifach, durch C_1–3-Alkylgruppen oder eifach durch eine Benzyl-, Cyclo-C₃_₆-alkyl-, Cyclo-C₃_₆-alkyl-C_1–3-alkyl, C_1–4-Alkylcarbonyl-, Hydroxy-, C_1–4-Alkoxy-, Amino-, C_1–4-Alkylamino-, Di-(C_1–4-Alkyl)-amino-, Hydroxycarbonyl-, C_1–3-Alkoxycarbonyl-, Hydroxycarbonyl-C_1–3-alkyl-, C_1–3-Alkoxycarbonyl-C_1–3-alkyl- oder C_1–3-Alkylsulfonyl-gruppen substituiert sein können,
oder auch, wenn Y¹ das Kohlenstoffatom darstellt, die Hydroxycarbonyl-, Aminomethyl-, C_1–4-Alkyl-aminomethyl- oder Di-(C_1–4-Alkyl)-aminomethylgruppe,
R⁵ ein Wasserstoffatom, einen C_1–3-Alkylrest oder, wenn Y¹ ein Stickstoffatom darstellt, auch ein freies Elektronenpaar,
R⁶ und R⁷, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom, eine C_1–3-Alkylgruppe oder auch, wenn Y¹ ein Kohlenstoffatom darstellt, eine C_1–3-Alkylamino- oder Di-(C_1–3-Alkyl)-aminogruppe, wobei die beiden C_1–3-Alkylgruppen unter Ausbildung eines Ringes miteinander verbunden sein können und
R⁸ und R⁹, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom oder eine C_1–3-Alkylgruppe darstellen,
bedeuten,
wobei, soweit nichts anderes erwähnt wurde, alle in den vorstehend definierten Resten erwähnten oder enthaltenen Alkyl-, Alkenyl- und Alkinylgruppen geradkettig oder verzweigt sein können, jede in den vorstehend definierten Resten enthaltene Methingruppe mit einem Fluoratom, jede Methylengruppe mit bis zu 2 Fluoratomen und jede Methylgruppe mit bis zu 3 Fluoratomen substituiert sein kann sowie zwei an ein Stickstoffatom gebundene Alkyl- und Alkenylgruppen unter Ausbildung eines 4-bis 7-gliedrigen, gesättigten oder ungesättigten heterocyclischen Ringes miteinander verbunden sein können,
alle in den vorstehend definierten Resten erwähnten oder enthaltenen aromatischen und heteroaromatischen Reste zusätzlich durch Halogen, durch Cyano- oder Hydroxygruppen mono-, di- oder trisubstituiert und die Substituenten gleich oder verschieden sein können,
deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen.An eighth embodiment of the present invention is the compounds of the above general formula (I) in which
A, X, Q and R ^{1 are defined} as mentioned above under the first, second, third, fourth, fifth, sixth or seventh embodiment, and
R ^{2 is} the hydrogen atom or
a phenylmethyl group or a C _2-7 -alkyl group which is in the ω-position by a cyclo-C _3-7 -alkyl, cyclo-C _3-7 -alkenyl, phenyl, pyridinyl, hydroxy, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, hydroxycarbonyl, C _1-6 alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, C _1-6 alkylamino, 4-morpholinyl group can be substituted,
wherein the phenyl and pyridinyl radicals mentioned in the groups defined above for R ² or as substituents are additionally substituted in the carbon skeleton by halogen, by C _1-3 -alkyl, C _1-3 -alkoxy, hydroxy, amino, C _{1 3-} alkylamino, di (C _1-3 alkyl) amino, aminoC _1-3 alkyl, C _1-3 alkylaminoC _1-3 alkyl, di (C _{1 3-} alkyl) -amino-C _1-3 -alkyl, C _1-3 -alkylcarbonylamino, C _1-3 -alkylcarbonyl-C _1-3 -alkylamino, aminocarbonyl, C _1-3 -alkylaminocarbonyl or Di- (C _1-3 alkyl) -aminocarbonyl groups mono-, di- or trisubstituted and the substituent ducks may be the same or different,
R ^{3 represents} the hydrogen atom or a C _1-3 alkyl group or
R ² and R ³ together with the enclosed nitrogen atom is a radical of the general formula

in the
Y ^{1 represents} the carbon atom or, if R ^{5 represents} a free electron pair, also the nitrogen atom,
q and r, when Y ^{1 represents} the carbon atom, the numbers 0 or 1 or
q and r when Y ^{1 represents} the nitrogen atom, the numbers 1 or 2,
R ^{4 is} the hydrogen atom, an amino, C _1-4 alkylamino, di (C _1-4 alkyl) alkylamino, C _1-6 alkyl, cycloC _3-7 alkyl , Cyclo-C _3-7 -alkenyl, amino-C _2-7 -alkyl, C _1-4 -alkyl-amino-C _2-7 -alkyl-, di- (C _1-4 -amino) -C _2-7 alkyl, C _1-4 alkyl aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, aminocarbonyl C _1-3 alkyl, C _1-4 alkyl aminocarbonyl C _1-3 alkyl, di (C _1-4 alkyl) aminocarbonyl C _1-3 alkyl, aminocarbonylamino C _1-3 alkyl, C _1-6 alkoxycarbonyl, C _{1- 6-} alkoxycarbonyl-C _1-3 -alkyl or hydroxycarbonyl-C _1-3 -alkyl group,
a phenyl, pyridinyl or diazinyl group, each represented by a halogen, by a C _1-3 alkyl, C _1-3 alkoxy, hydroxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) aminoaminoC _1-3 alkyl, C _1-4 alkylaminoC _1-3 alkyl, di (C _1-4 alkyl) amino-C _1-3 -alkyl group may be substituted,
a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to 7-membered oxaza- or diazacycloalkyl group and a 7- to 9-membered azabicycloalkyl group,
the abovementioned mono- and bicyclic heterocycles being bonded to Y ¹ in formula (II) via a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles, a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms, and
switch the above-mentioned mono- and bicyclic heterocycles or polysubstituted, for example mono- to trisubstituted, by C _1-3 alkyl groups or alkyl eifach by a benzyl, cyclo-C ₃ _ _6, cyclo-C ₃ _ ₆ - alkyl-C _1-3 alkyl, C _1-4 alkylcarbonyl, hydroxy, C _1-4 alkoxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) - amino, hydroxycarbonyl, C _1-3 alkoxycarbonyl, hydroxycarbonylC _1-3 alkyl, C _1-3 alkoxycarbonylC _1-3 alkyl or C _1-3 alkylsulfonyl groups .
or also, when Y ^{1 represents} the carbon atom, the hydroxycarbonyl, aminomethyl, C _1-4 alkylaminomethyl or di (C _1-4 alkyl) aminomethyl group,
R ^{5 is} a hydrogen atom, a C _1-3 -alkyl radical or, if Y ^{1 represents} a nitrogen atom, also a free electron pair,
R ⁶ and R ⁷ , which may be the same or different, each represents a hydrogen atom, a C _1-3 alkyl group or also, when Y ^{1 represents} a carbon atom, a C _1-3 alkylamino or di (C _1-3 -Alkyl) -amino group, wherein the two C _1-3 alkyl groups may be connected together to form a ring and
R ⁸ and R ⁹ , which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group,
mean,
Unless otherwise stated, all of the alkyl, alkenyl and alkynyl groups mentioned or included in the above-defined radicals may be straight or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms and two alkyl and alkenyl groups bonded to a nitrogen atom may be linked together to form a 4 to 7 membered, saturated or unsaturated heterocyclic ring,
all the aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxyl groups and the substituents may be identical or different,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

in der
Y¹ das Kohlenstoffatom oder, wenn R⁵ ein freies Elektronenpaar darstellt, auch das Stickstoffatom,
q und r, wenn Y¹ das Kohlenstoffatom darstellt, die Zahlen 0 oder 1 oder
q und r, wenn Y¹ das Stickstoffatom darstellt, die Zahlen 1 oder 2,
R⁴ das Wasserstoffatom, eine Amino-, C_1–4-Alkyl-amino-, Di-(C_1–4-Alkyl)-alkylamino-, C_1–6-Alkyl-, Cyclo-C_3–7-alkyl-, Cyclo-C_3–7-alkenyl-, Amino-C_2–7-alkyl-, C_1–4-Alkyl-amino-C_2–7-alkyl-, Di-(C_1–4-Amino)-C_2–7-alkyl-, C_1–6-Alkoxycarbonyl-, C_1–6-Alkoxycarbonyl-C_1–3-alkyl- oder Hydroxycarbonyl-C_1–3-alkylgruppe,
eine Phenyl- oder Pyridylgruppe, die jeweils durch ein Halogen, durch eine C_1–3-Alkyl-, C_1–3-Alkoxy-, Amino-, C_1–4-Alkyl-amino-, Di-(C_1–4-Alkyl)-amino-gruppe substituiert sein kann,
ein Heterocyclus ausgewählt aus einer 6- bis 7-gliedrige Azacycloalkylgruppe, einer 6- bis 7-gliedrige Diazacycloalkylgruppe und einer 7- bis 9-gliedrige Azabicycloalkylgruppe,
wobei die vorstehend genannten mono- und bicyclischen Heterocyclen über ein Stickstoff- oder ein Kohlenstoffatom an Y¹ in Formel (II) gebunden sind,
in den vorstehend genannten mono- und bicyclischen Heterocyclen eine nicht direkt mit einem Stickstoff-, Sauerstoff- oder Schwefelatom verknüpfte Methylengruppe durch ein oder zwei Fluoratome substituiert sein kann und
die vorstehend genannten mono- und bicyclischen Heterocyclen ein- oder mehrfach durch eine C_1–3-Alkylgruppe, durch eine Benzyl-, Cyclo-C₃_₆-alkyl-, Cyclo-C₃_₆-alkyl-C_1–3-alkyl, Amino-, C_1–4-Alkylamino- oder Di-(C_1–4-Alkyl)-amino-gruppen substituiert sein können,
oder auch, wenn Y¹ das Kohlenstoffatom darstellt die Hydroxycarbonyl-, Aminomethyl-, C_1–4-Alkyl-aminomethyl- oder Di-(C_1–4-Alkyl)-aminomethylgruppe,
R⁵ ein Wasserstoffatom oder, wenn Y¹ ein Stickstoffatom darstellt, auch ein freies Elektronenpaar,
R⁶ und R⁷, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom, eine C_1–3-Alkylgruppe oder auch, wenn Y¹ ein Kohlenstoffatom darstellt, eine C_1–3-Alkylamino- oder Di-(C_1–3-Alkyl)-aminogruppe, wobei die beiden C_1–3-Alkylgruppen unter Ausbildung eines Ringes miteinander verbunden sein können und
R⁸ und R⁹, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom oder eine C_1–3-Alkylgruppe darstellen,
bedeuten, deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen.A ninth embodiment of the present invention consists in the compounds of the above all common formula (I) in which
A, X, Q and R ^{1 are defined} as mentioned above under the first, second, third, fourth, fifth, sixth or seventh embodiment, and
R ^{2 is} the hydrogen atom or
a phenylmethyl group or a C _2-7 -alkyl group which may be substituted in the ω-position by a phenyl, amino, C _1-6 -alkylamino, di (C _1-6 -alkyl) -amino group,
in which the above-mentioned phenyl and phenylmethyl group are additionally bonded to an aromatic carbon atom by halogen, C _1-3 -alkyl, C _1-3 -alkoxy, aminoC _1-3 -alkyl, C _1-3 -alkylamino Mono- or disubstituted C _1-3 -alkyl or di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl groups and the substituents may be identical or different,
R ^{3 represents} the hydrogen atom or a C _1-3 alkyl group or
R ² and R ³ together with the enclosed nitrogen atom is a radical of the general formula

in the
Y ^{1 represents} the carbon atom or, if R ^{5 represents} a free electron pair, also the nitrogen atom,
q and r, when Y ^{1 represents} the carbon atom, the numbers 0 or 1 or
q and r when Y ^{1 represents} the nitrogen atom, the numbers 1 or 2,
R ^{4 is} the hydrogen atom, an amino, C _1-4 alkylamino, di (C _1-4 alkyl) alkylamino, C _1-6 alkyl, cycloC _3-7 alkyl , Cyclo-C _3-7 -alkenyl, amino-C _2-7 -alkyl, C _1-4 -alkyl-amino-C _2-7 -alkyl-, di- (C _1-4 -amino) -C _2-7- alkyl, C _1-6 -alkoxycarbonyl, C _1-6 -alkoxycarbonyl-C _1-3 -alkyl or hydroxycarbonyl-C _1-3 -alkyl group,
a phenyl or pyridyl group each represented by a halogen, by a C _1-3 alkyl, C _1-3 alkoxy, amino, C _1-4 alkylamino, di (C _1-4 Alkyl) amino group may be substituted,
a heterocycle selected from a 6- to 7-membered azacycloalkyl group, a 6- to 7-membered diazacycloalkyl group and a 7- to 9-membered azabicycloalkyl group,
the abovementioned mono- and bicyclic heterocycles being bonded to Y ¹ in formula (II) via a nitrogen or a carbon atom,
in the above-mentioned mono- and bicyclic heterocycles, a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms, and
switch the above-mentioned mono- and bicyclic heterocycles or polysubstituted by a C _1-3 alkyl group, alkyl- by a benzyl, cyclo-C ₃ _ _6, cyclo-C ₃ _ ₆ alkyl-C _1-3 - alkyl, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino groups may be substituted,
or also, when Y ^{1 represents} the carbon atom, the hydroxycarbonyl, aminomethyl, C _1-4 alkylaminomethyl or di (C _1-4 alkyl) aminomethyl group,
R ^{5 is} a hydrogen atom or, if Y ^{1 represents} a nitrogen atom, also a lone pair of electrons,
R ⁶ and R ⁷ , which may be the same or different, each represents a hydrogen atom, a C _1-3 alkyl group or also, when Y ^{1 represents} a carbon atom, a C _1-3 alkylamino or di (C _1-3 -Alkyl) -amino group, wherein the two C _1-3 alkyl groups may be connected together to form a ring and
R ⁸ and R ⁹ , which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

in der
R⁶ und R⁷ jeweils ein Wasserstoffatom oder eine Dimethylaminogruppe,
R⁸ und R⁹ jeweils das Wasserstoffatom und

• (a) Y¹ das Kohlenstoffatom, q und r die Zahlen 0 oder 1, R⁴ das Wasserstoffatom, eine Phenyl-, Pyridinyl- oder Pyrimidinylgruppe, die jeweils durch ein Halogen, durch eine Amino-, Methylamino-, Dimethylamino-, Methyl- oder Methoxygruppe substituiert sein kann, eine Hydroxy-, 2-Diethylamino-ethyl-, Amino-, Methylamino-, Dimethylamino-, Diethylamino-, Pyrrolidin-1-yl-, Piperidin-1-yl-, 4-Amino-piperidin-1-yl-, 4-Methylamino-piperidin-1-yl-, 4-Dimethylaminopiperidin-1-yl-, 3-Amino-piperidin-1-yl-, 3-Methylamino-piperidin-1-yl-, 3-Dimethylamino-piperidin-1-yl-, Perhydro-azepin-1-yl-, Perhydro-1,4-diazepin-1-yl-, 4-Methyl-perhydro-1,4-diazepin-1-yl-, 1-Methyl-piperidin-4-yl-, Piperidin-4-yl-, 1-Ethylpiperidin-4-yl-, 1-Cyclopropyl-piperidin-4-yl-, 1-Cyclopropylmethyl-piperidin-4-yl-, Piperazin-1-yl-, 4-Methyl-piperazin- 1-yl-, 4-Cyclopropylmethyl-piperazin-1-yl-, 4-Ethyl-piperazin-1-yl-, 4-Cyclopropyl-piperazin-1-yl-, 1,2-Dimethyl-piperazin-1-yl-, 3-Methylpiperazin-1-yl-, 3,4,5-Trimethyl-piperazin-1-yl-, 3,5-Dimethyl-piperazin-1-yl-, 3,3,4-Trimethyl-piperazin-1-yl-, 3,3-Dimethyl-piperazin-1-yl-, 3,3,4,5,5-Pentamethyl-piperazin-1-yl-, 3,3,5,5-Tetramethyl-piperazin-1-yl-, Morpholin-4-yl-, 4,4-Difluor-piperidin-1-yl-, 8-Methyl-8-azabicyclo[3.2.1]oct-3-yl-, 8-Aza-bicyclo[3.2.1]oct-3-yl-, Azetidin-1-yl-, 1-(Methoxycarbonylmethyl)-piperidin-4-yl-, 1-(Ethoxycarbonylmethyl)-piperidin-4-yl-, 4-(Ethoxycarbonylmethyl)-piperazin-1-yl-, 1-Hydroxycarbonylmethyl-piperidin-4-yl- oder 4-Hydroxycarbonylmethyl-piperazin-1-yl-gruppe, und R⁵ ein Wasserstoffatom, oder
• (b) Y¹ ein Stickstoffatom, q und r die Zahlen 1 oder 2, R⁴ das Wasserstoffatom, eine Phenyl-, Pyridinyl- oder Pyrimidinylgruppe, die jeweils durch ein Halogen, durch eine Amino-, Methylamino-, Dimethylamino-, Methyl- oder Methoxygruppe substituiert sein kann, eine Methyl-, Ethyl-, Isopropyl-, Cyclopropyl-, Cyclopropylmethyl-, 2-Diethylamino-propyl-, 1-Chinuclidin-3-yl-, 1-Piperidin-4-yl-, 1-Methylpiperidin-4-yl-, 1-Ethyl-piperidin-4-yl-, 1-Cyclopropyl-piperidin-4-yl-, 1-Cyclopropylmethyl-piperidin-4-yl-, 1-Hydroxycarbonylmethyl-piperidin-4-yl- oder 1-Ethoxycarbonylmethyl-piperidin-4-yl-gruppe und R⁵ ein freies Elektronenpaar darstellen,

bedeuten, deren Tautomere, deren Diastereomere, deren Enantiomere, deren Hydrate, deren Gemische und deren Salze sowie die Hydrate der Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen.A tenth embodiment of the present invention is the compounds of the above general formula (I) in which
A, X, Q and R ^{1 are defined} as mentioned above under the first, second, third, fourth, fifth, sixth or seventh embodiment, and
R ^{2 is} a phenylmethyl group or a C _2-7 alkyl group which may be substituted in the ω position by a phenyl, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino group can
wherein the above-mentioned phenyl and phenylmethyl group on an aromatic carbon atom are represented by an aminoC _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl or di- (C _1-3 -alkyl) - amino-C _1-3 -alkyl group substitu can be
R ^{3 is} the hydrogen atom or a C _1-3 alkyl group or
R ² and R ³ together with the enclosed nitrogen atom is a radical of the general formula

in the
R ⁶ and R ⁷ each represent a hydrogen atom or a dimethylamino group,
R ⁸ and R ⁹ each represent the hydrogen atom and

• (a) Y ^{1 is} the carbon atom, q and r are the numbers 0 or 1, R ^{4 is} the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group, each represented by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group may be substituted, a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1 -yl, 4-methylamino-piperidin-1-yl, 4-dimethylaminopiperidin-1-yl, 3-amino-piperidin-1-yl, 3-methylamino-piperidin-1-yl, 3-dimethylamino piperidin-1-yl, perhydro-azepin-1-yl, perhydro-1,4-diazepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl piperidin-4-yl, piperidin-4-yl, 1-ethylpiperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropylmethyl-piperidin-4-yl, piperazin-1-yl 4-methylpiperazin-1-yl, 4-cyclopropylmethylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, 1,2- Dimethyl-piperazin-1-yl, 3-methylpiperazin-1-yl, 3,4,5-trimethyl-p iperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 3,3,4-trimethyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yl, 3, 3,4,5,5-pentamethylpiperazin-1-yl, 3,3,5,5-tetramethylpiperazin-1-yl, morpholin-4-yl, 4,4-difluoropiperidine-1 -yl, 8-methyl-8-azabicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-3-yl, azetidin-1-yl, 1- ( Methoxycarbonylmethyl) -piperidin-4-yl, 1- (ethoxycarbonylmethyl) -piperidin-4-yl, 4- (ethoxycarbonylmethyl) -piperazin-1-yl, 1-hydroxycarbonylmethyl-piperidin-4-yl or 4-hydroxycarbonylmethyl -piperazin-1-yl group, and R ^{5 is} a hydrogen atom, or
• (b) Y ^{1 is} a nitrogen atom, q and r are the numbers 1 or 2, R ^{4 is} the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group, each represented by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group, a methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, 2-diethylamino-propyl, 1-quinuclidin-3-yl, 1-piperidin-4-yl, 1-methylpiperidine 4-yl, 1-ethyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-piperidin-4-yl or 1-ethoxycarbonylmethyl-piperidin-4-yl group and R ^{5 represent} a lone pair of electrons,

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

Further preferred embodiments of the present invention consist in the compounds of the above general formula (I), in which
Q, R ¹ , R ² and R ^{3 are defined} as mentioned above under the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments, and
A and X each represent an oxygen atom,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

An eleventh embodiment of the present invention consists in the compounds of the above general my formula (I) in which
A and X each represent an oxygen atom,
R ^{1 is} a 1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one-3-yl, 3,4-dihydro-1H-quinazolin-2-on-3-yl, 5-phenyl -2,4-dihydro-1,2,4-triazol-3-one-2-yl, 1,3-dihydroimidazo [4,5-c] quinolin-2-one-3-yl, 1,3-Dihydro-naphth [1,2-d] imidazol-2-one-3-yl, 1,3-dihydro-benzimidazol-2-one-3-yl, 4-phenyl-1,3- dihydroimidazol-2-one-1-yl, 3,4-dihydro-1H-thieno [3,2-d] pyrimidin-2-one-3-yl or 3,4-dihydro-1H-thieno [ 3,4-d] pyrimidin-2-on-3-yl group or together with the piperidine ring in formula (I) the 1 ', 2'-dihydro-2'-oxospiro-4H-3', 1-benzoxazine '-4,4'-piperidin-1-yl group means
and R ² and R ^{3 are defined} as mentioned above under the first embodiment,
wherein the heterocycles mentioned above under R ¹ in the carbon skeleton may additionally be monosubstituted by a methoxy group,
and wherein all of the aromatic and heteroaromatic radicals and moieties mentioned or contained in the radicals defined under R ¹ may additionally be mono-, di- or tri-substituted by halogen atoms, by cyano or hydroxyl groups and the substituents may be identical or different,
and wherein in this and all the above embodiments respectively the compounds in which
Q is defined as mentioned under the sixth embodiment,
is of paramount importance
the compounds in which
Q is defined as mentioned under the seventh embodiment,
a particularly outstanding importance,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A twelfth embodiment of the present invention is the compounds of the above general formula (I) in which
A and X each represent an oxygen atom,
R ^{1 is} as defined above under the fourth embodiment,
Q as defined above under the seventh embodiment,
and wherein in this and all the above embodiments respectively the compounds in which
R ² and R ^{3 are} as defined above in the eighth embodiment is of outstanding importance,
The compounds in which R ² and R ^{3 are} as defined above under the ninth embodiment, a particularly outstanding importance,
and the compounds in which R ² and R ^{3 are} as defined above under the tenth embodiment, a particularly outstanding importance,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A thirteenth embodiment of the present invention is the compounds of the above general formula (I) in which
A and X each represent an oxygen atom,
R ^{1 is defined} as mentioned under the fourth embodiment,
Q is defined as mentioned under the seventh embodiment,
R ² and R ^{3 are defined} as mentioned under the tenth embodiment,
their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

For example, the bi- and tricyclic heterocycles listed in Table I are suitable, and these may be substituted on a saturated nitrogen atom by the group R ^{a '} and, independently of this, in the carbon skeleton by the group R ^b , and
R ^{a 'represents} the methyl, ethyl or 2,2,2-trifluoroethyl group and
R ^{b is} the chlorine or bromine atom, the methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino or dimethylamino means group.

Q may in all the above-mentioned embodiments assume the meanings of the radicals shown in Table I, either unsubstituted as explicitly shown or, as mentioned above, optionally substituted by the radicals R ^{a '} or / and R ^b .

Table I:

deren Enantiomere, deren Diastereomere und deren Salze.Very particularly preferred compounds of the above general formula (I) are, for example, the following compounds:

their enantiomers, their diastereomers and their salts.

• (a) Zur Herstellung von Verbindungen der allgemeinen Formel (I), in der alle Reste wie eingangs erwähnt definiert sind: Kupplung einer Carbonsäure der allgemeinen Formel
  
  in der alle Reste wie eingangs erwähnt definiert sind, mit einem Amin der allgemeinen Formel HNR²R³, in der R² und R³ wie eingangs definiert sind. Vor Durchführung der Reaktion können in einer Verbindung der Formel (III) und/oder in den Resten R² und R³ des Amins der Formel HNR²R³ gegebenenfalls vorhandene Carbonsäurefunktionen, primäre oder sekundäre Aminofunktionen oder Hydroxyfunktionen durch übliche Schutzreste geschützt und gegebenenfalls verwendete Schutzreste nach Durchführung der Reaktion nach dem Fachmann geläufigen Methoden wieder abgespalten werden.

The compounds of general formula (I) are prepared by methods known in principle. The following processes have proven particularly suitable for the preparation of the compounds of general formula (I) according to the invention:

• (a) For the preparation of compounds of the general formula (I) in which all radicals are defined as mentioned above: coupling of a carboxylic acid of the general formula
  
  in which all the radicals are defined as mentioned above, with an amine of the general formula HNR ² R ³ , in which R ² and R ^{3 are} as defined above. Before carrying out the reaction in a compound of the formula (III) and / or in the radicals R ² and R ^{3 of} the amine of the formula HNR ² R ^3, optionally present carboxylic acid functions, primary or secondary amino functions or hydroxy functions can be protected by conventional protective radicals and any protective radicals used after the reaction has been carried out, methods which are familiar to the person skilled in the art are eliminated again.

The Coupling is preferred using peptide chemistry known processes (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example, carbodiimides, such as. B. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) -carbodiimide, O- (1H-benzotriazol-1-yl) -N, N-N ', N'-tetramethyluroniumhexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) are used. By addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction rate can be increased. The couplings are usually equimolar Proportions of Coupling Components and Coupling Reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures from these and at temperatures between -30 and + 30 ° C, preferably -20 and + 25 ° C, performed. Provided is required as additional Auxiliary base N-ethyldiisopropylamine (Hünig base) is preferred.

• (b) Zur Herstellung von Verbindungen der allgemeinen Formel (I), in der alle Reste wie eingangs erwähnt definiert sind: Kupplung einer Verbindung der allgemeinen Formel
  
  mit einem Amin der allgemeinen Formel HNR²R³, in denen alle Reste wie eingangs erwähnt definiert sind und Nu eine Austrittsgruppe, beispielsweise ein Halogenatom, wie das Chlor-, Brom- oder Iodatom, eine Alkylsulfonyloxygruppe mit 1 bis 10 Kohlenstoffatomen im Alkylteil, eine gegebenenfalls durch Chlor- oder Bromatome, durch Methyl- oder Nitrogruppen mono-, di- oder trisubstituierte Phenylsulfonyloxy- oder Naphthylsulfonyloxygruppe, wobei die Substituenten gleich oder verschieden sein können, eine 1H-Imidazol-1-yl-, eine gegebenenfalls durch eine oder zwei Methylgruppen im Kohlenstoffgerüst substituierte 1H-Pyrazol-1-yl-, eine 1H-1,2,4-Triazol-1-yl-, 1H-1,2,3-Triazol-1-yl-, 1H-1,2,3,4-Tetrazol-1-yl-, eine Vinyl-, Propargyl-, p-Nitrophenyl-, 2,4-Dinitrophenyl-, Trichlorphenyl-, Pentachlorphenyl-, Pentafluorphenyl-, Pyranyl- oder Pyridinyl-, eine Dimethylaminyloxy-, 2(1H)-Oxopyridin-1-yl-oxy-, 2,5-Dioxopyrrolidin-1-yloxy-, Phthalimidyloxy-, 1H-Benzo-triazol-1-yloxy- oder Azidgruppe bedeutet. Vor Durchführung der Reaktion können in einer Verbindung der Formel (IV) und/oder in den Resten R² und R³ des Amins der Formel HNR²R³ gegebenenfalls vorhandene Carbonsäurefunktionen, primäre oder sekundäre Aminofunktionen oder Hydroxyfunktionen durch übliche Schutzreste geschützt und gegebenenfalls verwendete Schutzreste nach Durchführung der Reaktion nach dem Fachmann geläufigen Methoden wieder abgespalten werden.

Another coupling method for the synthesis of compounds of the general formula (I) is the so-called "anhydride method" (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pages 58-59, M. Bodanszky, "Principles of Peptide Synthesis ", Springer-Verlag 1984, p 21-27). Preference is given to the "mixed anhydride process" in the variant according to Vaughan (JR Vaughan Jr., J. Amer.Chem.Soc.73, 3547 (1951)) using isobutyl chloroformate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine, the mixed anhydride is obtained from the to-be-coupled carboxylic acid of the general formula (III) and the carbonic monoisobutyl ester. The preparation of this mixed anhydride and the coupling with the amines of the general formula HNR ² R ³ is carried out in a one-pot process, using the abovementioned solvents and at temperatures between -20 ° C and + 25 ° C, preferably between 0 ° C and +25 ° C.

• (B) For the preparation of compounds of general formula (I), in which all radicals are defined as mentioned above: coupling of a compound of the general formula
  
  with an amine of the general formula HNR ² R ³ , in which all radicals are defined as mentioned above and Nu is a leaving group, for example a Ha halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, optionally by chlorine or bromine atoms, by methyl or nitro groups mono-, di- or trisubstituted phenylsulfonyloxy or Naphthylsulfonyloxygruppe, wherein the substituents may be the same or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl, optionally substituted by one or two methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl , 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl , Trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2 (1H) -oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H Benzo-triazol-1-yloxy or azide group. Before carrying out the reaction in a compound of the formula (IV) and / or in the radicals R ² and R ^{3 of} the amine of the formula HNR ² R ³ optionally present carboxylic acid functions, primary or secondary amino functions or hydroxy functions protected by conventional protecting groups and optionally used protective groups after the reaction has been carried out, methods which are familiar to the person skilled in the art are eliminated again.

The Implementation will be under bulkhead Baumann or unicorn conditions carried out, that is, the Components become in the presence of at least one equivalent an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C, and optionally in the presence of solvents reacted. As auxiliary bases are preferred alkali and Alkaline earth hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali carbonates, e.g. For example, sodium carbonate, potassium carbonate or cesium carbonate, Alkali acetates, e.g. Sodium or potassium acetate, as well as tertiary amines, for example, pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyldicyclohexylamine, 1,4-di-azabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] undec-7-ene, as a solvent, for example Dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, Dimethylacetamide, N-methylpyrrolidone or mixtures thereof; are used as auxiliary bases alkali or Alkaline earth metal hydroxides, alkali carbonates or acetates Water is also added as a cosolvent to the reaction mixture.

The new invention Compounds of general formula (I) contain one or more chiral centers. For example, if there are two chirality centers, then the Compounds in the form of two diastereomeric antipode pairs occur. The invention includes the individual isomers as well as their mixtures.

The Separation of the respective diastereomers succeeds due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high-pressure liquid or column chromatography using chiral or preferably achiral stationary phases.

The Separation of racemates covered by the general formula (I) succeeds for example by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates, which is a basic or acidic function can also be visualized via the diastereomers active salts which, when reacted with an optically active Acid, for example, (+) - or (-) - tartaric acid, (+) - or (-) - diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - or (-) - camphorsulfonic acid, or an optically active base, for example with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -Brucine, arise.

To a usual one Isomer separation process becomes the racemate of a compound of the general formula (I) with one of the abovementioned optically active acids or bases in equimolar amount in a solvent reacted and the resulting crystalline diastereomers, optically active salts taking advantage of their different solubility separated. This reaction can be carried out in any kind of solvents, as long as they have a sufficient difference in solubility having the salts. Preferably, methanol, ethanol or their mixtures, for example, in the volume ratio 50:50 used. thereupon each of the optically active salts is dissolved in water, with a base, such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or waterier Methanesulfonic acid, careful neutralizes and thereby the corresponding free connection in the (+) or (-) form receive.

Each only the (R) - or (S) -enantiomer or a mixture of two optical active, under the general formula (I) falling, diastereomeric Compounds are also obtained by using the ones described above Syntheses each with a suitable (R) or (S) -configured Reaction component performs.

in der R¹ wie eingangs erwähnt definiert ist, mit Kohlensäurederivaten der allgemeinen Formel

in der Y¹ und Y² nucleofuge Gruppen bedeuten, die gleich oder verschieden sein können, bevorzugt das Chloratom, die p-Nitrophenoxy- oder Trichlormethoxy-Gruppe, falls A das Sauerstoffatom darstellt, oder das Chloratom, falls A das Schwefelatom bedeutet,
und mit Verbindungen der allgemeinen Formel

in der X und Q wie eingangs erwähnt definiert sind und Z₁ eine Schutzgruppe für eine Carboxygruppe darstellt, beispielsweise eine C_1–6-Alkyl- oder Benzylgruppe, wobei die Alkylgruppen linear oder verzweigt sein können und die Benzylgruppe durch ein oder zwei Methoxygruppen substituiert sein kann. Bevorzugt ist für Z₁ die Methyl-, Ethyl-, tert-Butyl oder Benzylgruppe. Vor Durchführung der Reaktion können im Rest R¹ einer Verbindung der Formel (V) und/oder in einer Verbindung der Formel (VII) gegebenenfalls vorhandene Carbonsäurefunktionen, primäre oder sekundäre Aminofunktionen oder Hydroxyfunktionen durch übliche Schutzreste geschützt und gegebenenfalls verwendete Schutzreste nach Durchführung der Reaktion nach dem Fachmann geläufigen Methoden wieder abgespalten werden.The required as starting compounds hydroxycarboxylic acids of the general formula (III) are by reacting piperidines of the general formula

in which R ¹ is defined as mentioned above, with carbonic acid derivatives of the general formula

in which Y ¹ and Y ² denote nucleofuge groups which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, if A represents the oxygen atom, or the chlorine atom, if A represents the sulfur atom,
and with compounds of the general formula

in which X and Q are defined as mentioned above and Z _{1 represents} a protecting group for a carboxy group, for example a C _1-6 alkyl or benzyl group, wherein the alkyl groups may be linear or branched and the benzyl group substituted by one or two methoxy groups can. Z ₁ is preferably the methyl, ethyl, tert-butyl or benzyl group. Before carrying out the reaction, any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which may be present in the radical R ^{1 of} a compound of the formula (V) and / or in a compound of the formula (VII) may be protected by customary protective radicals and any protective radicals used may be used after the reaction has taken place The methods familiar to the person skilled in the art are split off again.

In a first step, the compounds of the general formula (V) in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof, in a Temperature between -20 up to 50 ° C in the presence of a base, for example triethylamine, pyridine or Ethyldiisopropylamin, with the carbonic acid derivatives of the general Reacted formula (VI). The resulting intermediate stage can be purified or further reacted without purification.

The Implementation of these intermediates with compounds of the general Formula (VII) also takes place in one of the abovementioned solvents, and at the above temperatures, in the presence of a base, such as triethylamine or pyridine, with or without the addition of an activating reagent, such as. 4-dimethylaminopyridine. To activate the Compounds of the general formula (VII) also by means of a metal hydride, such as. NaH or KH are deprotonated, in which case dispensed with the presence of the base or the Aktivierungsreagenzes can be.

The Starting compounds of the formulas (V) and (VI) are either commercially available, known from the literature or can be prepared by literature methods.

aus Verbindungen der allgemeinen Formel

gewonnen werden, wobei Q in beiden Formeln wie eingangs erwähnt definiert ist.If the group X in compounds of the general formula (VII) represents the oxygen atom, the hydroxycarboxylic acids required for the synthesis of the general formula

from compounds of the general formula

are obtained, wherein Q is defined in both formulas as mentioned above.

By Diazotization of compounds of general formula (IX) with a suitable diazotization reagent, preferably sodium nitrite in acidic Milieu, can the compounds of general formula (VIII) are obtained. When using enantiomerically pure compounds, the corresponding obtained enantiomerically pure hydroxycarboxylic acid compounds, wherein the reaction proceeds with retention of the configuration.

One alternative access to compounds of general formula (VIII), if Q is not over a nitrogen atom is bound, is the reaction of aldehydes of the general formula (X) with N-acetylglycine in acetic anhydride as solvent in the presence of alkali metal acetate, preferably sodium or potassium acetate at a suitable temperature, preferably at 80-130 ° C.

The primary resulting azlactones are without isolation to the compounds the general formula (XI) is hydrolyzed. Through further implementation in the presence of aqueous Mineral acids, such as sulfuric, phosphoric or hydrochloric acid, but preferably hydrochloric acid Compounds of the general formula (XII). These will then with suitable reducing agents in the compounds of the general Formula (VIII) transferred.

When Reducing agents can Alkaliborhydride, such as sodium or potassium borohydride can be used. Further Reducing agents are chlorodialkylboranes, such as chlorodicyclohexylborane, Are chiral Chlordialkylborane, such. B-chlorodiisopinocampheylborane used, can the compounds of general formula (VIII) in enantiomerically pure Form to be isolated.

mit Verbindungen der allgemeinen Formel

in der Hal ein Chlor-, Brom- oder Jodatom bedeutet, und Q wie eingangs erwähnt definiert sind, in Analogie zu literaturbekannten Methoden (Michael T. Crimmins, Kyle A. Emmitte und Jason D. Katz, Org. Lett. 2, 2165–2167 [2000]). Die entstehenden diastereomeren Produkte können dann mit Hilfe physikochemischer Methoden, bevorzugt mit Hilfe chromatographischer Methoden oder Umkristallisation, getrennt werden. Die hydrolytische Abspaltung des chiralen Auxiliars und Abspaltung der Benzylschutzgruppe eröffnet ebenfalls einen Zugang zu enantiomerenreinen Hydroxycarbonsäureverbindungen der allgemeinen Formel (VII). Die weitere Umsetzung von Verbindungen der allgemeinen Formel (VIII) zu Verbindungen der allgemeinen Formel (VII) erfolgt im alkoholischen Milieu, bevorzugt in Methanol oder Ethanol, in Gegenwart einer geeigneten Säure, wie Chlorwasserstoffsäure. Die Reaktion kann alternativ durch Umsetzung in alkoholischen Lösungsmitteln, bevorzugt Methanol, mit Thionychlorid erfolgen.If Q is not bonded via a nitrogen atom, there is a further access to compounds of the general formula (VIII) in the alkylation of compounds of the formula

with compounds of the general formula

in which Hal represents a chlorine, bromine or iodine atom, and Q are as defined above, in analogy to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165- 2167 [2000]). The resulting diastereomeric products can then be separated by means of physicochemical methods, preferably by means of chromatographic methods or recrystallization. Hydrolytic cleavage of the chiral auxiliary and cleavage of the benzyl protecting group also provides access to enantiomerically pure hydroxycarboxylic acid compounds of general formula (VII). The further reaction of compounds of the general formula (VIII) to give compounds of the general formula (VII) takes place in an alcoholic medium, preferably in methanol or ethanol, in the presence of a suitable acid, such as hydrochloric acid. Alternatively, the reaction can be carried out by reaction in alcoholic solvents, preferably methanol, with thionyl chloride.

in der Q wie eingangs erwähnt definiert ist und Z₁ eine wie unter Verfahren (a) beschriebene Schutzgruppe für eine Carboxygruppe darstellt, aus Verbindungen der allgemeinen Formel (VII) gewonnen werden, in der X das Sauerstoffatom darstellt.If the group X in compounds of the general formula (VII) represents the sulfur atom, the thiocarboxylic acids required for the synthesis of the general formula

in which Q is defined as mentioned above and Z _{1 represents} a protective group for a carboxy group as described under process (a), are obtained from compounds of the general formula (VII) in which X represents the oxygen atom.

By a Mitsunobu reaction of the compounds of general formula (VII) with C _1-6 alkylthiocarboxylic acids, wherein the alkyl chain may be linear or branched but this is preferably the methyl group, the corresponding Alkylthiocarbonsäureester these compounds are obtained. These can be hydrolyzed by known methods to the compounds of the general formula (XV) (Bert Strijtveen and Richard M. Kellogg, J. Org. Chem. 51, 3664-3671 [1986]).

All Compounds of general formula (I), the primary or secondary Amino, hydroxy or hydroxycarbonyl functions are included preferably obtained from protective groups provided with protective groups. When Protecting groups for Amino functions include, for example, a benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-Chloro-benzyloxy-carbonyl, 4-biphenylyl-α, α-dimethyl-benzyloxycarbonyl- or 3,5-dimethoxy-α, α-dimethyl-benzyloxycarbonyl group, an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety, for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or terf-butyloxycarbonyl group, the Allyloxycarbonyl, 2,2,2-trichloro (1,1-dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl group or a formyl, acetyl or trifluoroacetyl group in question.

When Protective group for Hydroxy functions, for example, a trimethylsilyl, triethylsilyl, Triisopropyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl group, a tert-butyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl group in question.

When Protective group for Hydroxycarbonyl functions, for example, is an alkyl group having a total of 1 to 5 carbon atoms, for example the methyl, Ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, 2,2,2-trichloroethyl, Benzyl or 4-methoxybenzyl group in question.

The compounds of the general formula (I) obtained may, provided they contain suitable basic functions, be converted, in particular for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, milk acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid into consideration.

In addition, let the new compounds of the formula (I), if they carboxylic acid function contained in their addition salts with inorganic or organic Bases, in particular for the pharmaceutical application in its physiologically acceptable Transfer addition salts. When Bases come for this for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, Dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine into consideration.

The The present invention relates to racemates, as far as the compounds of the general formula (I) have only one chiral element. The registration however, also encompasses the individual diastereomeric antipode pairs or their mixtures, which are present when more than one chiral element is present in the compounds of general formula (I), as well as the individual optically active enantiomers that make up the mentioned racemates put together.

Also with the subject of this invention are the compounds of the invention, including their Salts in which one or more hydrogen atoms, for example one, two, three, four or five Hydrogen atoms are replaced by deuterium.

The new compounds of general formula (I) and their physiological compatible Salts have valuable pharmacological properties their selective CGRP antagonistic properties decline. Another object of the invention are those compounds containing Medicines, their use and their manufacture.

The above-mentioned new compounds and their physiological compatible Salts have CGRP antagonistic properties and show good affinities in CGRP receptor binding studies. The compounds have in the CGRP antagonistic pharmacological test systems described below Properties on.

To the Proof of affinity the above compounds to human CGRP receptors and their antagonistic properties were the following experiments carried out:

A. Binding studies with (the human CGRP receptor expressing) SK-N-MC cells

SK-N-MC cells are cultured in "Dulbecco's modified Eagle Medium". The medium of confluent cultures is removed. The cells are washed twice with PBS buffer (Gibco 041-04190 M), removed by addition of PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO ₃ 16.2, MgSO ₄ 0.8, NaHPO ₄ 1.0, CaCl ₂ 1.8, D-glucose 5.5, HEPES 30, pH 7.40] The cells are centrifuged twice at 100 x g and resuspended in BSS. After determining the number of cells, the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 × g. The supernatant is discarded and the pellet recentrifuged and resuspended in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl ₂ , 1 mM EDTA, pH 7.40) supplemented with 1% bovine serum albumin and 0.1% bacitracin (1 ml / 1000000 cells). The homogenate is frozen at -80 ° C. The membrane preparations are stable under these conditions for more than 6 weeks.

After thawing, the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl ₂ , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 μl of the homogenate are incubated for 180 minutes at room temperature with 50 pM ¹²⁵ I-iodotyrosyl-calcitonin gene-related peptides (Amersham) and increasing concentrations of the test substances in a total volume of 250 μl. Incubation is terminated by rapid filtration through polyethyleneimine (0.1%) treated GF / B glass fiber filters using a cell harvester. The protein bound radioactivity is determined using a gamma counter. Non-specific binding is defined as the bound radioactivity after the presence of 1 μM human CGRP-alpha during the incubation.

The Analysis of the concentration-binding curves is carried out with the help of a computerized nonlinear curve fitting.

The compounds mentioned in the introduction exhibit IC ₅₀ values ≦ 10000 nM in the test described.

B. CGRP antagonism in SK-N-MC cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and at 37 ° C for 15 minutes pre-incubated. After addition of CGRP (10 μl) as agonist in increasing concentrations (10 ^-11 to 10 ^-6 M) or additionally of substance in 3 to 4 different concentrations is incubated again for 15 minutes.

Intracellular cAMP will follow by adding 20 μl 1M HCl and centrifugation (2000 x g, 4 ° C for 15 minutes). The supernatants are in liquid Nitrogen frozen and stored at -20 ° C.

The cAMP contents of the samples are determined by means of radioimmunoassay (Amersham) and the pA ₂ values of antagonistic substances are determined graphically.

In the described in vitro test model, the compounds according to the invention exhibit CGRP-antagonistic properties in a dose range between 10 ^-12 to 10 ^-5 M.

by virtue of their pharmacological properties are the compounds of the invention and their salts with physiologically tolerated acids thus acute and prophylactic Treatment of headache, especially migraine or cluster headache. Furthermore, the compounds of the invention also affect the following Diseases positive: non-insulin-dependent diabetes mellitus ("NIDDM"), complex regional pain syndrome (CRPS1), cardiovascular disease, morphine tolerance, Clostritium toxin-related diarrheal diseases, diseases of the Skin, especially thermal and radiation-related skin damage included Sunburn, inflammatory Diseases, e.g. inflammatory Joint disease (arthritis), neurogenic inflammation of the oral mucosa, inflammatory Lung diseases, allergic rhinitis, asthma, diseases, those with an overshooting vascular dilation and concomitantly reduced tissue perfusion, e.g. Shock and sepsis. About that In addition, the compounds of the invention show a soothing effect on pain conditions in general.

The Symptoms of menopausal, caused by vascular dilation and increased blood flow Hot flashes Ostrogendefizienter Women as well as hormone-treated prostate cancer patients will by the CGRP antagonists of the present application are preventive and acutely beneficial affected whereby this therapeutic approach before the hormone substitution by Low side effects characterized.

The To achieve a corresponding effect required dosage is expediently at intravenous or subcutaneous administration 0.0001 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, and by oral, nasal or inhalation administration 0.01 to 10 mg / kg Body weight, preferably 0.1 to 10 mg / kg of body weight, 1 to 3 times a day.

Provided treatment with CGRP antagonists and / or CGRP release inhibitors in addition to a usual Hormone substitution takes place, it is recommended to reduce the above dosages, the dosage then 1/5 the lower limits specified above up to 1/1 of the above may be upper limits.

The produced according to the invention Connections can either alone or optionally in combination with others Active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, wherein For inhalation in particular aerosol formulations are suitable. The combinations can be administered either simultaneously or sequentially.

Possible combinations of agents include antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, angiotensin receptor blockers (angiotensin II antagonists), iNOS inhibitors, AMPA antagonists, anticonvulsants, histamine H1 receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, weak analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, calcium antagonists, 5-HT _{1B / 1D} agonists or other antimigraine agents, together with one or more inert conventional carriers and / or diluents, eg corn starch, lactose , Cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in conventional galenic To preparations such as tablets, dragees, capsules, powders, Sus pensions, solutions, metered aerosols or suppositories can be incorporated.

For the above-mentioned combinations, the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, Pirnxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts, as well as meloxicam and other selective COX ₂ inhibitors, such as rofecoxib and celecoxib.

Furthermore, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isomethepten, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochlorperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, Propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitryptiline, lidocaine or diltiazem and other 5-NT _{1B / 1D} agonists such as almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan ,

The Dose for these active substances is this expediently 1/5 of the usual recommended lowest dosage up to 1/1 of the normally recommended Dosage, so for example 20 to 100 mg Sumatriptan.

One Another object of the invention is the use of the compounds of the invention as valuable tools for the production and purification (affinity chromatography) of antibodies and, after suitable radioactive labeling, for example by Tritiation of suitable precursors, for example by catalytic Hydrogenation with trithium or replacement of halogen atoms with tritium, in RIA and ELISA assays and as diagnostic or analytical Aids in neurotransmitter research.

experimental part

For prepared compounds are usually present IR, ¹ H-NMR and / or mass spectra. Unless otherwise indicated, R _f values are determined using GCF Finished Tops Kieselgel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation. The R _f values determined under the name Alox are determined using TLC plates alumina 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation. The ratios indicated for the flow agents relate to volume units of the respective solvents. The indicated volume units at NH ₃ refer to a concentrated solution of NH ₃ in water.

So far Unless otherwise stated, the acid, base and acid used in the workup of the reaction solutions and salt solutions aqueous Systems of specified concentrations.

For chromatographic purifications, silica gel from Millipore (MATREX ^™ , 35-70 μm) is used. For chromatographic purifications Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 microns, item no: 1.01097.9050) is used.

The indicated HPLC data are measured under the following parameters:
Analytical column: Zorbax column (Agilent Technologies), SB (stable bond) - C18; 3.5 μm; 4.6 × 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm

Method A:

In preparative HPLC purifications, the same gradients are usually used as in the collection of analytical HPLC data were used.

The Collection of the products is mass-controlled, the product-containing fractions are combined and freeze-dried.

If details Information about the configuration is missing, remains open, whether it is pure Enantiomers or whether partial or even complete racemization occurred is.

abs.

absolutiert

Boc

tert.-Butoxycarbonyl

CDI

N,M-Carbonyldiimidazol

CDT

1,1'-Carbonyldi-(1,2,4-triazol)

Cyc

Cyclohexan

DCM

Dichlormethan

DMF

N,N-Dimethylformamid

EtOAc

Essigsäureethylester

EtOH

Ethanol

halbkonz.

halbkonzentriert

HCl

Salzsäure

HOAc

Essigsäure

HOBt

1-Hydroxybenzotriazol-hydrat

i.vac.

in vacuo (im Vakuum)

KOH

Kaliumhydroxid

konz.

konzentriert

McOH

Methanol

NaCl

Natriumchlorid

NaOH

Natriumhydroxid

NMP

N-Methyl-2-pyrrolidinon

org.

organisch

PE

Petrolether

RT

Raumtemperatur

TBTU

2-(1N-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-Tetrafluorborat

TFA

Trifluoressigsäure

THF

Tetrahydrofuran

The test descriptions use the following abbreviations:

Section.

made absolute

Boc

tert-butoxycarbonyl

CDI

N, M-carbonyldiimidazole

CDT

1,1'-Carbonyldi- (1,2,4-triazole)

Cyc

cyclohexane

DCM

dichloromethane

DMF

N, N-dimethylformamide

EtOAc

ethyl acetate

EtOH

ethanol

half-concentrated.

semi focused

HCl

hydrochloric acid

HOAc

acetic acid

HOBt

1-hydroxybenzotriazole hydrate

dried i.

in vacuo (in vacuum)

KOH

potassium hydroxide

conc.

concentrated

MeOH

methanol

NaCl

sodium chloride

NaOH

sodium hydroxide

NMP

N-methyl-2-pyrrolidinone

org.

organic

PE

petroleum ether

RT

room temperature

TBTU

2- (1N-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate

TFA

trifluoroacetic

THF

tetrahydrofuran

example 1

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1- (7-methyl-1H-indazol-5 ylmethyl) -2- [4- (4-methyl-piperazin-1-yl) -piperidin-1-yl] -2-oxoethyl ester

1a 7-methyl-1H-indazole-5-carbaldehyde

2.8 g (70 mmol, 55% in mineral oil) were added portionwise to a solution of 13.5 g (64 mmol) of 5-bromo-7-methyl-1H-indazole in 120 mL of dry THF under argon atmosphere, the temperature being about 35 ° C rise. After 15 min, the reaction mixture was cooled to -78 ° C and within 30 min 100 mL sec. BuLi (140 mmol, 1.4 M in cyclohexane) was added dropwise. It was held for another hour Temperature before addition of a solution of 20 mL DMF in 20 mL dry THF (strongly exothermic reaction). The reaction mixture was stirred overnight at RT, cooled to 0 ° C and added dropwise under argon with 140 mL of 2 M HCl (highly exothermic reaction). The acidic solution was brought to pH 7-8 with solid NaHCO ₃ , combined with 500 mL water and extracted with 500 mL EtOAc. The organic phase was separated, filtered through charcoal and i.vac. concentrated. The resulting residue was recrystallized from 70 mL EtOAc; The resulting mother liquor was concentrated and the residue purified by chromatography (silica gel, PE / EtOAc 2: 1). Yield: 6.9 g (67% of theory) ESI-MS: (M + H) ⁺ = 161 R _f = 0.5 (silica gel, PE / EtOAc 1: 1)

1b 7-Methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazole-5-carbaldehyde

To a solution of 8.5 g (53.07 mmol) of 7-methyl-1H-indazole-5-carbaldehyde in 250 mL DCM was added 22.5 mL (160 mmol) triethylamine and then slowly added a solution of 15.96 g (79.5 mmol) 2-trimethylsilanyl- Ethanesulfonylchlorid added dropwise in 50 mL DCM and the reaction solution was then stirred overnight at RT. One narrowed i.vac. and the residue was purified by chromatography (silica gel, PE / EtOAc 8: 2). Yield: 14.0 g (81% of theory) ESI-MS: (M + H) ⁺ = 325 R _f = 0.35 (silica gel, PE / EtOAc 8: 2)

1c (Z, E) -2-acetylamino-3- (7-methyl-1H-indazol-5-yl) -acrylic acid

A mixture of 14 g (43.15 mmol) of 7-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazole-5-carbaldehyde, 10.12 g (86.4 mmol) of N-acetylglycine and 7.09 g (86.4 mmol) of NaOAc in 60 mL of acetic anhydride was refluxed for 3 hours. The reaction mixture was cooled to about 60 ° C and added dropwise with 40 mL of water, stirred for 10 min at this temperature and then heated to 95 ° C for 1 h. The reaction solution was poured into 500 ml of water, extracted three times with 300 ml of EtOAc each time, the combined organic phases were extracted twice with 200 ml of 7% K ₂ CO solution each time, the combined aqueous phases were treated with conc. HCl and extracted again three times with 200 mL EtOAc each time. The combined organic phases were filtered through charcoal and i.vac. concentrated.

A mixture of the desired product and (Z, E) -2-acetylamino-3- (1-acetyl-7-methyl-1H-indazol-5-yl) -acrylic acid was obtained, which was further reacted without purification. Yield: 2.1 g (19% of theory) ESI-MS: (M + H) ⁺ = 260 Retention time (HPLC): 4.2 min (method A) (Z, E) -2-acetylamino-3- (1-acetyl-7-methyl-1H-indazol-5-yl) -acrylic acid Yield: 2.1 g (16% of theory) ESI-MS: (M + H) ⁺ = 302 Retention time (HPLC): 5.8 min (method A)

1d 3- (7-methyl-1H-indazol-5-yl) -2-oxo-propionic acid

To a solution of 4.25 g of the above crude product in 40 mL NMP, 70 mL 4M HCl and the reaction mixture heated for 3 h at 100 ° C bath temperature.

The reaction solution was poured into 400 ml of water, extracted five times with 200 ml of EtOAc each time, the combined organic phases were washed twice with 300 ml of water each time, dried over Na ₂ SO ₄ and concentrated by evaporation i.vac. evaporated. Yield: 1.3 g (36% of theory) EI-MS: (M) ⁺ = 218 Retention time (HPLC): 5.4 min (method

1e (R) -2-hydroxy-3- (7-methyl-1H-indazol-5-yl) -propionic acid ethyl ester

To a cooled to about -25 ° C solution of 1.3 g (5.96 mmol) of 3- (7-methyl-1H-indazol-5-yl) -2-oxo-propionic acid and 0.84 mL (7.2 mmol) of triethylamine in 50 mL THF were added dropwise within 30 min, a solution of 2.31 g (7.2 mmol) (1R) -B-Chlordiisopinocampheylboran in 20 mL THF and the reaction mixture 1.5 h held at this temperature and then heated to RT within a further hour. One narrowed i.vac. The residue was taken up in 100 mL of 4 M ethanolic HCl and stirred at RT overnight. It was mixed with 200 mL EtOAc and 200 mL 15% K ₂ CO ₃ solution, the organic phase was separated and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was purified by HPLC chromatography. Yield: 0.45 g (30% of theory) ESI-MS: (M + H) ⁺ = 249 Retention time (HPLC): 5.8 min (method A)

1f 5 - ((R) -2-ethoxycarbonyl-2-hydroxyethyl) -7-methyl-indazole-1-carboxylic acid tert-butyl ester

To a solution of 450 mg (1.81 mmol) of (R) -2-hydroxy-3- (7-methyl-1H-indazol-5-yl) -propionic acid ethyl ester, 55 mg (0.45 mmol) of DMAP and 0.27 mL (1.82 mmol 9 triethylamine in 15 mL DCM, a solution of 397 mg (1.82 mmo) Boc anhydride in 5 mL DCM was slowly added dropwise and the reaction was stirred at RT overnight, diluted with 50 mL DCM, washed with 10% citric acid and 15% K ₂ CO ₃ solution and dried over Na ₂ SO _4. After removal of the drying agent and solvent, the residue was further reacted without purification. Yield: 0.63 g (100% of theory) ESI-MS: (2M + Na) ⁺ = 719 Retention time (HPLC): 8.3 min (method A)

1 g of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carbonyl chloride

To one at 0 ° C cooled solution of 2.5 g (10.2 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one and 2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM were added 6 g (12.1 mmol) of phosgene (20 weight percent in toluene) was added and the reaction mixture stirred for 30 min at this temperature.

The mixture was allowed to warm to RT, narrowed i.vac. to about 50 mL and filtered through silica gel, washed with 200 mL DCM / EtOAc (1: 1), and the combined filtrates again concentrated i.vac. one. The residue was stirred with diisopropyl ether, filtered off with suction and i.vac. dried. Yield: 2.42 g (77% of theory) R _f = 0.43 (silica gel, DCM / EtOAc 1: 1)

1h 5 - {(R) -2-ethoxycarbonyl-2- [4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carbonyloxy] - ethyl} -7-methyl-indazole-1-carboxylic acid tert-butyl ester

Under nitrogen atmosphere became one at 0 ° C cooled solution of 632 mg (1.81 mmol) of tert-butyl 5- ((R) -2-ethoxycarbonyl-2-hydroxy-ethyl) -7-methyl-indazole-1-carboxylate in 60 mL dry THF 92 mg (2.1 mmol, 55% in mineral oil) NaH in portions added and stirred for a further hour at this temperature. Subsequently were portionwise under cooling 800 mg (1.82 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carbonyl chloride are added and the reaction mixture over Stirred overnight at RT.

One narrowed i.vac. , 200 mL 10% citric acid solution, extracted twice with 200 mL EtOAc each time, washed the combined organic phases with 200 mL 15% K ₂ CO ₃ solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, EtOAc / PE 2: 1). Yield: 330 mg (29% of theory) ESI-MS: (M + H) ⁺ = 620 R _f = 0.45 (silica gel, EtOAc / PE 2: 1)

1i 5 - {(R) -2-carboxy-2- [4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carbonyloxy] - ethyl} -7-methyl-indazole-1-carboxylic acid tert-butyl ester

To a solution of 330 mg (0.53 mmol) of 5 - {(R) -2-ethoxycarbonyl-2- [4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl ) piperidine-1-carbonyloxy] -ethyl} -7-methyl indazole-1-carboxylic acid tert-butyl ester in 30 mL THF was added at RT a solution of 19.2 mg (0.8 mmol) of lithium hydroxide hydrate in 10 mL water and the reaction mixture Stirred for 30 min at RT. One narrowed i.vac. , the residue was taken up in 100 mL of water, 10% citric acid added with stirring, extracted twice with 100 mL DCM each time, and the combined organic phases dried over Na ₂ SO ₄ . After removal of the drying and solvent, the residue was further reacted without purification. Yield: 440 mg (raw) ESI-MS: (M + H) ⁺ = 592 Retention time (HPLC): 8.2 min (method A)

1k 7-Methyl-5 - {(R) -3- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3-oxo-2- [4- (2-oxo) 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carbonyloxy] -propyl} -indazole-1-carboxylic acid tert-butyl ester

A solution of 440 mg of 5 - {(R) -2-carboxy-2- [4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1 -carbonyloxy] -ethyl} -7-methyl-indazole-1-carboxylic acid tert-butyl ester, 256 mg (0.8 mmol) of TBTU, 146 μL (1.0 mmol) of triethylamine and 147 mg (0.8 mmol) of 1-methyl-4-piperidine-4 -yl-piperazine in 8 mL DMF was stirred for 2 h at RT. The reaction solution was filtered through a syringe filter and purified directly via HPLC without further work-up. The fractions containing the product were combined, i.vac. concentrated, made alkaline with 15% K ₂ CO ₃ solution, extracted three times with 30 mL DCM, the combined organic phases over Na ₂ SO ₄ dried and the solvent i.vac. away. Yield: 160 mg (28% of theory) ESI-MS: (M + H) ⁺ = 757 Retention time (HPLC): 6.6 min (method A)

1l 4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1- (7-methyl-1H-indazole-5 ylmethyl) -2- [4- (4-methyl-piperazin-1-yl) piperidin-1-yl] -2-oxo-ethyl ester

A solution of 160 mg (0.21 mmol) of 7-methyl-5 - {(R) -3- [4- (4-methyl-piperazin-1-yl) -piperidin-1-yl] -3-oxo-2-one [4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carbonyloxy] -propyl} -indazole-1-carboxylic acid tert-butyl ester in 10 mL 1 M HCl was stirred for 1 h at RT. To complete the reaction was heated for 10 min at 50 ° C and stirred for a further hour at RT. It was mixed with 15% K ₂ CO ₃ solution, extracted three times with 30 mL DCM and the combined organic phases were dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was triturated with 30 ml of diisopropyl ether, filtered off with suction, washed with 10 ml of diisopropyl ether and dried in air. Yield: 100 mg (72% of theory) ESI-MS: (M + H) ⁺ = 657 Retention time (HPLC): 4.9 min (method A)

The The following examples describe the preparation of pharmaceutical Forms of use, as the active ingredient any compound of general formula (I) include:

Example I

Capsules for powder inhalation with 1 mg of active ingredient

Composition:

1 capsule for powder inhalation contains: active substance 1.0 mg lactose 20.0 mg Hard gelatin capsules 50.0 mg 71.0 mg

Production method:

Of the Active ingredient will be on the for Inhalativa required grain size ground. The ground active substance is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.

Example II

Inhalation solution for Respimat ^® with 1 mg active substance

Composition:

1 hub contains: active substance 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg Water cleaned ad 15.0 μl

Production method:

The active ingredient and benzalkonium chloride are dissolved in water and filled into Respimat ^® cartridges.

Example III

Inhalation solution for nebulizers with 1 mg of active ingredient

Composition:

1 vial contains: active substance 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g Water cleaned ad 20.0 ml

Production method:

agent Sodium chloride and benzalkonium chloride are dissolved in water.

Example IV

LPG metered with 1 mg of active ingredient

Composition:

1 hub contains: active substance 1.0 mg lecithin 0.1% Propellant ad 50.0 μl

Production method:

Of the Micronized drug is in the mixture of lecithin and propellant homogeneously suspended. The suspension is in a pressure vessel with Dispensed filling valve.

Example V

• Nasal spray with 1 mg active ingredient Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg Water cleaned ad 0.1 ml

Production method:

Of the Active ingredient and the excipients are dissolved in water and in a corresponding container bottled.

Example VI

• Injection solution with 5 mg active substance per 5 ml composition: active substance 5 mg glucose 250 mg Human serum albumin 10 mg glycofurol 250 mg Water for injections ad 5 ml

production:

glycofurol and glucose in water for Dissolve injections (Wfl); Human serum albumin release; Active ingredient with heating dissolve; fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Example VII

• Injection solution with 100 mg active substance per 20 ml Composition: active substance 100 mg Monopotassium dihydrogenphosphate = KH ₂ PO ₄ 12 mg Disodium hydrogen phosphate = Na ₂ HPO ₄ .2H ₂ O 2 mg sodium chloride 180 mg Human serum albumin 50 mg Polysorbate 80 20 mg Water for injections ad 10 ml

production:

polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for Injection (Wfl) dissolve; Add human serum albumin; Dissolve active ingredient with heating; with Wfl on batch volume fill up; fill in ampoules.

Example VIII

• Lyophilisate with 10 mg active substance Composition: active substance 10 mg mannitol 300 mg Human serum albumin 20 mg Water for injections ad 2 ml

production:

Dissolve mannitol in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; to fill in vials; freeze-dry. Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg mannitol 200 mg Water for injections ad 10 ml

production:

polysorbate 80 and mannitol in water for Injection (Wfl) dissolve; fill in ampoules.

Example IX

• Tablets containing 20 mg of active substance Composition: active substance 20 mg lactose 120 mg corn starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg

production:

Active substance, Lactose and corn starch mix homogeneously; with a watery solution granulate of povidone; mix with magnesium stearate; on a Press off tablet press; Tablet weight 200 mg.

Example X

• Capsules with 20 mg active substance Composition: active substance 20 mg corn starch 80 mg Silica, highly dispersed 5 mg magnesium stearate 2.5 mg

production:

Active substance, corn starch and silica mix homogeneously; mix with magnesium stearate; Mix on one capsule fill into hard gelatin capsules size 3.

Example XI

• Suppository with 50 mg active substance Composition: active substance 50 mg Hard fat (Adeps solidus) qs ad 1700 mg

production:

hard fat at about 38 ° C melt; homogeneously disperse the ground active substance in the molten hard fat; after cooling to about 35 ° C in pre-cooled Pour out molds.

Example XII

• Injection solution with 10 mg active substance per 1 mL composition: active substance 10 mg mannitol 50 mg Human serum albumin 10 mg Water for injections ad 1 ml

production:

mannitol in water for Dissolve injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; With Fill Wfl to batch volume; Fill into ampoules under nitrogen fumigation.

Claims (6)

CGRP antagonists of the general formula

in the A is an oxygen or sulfur atom, X is an oxygen or sulfur atom, Q is a bonded via a carbon or nitrogen heterocycle consisting of two or three each 4- to 8-membered, independently saturated, partially unsaturated or fully unsaturated condensed Rings wherein the heterocycle may contain one to five heteroatoms independently selected from the group consisting of O, N and S, may contain one or two carbonyl groups as ring members and any saturated nitrogen atom as the ring member of the heterocycle through the group R ^a and one or two carbon atoms Ring members of the heterocycle may be substituted by the group R ^b , R ^{1 is} a saturated, mono- or diunsaturated 5- to 7-membered aza-, diaza-, triaza-, oxaza-, thiaza-, thiadiaza- or S, S-dioxide -thiadiaza heterocycle, wherein the above-mentioned heterocycles via a carbon or nitrogen atom with the pip eridinring in formula I or via two carbon atoms, via a carbon and a nitrogen atom, via a carbon and an oxygen atom or via a carbon and a sulfur atom with the piperidine ring in formula I spirocyclic are linked to, one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom contained on one of the nitrogen atoms by a C _1-6 alkyl, C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkenyl group may be substituted at one or at two carbon atoms by a C _1-6 alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl -, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1- (C _1-3 alkyl) pyrazolyl, imidazolyl or 1- (C _{1 3-} alkyl) -imidazolyl group, where the substituents may be the same or different, and an olefinic double bond of one of the aforementioned unsaturated heterocycles with a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole , Thienyl, furan, thiazole, pyrrole, NC _1-3 alkyl pyrrole or quinoline ring, with one on the nitrogen atom optionally substituted by a C _1-6 -A alkyl, C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkynyl group substituted 1H-quinolin-2-one ring or with an imidazole or NC _1-3 alkyl-imidazole ring may be condensed or two olefinic Double bonds of one of the above-mentioned unsaturated heterocycles may each be condensed with a phenyl or pyridine ring, wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, contained in R ¹ , 1 , 3-thiazolyl, isoxazolyl, pyrazolyl, 1-C _1-3 -alkylpyrazolyl, imidazolyl or 1-C _1-3 -alkyl-imidazolyl groups and benzo, thieno, pyrido and diazinokondensierten heterocycles in the carbon skeleton in addition by halogen atoms, C _1-6 alkyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, cyclo-C _3-7 -alkyl, cyclo-C _3-7 alkenyl, cyano, hydroxy, hydroxy-C _{1- 6} alkyl, hydroxy-C ₃ _ ₆ alkenyl, hydroxy-C ₃ _ ₆ alkynyl, C _{1- 6} alkoxy, C _{1- 6} alkoxy-C _{1 -} alkyl _6, C _{1- 6} alkoxy-C _3-6 alkenyl, C _{1- 6} alkoxy C ₃ _ ₆ alkynyl, C ₃ _ ₆ -alkenoxy-C _{1- 6} alkyl, C _3-6 -alkenoxy-C _3-6 -alkenyl, C _3-6 -alkenoxy-C _3-6 alkynyl, C _3-6 alkynoxy-C _1-6 alkyl, C _3-6 alkynoxy-C _3-6 alkenyl, C _3-6 alkynoxy-C ₃ _ ₆ alkynyl, thiohydroxy -, C _1-6 alkylthio, C _3-6 -Alkenylthio-, C ₃ _ ₆ -Alkinylthio-, amino, C _1-6 alkyl-amino, C ₃ _ ₆ alkenyl-amino, C ₃ _ ₆ alkynyl-amino, di- (C _1-6 alkyl) amino, di- (C ₃ _ ₆ alkenyl) -amino, di- (C ₃ _ ₆ alkynyl) amino , Amino C _1-6 alkyl, C _1-3 alkyl amino C _1-6 alkyl, di (C _1-3 alkyl) amino C _1-6 alkyl, amino C ₃ _ ₆ alkenyl, C _1-3 alkyl-amino-C ₃ _ ₆ alkenyl, di- (C _1-3 -alkyl) -amino-C ₃ _ ₆ alkenyl, amino-C _3-6 -alkynyl, C _1-3 -alkyl-amino-C ₃ _ ₆ -alkynyl, di- (C _1-3 -alkyl) -amino-C ₃ _ ₆ -alkynyl, hydroxycarbonyl, phenylcarbonyl , Pyridylcarbonyl-, C _1-6 alkyl-carbonyl, C ₂ _ ₆ alkenyl-carbonyl, C ₂ _ ₆ -Alkinylcarbonyl-, formyl, C _1-6 alkoxy-carbonyl, C ₃ _ ₆ - alkenoxy -carbonyl, C ₃ _ ₆ alkynoxy-carbonyl, aminocarbonyl, C _1-6 -alkyl-aminocarbonyl, C ₃ _ ₆ alkenyl aminocarbonyl, C ₃ _ ₆ alkynyl-aminocarbonyl, di- ( C _1-6 alkyl) aminocarbonyl, di- (C ₃ _ ₆ alkenyl) -aminocarbonyl, di- (C ₃ _ ₆ alkynyl) -aminocarbonyl, formylamino, _C1-6 alkyl-carbonylamino -, C ₂ _ ₆ -Alkenylcarbonylamino-, C ₂ _ ₆ alkynyl-carbonylamino, formyl-C _1-6 -alkyl-amino, formyl-C ₃ _ ₆ alkenyl-amino, formyl-C _3-6 -alkynyl-amino, C _1-6 -alkyl-carbonyl-C _1-6 -alkyl-amino, C _2-6 -alkenyl-carbonyl-C _1-6 -alkyl-amino, C _2-6 -alkynylcarbonyl -C _1-6 -alkyl-amino, C _1-6 -alkyl-carbonyl-C ₃ _ ₆ alkenyl-amino, C _2-6 -alkenyl-carbonyl-C _3-6 -alkenyl-amino, C _2-6 -alkynyl-carbonyl-C _3-6 -alkenylamino-, C _1-6 -alkyl-carbonyl-C ₃ _ ₆ alkynyl-amino, C ₂ _ ₆ alkenyl-carbonyl-C _3-6 -alkynyl -amino, C _2-6 -alkynyl-carbonyl-C _3-6 -alkynyl-amino, C _1-6 alkylsulphonyl, C ₂ _ ₆ alkenyl-sulfonyl, C ₂ _ ₆ alkynyl-sulfonyl , _{C1 6} alkyl-sulfinyl, C ₂ _ ₆ alkenyl-sulphinyl, C ₂ _ ₆ alkynyl-sulphinyl, C _1-6 alkyl-sulfonylamino, C ₂ _ ₆ alkenyl-sulfonylamino, C ₂ _ ₆ alkynyl-sulfonylamino, C _1-6 alkyl-sulfonyl-C _1-6 alkylamino, C _1-6 alkyl-sulfonyl-C ₃ _ ₆ -alkenylamino-, C _1-6 alkyl-sulfonyl C _3-6 -alkinylamino-, C ₂ _ ₆ alkenyl-sulfonyl-C _1-6 alkylamino, C ₂ _ ₆ alkenylsulfonyl-C _3-6 -alkenylamino-, C _2-6 -alkenyl-sulphonyl-C _3-6 -alkinylamino-, C _2-6 -alkynyl-sulphonyl-C _1-6 alkylamino, C _2-6 -alkynyl-sulphonyl-C _3-6 -alkenylamino-, C ₂ _ ₆ alkynyl-sulfonyl C ₃ _ ₆ -alkinylamino-, aminosulfonyl, C _1-6 alkylaminosulfonyl, di (C _1-6 alkyl) -aminosulfonyl-, C ₃ _ ₆ -Alkenylaminosulfonyl-, di- (C ₃ _ ₆ alkenyl ) -aminosulfonyl, C ₃ _ ₆ -alkynylaminosulfonyl, di- (C ₃ _ ₆ -alkynyl) -aminosulfonyl groups may be mono-, di- or trisubstituted, where the substituents may be identical or different, R ^{2 is} the hydrogen atom , a phenylmethyl group od it is a C _2-7 alkyl group in ω-position by a cyclo-C _3-7 -alkyl, cyclo-C _3-7 alkenyl, phenyl, pyridinyl, diazinyl, hydroxy, amino , C ₍₃ _ ₆ alkenyl C) amino- _1-6 alkylamino, di- (C _1-6 alkyl) amino, C ₃ _ ₆ -Alkenylamino-, di-, C ₃ _ ₆ -alkynylamino -, di (C ₃ _ ₆ alkynyl) amino, hydroxycarbonyl, C _1-6 alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, C _1-6 alkylcarbonylamino, C ₂ _ ₆ -Alkenylcarbonylamino-, C _{2 6-} alkynylcarbonylamino, 4-morpholinyl, [bis (2-hydroxyethyl)] amino, 4- (C _1-6 alkyl) -1-piperazinyl or 4- (ω-hydroxy-C ₂ _ ₇ a phenyl or pyridinyl group, wherein the phenyl, pyridinyl and diazinyl groups mentioned in the groups defined above for R ² or contained as substituents additionally in the carbon skeleton by halogen, by C _1-3 Alkyl, C ₂ _ ₃ alkenyl, C ₂ _ ₃ alkynyl, C _1-3 alkoxy, hydroxy, amino, C _1-3 alkylamino, di (C _{1 3-} alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di (C _1-3 alkyl) amino C _1-3 alkyl, C _1-3 alkylcarbonylamino, C _1-3 alkylcarbonylaminoC _1-3 alkyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) -aminocarbonyl, cyano, aminosulphonyl, C _1-3 -alkyl-aminosulphonyl, di- (C _1-3 alkyl) -aminosulfonyl-, C ₁ _ ₃ -alkyl-thio, C _{1- 3-} alkyl-sulfinyl-, or C _1-3 -alkyl-sulfonyl mono-, di- or trisubstituted and the substituents may be identical or different, R ^{3 is} the hydrogen atom or a substituted by a phenyl or pyridinyl C _1-3 -Alkyl group, wherein the C _1-3 alkyl group with an alkyl group contained in R ² or a phenyl contained in R ² or Pyridylring including the nitrogen atom to which R ² and R ^{3 are} bonded, may be connected to form a 4- 7-membered ring, or R ² and R ³ together with the enclosed nitrogen atom is a radical of the general formula

in the Y ^{1 represents} the carbon atom or, when R ^{5 represents} a lone pair, also the nitrogen atom, q and r when Y ^{1 represents} the carbon atom, the numbers 0, 1 or 2, or q and r when Y ^{1 represents} the nitrogen atom , the numbers 1 or 2, R ^{4 is} the hydrogen atom, an amino, C _1-4 alkylamino, di (C _1-4 alkyl) alkylamino, C _1-6 alkyl, cyclo C _3-7 alkyl, cyclo C _3-7 alkenyl, amino C _2-7 alkyl, C _1-4 alkyl amino C _2-7 alkyl, di (C _{1 4-} amino) C _2-7 alkyl, aminoiminomethyl, aminocarbonylamino, C _1-4 alkylaminocarbonylamino, di (C _1-4 alkyl) aminocarbonylamino, C _1-4 alkyl -aminocarbonyl-C _1-4 -amino, di (C _1-4 -alkyl) -aminocarbonyl-C _1-4 -amino, phenylaminocarbonylamino, aminocarbonyl, C _1-4 -alkylaminocarbonyl-, di- (C _1-4 alkyl) aminocarbonyl, aminocarbonylC _1-3 alkyl, C _1-4 alkylaminocarbonylC _1-3 alkyl, di (C _1-4 alkyl) - aminocarbonyl-C _1-3 -alkyl, aminocarbonylamino-C _1-3 -alkyl, C _1-6 alkoxycarbonyl, C ₃ _ ₆ -Alkenoxycarbonyl-, C ₃ _ ₆ -Alkinoxycarbonyl-, C _1-6 alkoxycarbonyl-C _1-3 alkyl, C _{1-6-C 1-3} -Alkenoxycarbonyl alkyl, C _1-6 -alkenoxycarbonyl-C _1-3 -alkyl or hydroxycarbonyl-C _1-3 -alkyl group, a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group, each in the carbon skeleton by halogen, by C _1-3 alkyl, C ₂ _ ₃ alkenyl, C ₂ _ ₃ alkynyl, C _1-3 alkoxy, hydroxy, amino, C _1-4 -alkylamino, di- (C _1-4 -alkyl) -amino, amino-C _1-3 -alkyl, C _1-4 -alkylamino-C _1-3 -alkyl-, di- (C _1-4 alkyl) aminoC _1-3 alkyl, C _1-4 alkylcarbonylamino, C _1-4 alkylcarbonylaminoC _1-3 alkyl, aminocarbonyl, C _1-4 Alkyl aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, cyano, aminosulfonyl, C _1-4 alkyl aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, or C _1-4 alkylsulfonyl mono-, di- or r is trisubstituted and the substituents may be the same or different, a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered oxaza-, thiaza- and diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl group, a 1 Alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group, wherein the above-mentioned mono- and bicyclic heterocycles are bonded via a nitrogen or a carbon atom to Y ¹ in formula (II), in the abovementioned mono- and bicyclic heterocycles a methine group not directly linked to a nitrogen, oxygen or sulfur atom by a fluorine atom and a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms, the aforementioned mono- and bicyclic Heterocycles and the 1- (C _1-6 alkyl) -4-piperidinylcarbonyl and 4- (C _1-6 alkyl) -1-piperazinylc arbonylgruppe in the ring one to four times by C _1-6 alkyl groups, or, optionally additionally, monosubstituted by a cyclo-C _3-7 -alkyl, cyclo-C _3-7 -alkenyl, cyclo-C _3-7 - alkyl C _1-3 alkyl, phenyl C _1-3 alkyl, pyridyl C _1-3 alkyl, C _1-6 alkylcarbonyl, hydroxy, C _1-6 alkoxy, amino -, C _1-4 alkylamino, di- (C _1-4 alkyl) amino, phenylcarbonyl, Pyridinylcarbonyl-, hydroxycarbonyl, hydroxycarbonyl-C _1-3 alkyl-, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylC _1-3 alkyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-4 alkyl) aminocarbonyl or C _1-3 alkylsulphonyl group, by an im Ring optionally C _1-3 alkyl-substituted cyclo-C _3-7 -alkyl-carbonyl, azacyclo-C _4-7 -alkyl-carbonyl, diazacyclo-C _5-7 -alkyl-carbonyl or oxazacyclo-C _5-7 - alkylcarbonyl group, wherein the substituents may be the same or different and bonded to a ring carbon or ring nitrogen atom, w obei the phenyl and pyridinyl radicals contained in the radicals defined above for R ^{4 in} turn by halogen atoms, by C _1-3 alkyl, C ₂ _ ₃ alkenyl, C ₂ _ ₃ alkynyl, C _1-3 Alkoxy, hydroxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, amino C _1-3 alkyl, C _1-4 alkylamino C _1-3 -alkyl, di- (C _1-4 -alkyl) -amino-C _1-3 -alkyl, C _1-4 -alkylcarbonylamino, C _1-4 -alkylcarbonylamino-C _1-3 -alkyl- , Aminocarbonyl, C _1-3 -alkylaminocarbonyl, di-C _1-4 -alkylaminocarbonyl, cyano, aminosulfonyl, C _1-4 -alkyl-aminosulfonyl, di- (C _1-4 -alkyl) -amino-sulfonyl, C _1-3 -alkyl-thio, C _1-3 -alkyl-sulfinyl-, or C _1-3 -alkyl-sulfonyl-mono-, di- or trisubstituted, wherein the substituents are identical or different or, when Y ^{1 represents} the carbon atom, the hydroxycarbonyl, aminomethyl, C _1-4 alkyl aminomes thyl- or di- (C _1-4 alkyl) -aminomethylgruppe, R ⁵ is a hydrogen atom, a C _1-4 alkyl group, wherein an unbranched alkyl radical in ω-position by a phenyl, pyridinyl, diazinyl, amino , C _1-4 -alkylamino, di (C _1-4 -alkyl) -amino, 4-C _1-4 -alkyl-1-piperazinyl or 4-morpholinyl group, a C _{1 6} -alkoxycarbonyl, cyano or aminocarbonyl group or also, when Y ^{1 represents} a nitrogen atom, a lone pair of electrons, or, if Y ^{1 represents} the carbon atom, the fluorine atom, or R ⁴ together with R ⁵ and Y ^{1 is} a 4- to 7-membered cycloaliphatic ring in which a methylene group is represented by a group -NH-, -N (C _1-4 -alkyl) -, -N (C _3-4 -alkenyl) -, -N (C _3-4 -alkynyl ) -, -N (cyclo-C _3-7 -alkyl) - or -N (C _3-7 -cycloalkyl-C _1-3 -alkyl) - may be replaced, wherein one to a nitrogen atom in one of R ⁴ R ^vorstehend and R ⁷ , R R and R ⁷ , as defined above, may be replaced by a protecting group. which may be the same or different, each represents a hydrogen atom, a C _1-4 alkyl group or, when Y ^{1 represents} a carbon atom, the fluorine atom, a C _1-4 alkylamino or di (C _1-4 alkyl) amino group, wherein the two C _1-4 alkyl groups may be bonded together to form a ring and R ⁸ and R ⁹ , which may be the same or different, each represents a hydrogen atom or a C _1-3 alkyl group, wherein R ^a a hydrogen atom, a linear or branched C _1-6 alkyl, C ₃ _ ₆ alkenyl, C ₃ _ ₆ alkynyl or cyclo C _3-7 alkyl group in which every hydrogen atom, unless it is in is α-position to a nitrogen atom may be replaced by fluorine, R ^b is a halogen atom, a linear or branched C _1-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, CycloC _3-7 alkyl, cyano, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, amino -, C _1-6 -alkyl- amino or di-C _1-6 -alkylamino group in which each hydrogen atom, unless it is in the α-position to a nitrogen atom, may be replaced by fluorine and the two alkyl groups of the di-C _1-6 - Alkylamino substituents may be linked together to form a 4- to 8-membered ring, a methylene group in α-position to a substituted by the group R ^a saturated nitrogen atom, an oxygen or sulfur atom as a ring member of the heterocycle of group Q is not substituted by hydroxy, C _1-6 alkoxy, amino, C _1-6 alkylamino or di C _1-6 alkylamino group, the double and triple bonds of those described in R ^a , R ^b , and R ¹ C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkynyl groups as defined above are optionally isolated from heteroatoms also optionally contained in these groups, and, unless stated otherwise, all in the above-defined radicals mentioned or each of the methines group contained in the above-defined groups may be substituted with one fluorine atom, each methylene group having up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, and two bonded to a nitrogen atom may be substituted with straight chain or branched alkyl, alkenyl and alkynyl groups Alkyl and alkenyl groups to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring may be joined together, all mentioned in the above defined radicals or aromatic and heteroaromatic radicals in addition by halogen, by cyano or hydroxy mono-, di or trisubstituted and the substituents may be the same or different, and the protection groups mentioned in the definitions above and below are understood to include the protective groups known from peptide chemistry, in particular one in the phenyl nucleus optionally by a halogen atom, by a nitro- phenyl group, phenylalkoxycarbonyl group having 1 to 3 carbon atoms in the alkoxy moiety substituted by one or two methoxy groups, for example benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3 Chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-α, α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α, α-dimethyl-benzyloxy carbonyl group, an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the Alkyl moiety, for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert-butyloxycarbonyl group, the allyloxycarbonyl, 2,2,2-trichloro - (1,1-dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl group or the formyl, acetyl or trifluoroacetyl group, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their Salts, the hydrates of the salts and those compounds of general formula I, in which one or more hydrogen atoms are replaced by deuterium. Physiologically acceptable salts of the compounds according to claim 1 with inorganic or organic acids or Bases. A pharmaceutical composition containing a compound according to claim 1 or a physiologically acceptable Salt according to claim 2 next to optionally one or more inert carriers and / or diluents. Use of a compound according to any one of claims 1 or 2 for the manufacture of a medicament for acute and prophylactic Treatment of headache, especially migraine or cluster headache, for the treatment of non-insulin-dependent diabetes mellitus ("NIDDM"), the complex regional pain syndrome (CRPS1), cardiovascular Diseases, morphine tolerance, clostritium toxin-related diarrheal diseases, Skin disorders, especially thermal and radiation-related skin damage including sunburn, inflammatory Diseases, e.g. inflammatory Joint disease (arthritis), neurogenic inflammation of the oral mucosa, inflammatory Lung diseases, allergic rhinitis, asthma, diseases, those with an overshooting vascular dilation and concomitantly reduced tissue perfusion, e.g. Shock and sepsis, for relief of pain, or for preventive or acute-therapeutic treatment of the symptoms of menopausal, by vascular dilatation and increased Blood flow caused Hot flashes Ostrogendefizienter Women and hormone-treated prostate cancer patients. Process for the preparation of a medicament according to claim 3, characterized in that non-chemical way a compound according to one of the claims 1 or 2 in one or more inert carriers and / or diluents is incorporated. A process for the preparation of the compounds of the general formula (I) according to any one of claims 1 or 2, characterized in that (a) for the preparation of compounds of the general formula (I) in which all radicals are as defined in claim 1, a carboxylic acid the general formula

in which all the radicals are as defined in claim 1, coupled with an amine of the general formula HNR ² R ³ , in which R ² and R ^{3 are} as defined in claim 1, or (b) for the preparation of compounds of the general formula ( I), in which all radicals are defined as in claim 1, a compound of the general formula

with an amine of the general formula HNR ² R ³ , in which all radicals are as defined in claim 1 and Nu is a leaving group is coupled, wherein, if desired, before carrying out the coupling reactions in the starting compounds optionally present carboxylic acid functions, primary or secondary amino functions or hydroxy functions protecting customary protecting groups and optionally used protective groups are split off again after carrying out the reaction, if desired, a compound of general formula (I) thus obtained is separated into its stereoisomers and / or a compound of general formula (I) thus obtained in its salts, especially for the pharmaceutical Application is converted into their physiologically acceptable salts.