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C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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Abstract
The invention relates to basic quaternary amides of formula <IMAGE> in which - Ar represents an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group; - T represents a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is C1-C4 or a C1-C5 alkylene group; - Ar' represents a phenyl which is unsubstituted or substituted one or a number of times, a thienyl, a benzothienyl, a naphthyl or an indolyl; - R represents hydrogen, a C1-C4 alkyl, an omega -(C1-C4)alkoxy(C2-C4)alkyl or an omega -(C1-C4)alkanoyloxy(C2-C 4)alkyl, - Q represents hydrogen; - or else Q and R, together, form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; - Am<(+)> represents the radical <IMAGE> in which X1, X2 and X3, together and with the nitrogen atom to which they are bonded, form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; - A<(-)> is a pharmaceutically acceptable anion. These compounds are useful in the preparation of medicaments intended for the treatment of pathologies involving the tachykinin system.
Claims (14)
1 PATENTNI ZAHTEVKI 1. Kvartemi bazičen amid s formulo R Q i -N-CH2-C-CH2-CH«j-Am ^ , A^ * Ar' v kateri Ar predstavlja fenilno skupino, kije nesubstituirana ali substituirana z enim ali več substituenti, izbranimi izmed naslednjih, kot so: F; Cl; Br; I; CN; OH; NH2; NH-CONH2; N02; CONH2; CF3; Ci-Ci0-alkil; alkenil z 2 do 10 atomi ogljika; alkinil z 2 do 10 atomi ogljika; cikloalkil s 3 do 8 atomi ogljika; bicikloalkil s 4 do 11 atomi ogljika; hidroksialkil z 1 do 5 atomi ogljika; alkoksi z 1 do 10 atomi ogljika; alkoksialkil z 2 do 10 atomi ogljika; alkoksialkoksialkil z do 10 atomi ogljika; alkoksialkoksi z 2 do 10 atomi ogljika; alkeniloksi z 2 do 10 atomi ogljika; alkeniloksialkil z do 10 atomi ogljika; alkeniloksi z 2 do 10 atomi ogljika; alkeniloksialkil s 3 do 10 atomi ogljika; cikloalkoksi s 3 do 8 atomi ogljika; alkiltio z 1 do 10 atomi ogljika; alkiltioalkil z 2 do 10 atomi ogljika; acilamino z 1 do 7 atomi ogljika; acilaminoalkil z 2 do 8 atomi ogljika; aciloksi z 1 do 6 atomi ogljika; alkoksikarbonil z 2 do 5 atomi ogljika; cikloalkoksikarbonil s 4 do 8 atomi ogljika; alkilaminokarbonilamino z 2 do 4 atomi ogljika; dialkilaminokarbonilamino s 3 do 7 atomi ogljika; (1-pirolidinojkarbonilamino; cikloalkilaminokarbonilamino s 4 do 8 atomi ogljika; alkilaminokarbonilaminoalkil s 3 do 9 atomi ogljika; dialkilaminokarbonil-aminoalkil s 4 do 11 atomi ogljika; (l-pirolidino)karbonilaminoetil; (1-piperidinojkarbonilaminoetil; cikloalkilaminokarbonilaminoalkil s 5 do 12 atomi ogljika; alkoksikarbonilaminoalkil s 3 do 12 atomi ogljika; cikloalkoksi-karbonilaminoalkil s 5 do 12 atomi ogljika; karbamoilalkil z 2 do 5 atomi ogljika; alkilaminokarbonilalkil s 3 do 9 atomi ogljika; dialkilaminokarbonil-alkil s 4 do 11 atomi ogljika; (l-pirolidino)karbonilmetil; (1-piperidinojkarbonilmetil; (1 -piperidinojkarboniletil; cikloalkilaminokarbonil- 2 alkil s 5 do 12 atomi ogljika; alkilaminokarbonilalkoksi s 3 do 10 atomi ogljika; dialkilaminokarbonilalkoksi s 4 do 10 atomi ogljika; (piperidinil-l)karbonilmetoksi; cikloalkilaminokarbonilalkoksi s 5 do 11 atomi ogljika; ali Ar predstavlja 1- ali 2-naftilno skupino, 1-, 2-, 3-, 4-, 5-, 6-, 7-indenilno skupino; katerih ena ali več vezi je lahko hidrogeniranih, pri čemer so lahko te skupine nesubstituirane ali substituirane z enim ali več substituenti, izbranimi izmed naslednjih, kot so: halogen, alkilna, fenilna, ciano, hidroksialkilna, hidroksi, alkoksi, okso, alkilkarbonilamino, alkoksikarbonilna in tioalkilna skupina, v katerih so Ci-C4-alkili; piridilna, tiadiazolilna, indolilna, indazolilna, imidazolilna, benzimidazolilna, kinolilna, benzotriazolilna, benzofuranilna, benzotienilna, benzotiazolilna, benzizotiazolilna, izokinolilna, benzoksazolilna, benzoksazinilna, benzodioksinilna, izoksazolilna, benzopiranilna, tiazolilna, tienilna, furilna, piranilna, kromenilna, izobenzofuranilna, pirolilna, pirazolilna, pirazinilna, pirimidinilna, piridazinilna, indolizinilna, ftalazinilna, kinazolinilna, akridinilna, izotiazolilna, izokromanilna, kromanilna skupina, katerih ena ali več dvojnih vezi je lahko hidrogeniranih, pri čemer so lahko te skupine nesubstituirane ali substituirane z enim ali več substituenti, izbranimi izmed naslednjih, kot so: alkilna, fenilna, ciano, hidroksialkilna, hidroksi, alkilkarbonilamino, alkoksikarbonilna, in tioalkilna skupina, v kateri so Ci-C4 -alkih; T predstavlja direktno vez, hidroksimetilensko skupino, alkoksimetilensko skupino, katere alkoksi skupina je s CrC4, ali Ci-C5-alkilensko skupino; Ar' predstavlja fenil, ki je nesubstituiran ali je enkrat ali večkrat substituiran z enim od substituentov, izbranim izmed naslednjih, kot so: atom halogena, trifluormetil, CrC4-alkoksi, CrC4-alkil, pri čemer so ti substituenti enaki ali različni; tienil; benzotienil; nafti 1 ali indolil; R predstavlja vodik; Ci-C4-alkil; ®-(CrC4)alkoksi(C2-C4)alkil; ali co-(C2-C4)alkanoiloksi(C2-C4)alkil; Q predstavlja vodik; ali pa Q in R skupaj tvorita 1,2-etilensko, 1,3-propilensko ali 1,4-butilensko skupino; 3 Am® predstavlja ostanekA quaternary basic amide of the formula RQ and -N-CH2-C-CH2-CH2-Am2, A2 * Ar 'in which Ar represents a phenyl group which is unsubstituted or substituted by one or more substituents, selected from the following: F; Cl; Br; I; CN; OH; NH2; NH-CONH2; NO2; CONH2; CF3; C1-C10-alkyl; alkenyl of 2 to 10 carbon atoms; alkynyl of 2 to 10 carbon atoms; cycloalkyl having 3 to 8 carbon atoms; bicycloalkyl having 4 to 11 carbon atoms; hydroxyalkyl having 1 to 5 carbon atoms; alkoxy of 1 to 10 carbon atoms; alkoxyalkyl of 2 to 10 carbon atoms; alkoxyalkoxyalkyl of up to 10 carbon atoms; alkoxyalkoxy of 2 to 10 carbon atoms; alkenyloxy having 2 to 10 carbon atoms; alkenyloxyalkyl of up to 10 carbon atoms; alkenyloxy having 2 to 10 carbon atoms; alkenyloxyalkyl having 3 to 10 carbon atoms; cycloalkoxy of 3 to 8 carbon atoms; alkylthio of 1 to 10 carbon atoms; alkylthioalkyl of 2 to 10 carbon atoms; acylamino with 1 to 7 carbon atoms; acylaminoalkyl having 2 to 8 carbon atoms; acyloxy of 1 to 6 carbon atoms; alkoxycarbonyl of 2 to 5 carbon atoms; cycloalkoxycarbonyl having 4 to 8 carbon atoms; alkylaminocarbonylamino having 2 to 4 carbon atoms; dialkylaminocarbonylamino having 3 to 7 carbon atoms; (1-pyrrolidinocarbonylamino; cycloalkylaminocarbonylamino having 4 to 8 carbon atoms; alkylaminocarbonylaminoalkyl having 3 to 9 carbon atoms; dialkylaminocarbonylaminoalkyl having 4 to 11 carbon atoms; (1-pyrrolidino) carbonylaminoethyl] ethylcarbonylaminoethyl; ; alkoxycarbonylaminoalkyl of 3 to 12 carbon atoms; cycloalkoxycarbonylaminoalkyl of 5 to 12 carbon atoms; carbamoylalkyl of 2 to 5 carbon atoms; alkylaminocarbonylalkyl of 3 to 9 carbon atoms; dialkylaminocarbonyl-alkylpyrrolidine of 4 to 11; carbonylmethyl; (1-piperidinocarbonylmethyl; (1-piperidinocarbonylethyl; cycloalkylaminocarbonyl-2 alkyl of 5 to 12 carbon atoms; alkylaminocarbonylalkoxy of 3 to 10 carbon atoms; dialkylaminocarbonylalkoxy; 4 to 10 carbonylcarbonyl; 5 to 10 carbonyl atoms); 11 carbon atoms, or Ar represents a 1- or 2-naphthyl group, a 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl group; h one or more bonds may be hydrogenated, these groups being unsubstituted or substituted by one or more substituents selected from halogen, alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkoxy, oxo, alkylcarbonylamino, alkoxycarbonyl and a thioalkyl group in which C1-C4-alkyl are; pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, isoquinolyl, benzoxazolyl, benzoxazinyl, isodiopynyl, benzodioxinyl pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl groups, one or more of which may be hydrogenated, these groups being unsubstituted or substituted by one or more substituents the following being: alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl, and a thioalkyl group in which they are C1-C4 alkyl; T represents a direct bond, a hydroxymethylene group, an alkoxymethylene group whose alkoxy group is C1-C4, or a C1-C5-alkylene group; Ar 1 represents phenyl which is unsubstituted or is mono- or polysubstituted by one of the substituents selected from: halogen atom, trifluoromethyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, these substituents being the same or different; thienyl; benzothienyl; naphtha 1 or indolyl; R represents hydrogen; C1-C4-alkyl; ®- (C1-C4) alkoxy (C2-C4) alkyl; or co- (C2-C4) alkanoyloxy (C2-C4) alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; 3 Am® represents the residuekjer X], X2, Χ3 skupaj in z atomom dušika, na katerega so vezani, tvorijo azabicikličen sistem, izbran izmed l-azoniabiciklo[2.2.1]heptana in 1-azoniabiciklo[2.2.2]oktana, v danem primeru substituiran s fenilno ali benzilno skupino; A' je farmacevtsko sprejemljiv anion.wherein X], X2, Χ3 together and with the nitrogen atom to which they are attached form an azabicyclic system selected from 1-azoniabicyclo [2.2.1] heptane and 1-azoniabicyclo [2.2.2] octane, optionally substituted by phenyl or a benzyl group; A 'is a pharmaceutically acceptable anion.2. Kvarterni bazičen amid s formulo (I) po zahtevku 1, označen s tem, da Am® predstavlja l-azoniabiciklo[2.2.2]oktansko skupino ali 4-fenil-l-azoniabiciklo[2.2.2]oktansko skupino.Quaternary basic amide of formula (I) according to Claim 1, characterized in that Am® represents a 1-azoniabicyclo [2.2.2] octane group or a 4-phenyl-1-azoniabicyclo [2.2.2] octane group.3. Kvarterni bazičen amid po zahtevku 1 ali 2 s formulo I R Q i Ar-T^O-N-CH2<:-CH2-CH2-Am®,AG (I) Ar’ v kateri so Ar, T, Ar', R in Q, kot je definirano v zahtevku 1, označen s tem, daje Am® ostanek Θ x2-n- x3 v formuli (I) in je ostanek azabicikličnega ali azatricikličnega sistema, izbran izmed naslednjih, kot so: (a) l-azoniabiciklo[2.2.2]oktan (b) 4-fenil-l-azoniabiciklo[2.2.2]oktan, 4 ter je A' farmacevtsko sprejemljiv anion.A quaternary basic amide according to claim 1 or 2 of the formula IRQ and Ar-T 1 ON-CH 2 < -: CH 2 -CH 2 -Am®, AG (I) Ar 'in which Ar, T, Ar', R and Q as defined in claim 1, characterized in that the Am® residue Θ x2-n- x3 in formula (I) and the residue of an azabicyclic or azatricyclic system is selected from the following, such as: (a) 1-azoniabicyclo [2.2 .2] octane (b) 4-phenyl-1-azoniabicyclo [2.2.2] octane, 4 and A 'is a pharmaceutically acceptable anion.4. Kvartemi bazičen amid s formulo I po kateremkoli od zahtevkov 1 do 3, označen s tem, da so T, R, Ar' in Q, kot je definirano za (I), Am® je 1-azoniabiciklo[2.2.2]oktanski ali 4-fenil-l-azoniabiciklo[2.2.2]oktanski ostanek, Arje fenil, substituiran s CrC4-alkoksi, in je A" farmacevtsko sprejemljiv anion.Quartheme basic amide of formula I according to any one of claims 1 to 3, characterized in that T, R, Ar 'and Q are as defined for (I), Am® is 1-azoniabicyclo [2.2.2] octane or 4-phenyl-1-azoniabicyclo [2.2.2] octane residue, Ar is phenyl substituted with C1-C4-alkoxy, and A " a pharmaceutically acceptable anion.5. Kvartemi bazičen amid s formulo iPr-0 R’ Q'5. Quartheme basic amide with formula iPr-0 R ’Q 'R" . A® (Γ) kjer sta R' in Q' metil in vodik oz. 2-acetoksietil in vodik; ali R' in Q skupaj tvorita 1,3-propilensko skupino, R" je vodik ali fenilna skupina in je A' farmacevtsko sprejemljiv anion.R " . A® (Γ) wherein R 'and Q' are methyl and hydrogen or 2-acetoxyethyl and hydrogen; or R 1 and Q together form a 1,3-propylene group, R " is hydrogen or a phenyl group and A 'is a pharmaceutically acceptable anion.6. Kvartemi bazičen amid s formulo6. Quartheme basic amide of formulaiPr-0 kjer je A' farmacevtsko sprejemljiv anion.iPr-0 wherein A 'is a pharmaceutically acceptable anion.7. Kvartemi bazičen amid po kateremkoli od zahtevkov 1 do 6, označen s tem, daje A' izbran izmed klorida, bromida, jodida, hidrogensulfata, metansulfonata, paratoluensulfonata in acetata. 5 8. (+)-l-[2-[3-(3,4-diklorofenil)-l-[(3-izopropoksifenil)acetil]piperidin-3-il]etil]-4-fenil-1 -azoniabiciklo [2.2.2] oktan-klorid.Quartemic basic amide according to any one of claims 1 to 6, characterized in that A 'is selected from chloride, bromide, iodide, hydrogen sulphate, methanesulfonate, paratoluenesulfonate and acetate. 5 8. (+) - 1- [2- [3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] piperidin-3-yl] ethyl] -4-phenyl-1-azoniabicyclo [ 2.2.2] octane chloride.9. Postopek za pripravo spojin s formulo (I), označen s tem, da derivat s formulo R Q I I Ar-T-C0-N-CH2-C-CH2-CH2-0-Y (II) Ar' kjer je Y katerakoli odstranljiva skupina, prednostno metansulfonil ali benzensulfonil, obdelujemo s cikličnim terc.aminom s formulo f1 X2 ~ N (III) X3 kjer Xj, X2 in X3 skupaj z atomom dušika, na katerega so vezani, tvorijo azabiciklični ali azatriciklični sistem, v danem primeru substituiran s fenilno skupino, v polarnem aprotičnem topilu pri temperaturi med sobno temperaturo in 120 °C in nato po potrebi izmenjamo anion dobljene kvarteme soli z drugim farmacevtsko sprejemljivim anionom.Process for the preparation of compounds of formula (I), characterized in that the derivative of formula RQII Ar-T-C0-N-CH2-C-CH2-CH2-O-Y (II) Ar 'wherein Y is any removable the group, preferably methanesulfonyl or benzenesulfonyl, is treated with a cyclic tert-amine of formula f1 X2 ~ N (III) X3 wherein X 1, X 2 and X 3 together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system optionally substituted with phenyl group, in a polar aprotic solvent at a temperature between room temperature and 120 ° C and then, if necessary, exchanging the anion of the obtained quartet salt with another pharmaceutically acceptable anion.10. Postopek po zahtevku 8, označen s tem, da je odhodna skupina OY metansulfonatna ali benzensulfonatna skupina.Process according to Claim 8, characterized in that the leaving group OY is a methanesulfonate or benzenesulfonate group.11. Postopek po enem od zahtevkov 8 ali 9, označen s tem, da cikličen terc.amin (III) izberemo izmedProcess according to one of Claims 8 or 9, characterized in that the cyclic tert-amine (III) is selected from6612. Farmacevtski sestavek, označen s tem, daje spojina s formulo (I) po zahtevku 1 prisotna kot aktivna snov.Pharmaceutical composition, characterized in that the compound of formula (I) according to Claim 1 is present as an active substance.13. Farmacevtski sestavek po zahtevku 12 v obliki dozirne enote, označen s tem, da aktivno snov pomešamo z vsaj enim farmacevtskim nosilcem.Pharmaceutical composition according to Claim 12, in the form of a dosage unit, characterized in that the active substance is mixed with at least one pharmaceutical carrier.14. Sestavek po zahtevku 13, označen s tem, da vsebuje 0,5 do 1000 mg aktivne snovi.Composition according to Claim 13, characterized in that it contains 0.5 to 1000 mg of active substance.15. Sestavek po zahtevku 14, označen s tem, da vsebuje od 2,5 do 250 mg aktivne snovi.Composition according to Claim 14, characterized in that it contains from 2.5 to 250 mg of active substance.
SI9300513A1992-09-301993-09-30Basic quaternary amids, procedure for their preparation and pharmaceutical compositions comprising them
SI9300513B
(en)
A COMPOUND DERIVED FROM QUINO- AND QUINAZOLINS ANTAGONISTS OF THE CORTICOTROPIN RELEASING FACTOR, A PROCEDURE FOR THEIR PREPARATION, A COMPOSITION THAT INCLUDES THEM, A PROCEDURE FOR THE PREPARATION OF SUCH COMPOSITION, INTERMEDIARIES AND THE USE OF SUCH COMPOUNDS.