MXPA97001857A - Aminoalquil-eteres and acilaminoalquil-eteres, procedure for its preparation and its use as antagonists of bradiquin receptors - Google Patents

Abstract

Aminoalkyl ethers and acylaminoalkyl ethers are described, which are distinguished by a high affinity for the B2 receptor of bradykinin and by an improved solubility in water. These aminoalkyl ethers and acylaminoalkyl ethers can be represented by the general formula (I) :( See Formula) wherein R 1, R 2, R 3 signify alkyl, aryl, alkylaryl, halogen, hydrogen, cycloalkyl, CHO, CO-O- alkyl, COOH, R4, R5 are hydrogen, halogen, alkoxy, nitro, cyano, S-alkyl, n denotes a number from 1 to 8, R6 is hydrogen, alkyl, alkylalkenyl, alkylaryl, R7 is hydrogen and a substituted acyl radical or without replacing Also disclosed is a process for the preparation of the components of the formula (

Description

Aminoalkyl ethers and acylaminoalkyl ethers, process for their preparation and their use as antagonists of bradykinin receptors From EP-A 622,361 and from US Pat. No. 5,212,182, US-A-5,216,165 and US-5,438,034, O-substituted quinolines are known. and N, and their use as antagonists of bradykinin receptors. Quinolines are not described, which in position 8 have substituents with an aminoalkyl ether function and an acylaminoalkyl ether function. The aminoalkyl ethers and acylaminoalkyl ethers described in the present application are distinguished by a high affinity for the B2 receptor of bradykinin and by an improved solubility in water, and are represented by the general formula (I), in which the symbols have the following meanings: R1, R2, R3 equal or different 1. alkyl (C2PC5), 2. aryl (C6-C10), 3. alkyl (C ^ Cj) -aryl (C6-C10), 4. halogen, 5. hydrogen, 6. (C3-C8) cycloalkyl, 7. CHO, 8. CO-O- (C1-C3) alkyl, 9. COOH; R4, R5 equal or different 1. hydrogen, 2. halogen, 3. (C1-C3) alkoxy, 4. nitro, 5. cyano, 6. S-alkyl (C ^ pC-j); n a number from 1 to 8; R6 l. hydrogen, 2. (C1-C3) alkyl, 3. (C3-C5) alkylalkenyl, 4. (C1-C3) alkyl-aryl (Cg-C10); R7 hydrogen and the following substituted or unsubstituted acyl radicals: alkanoyl (C - ^ - Cg) (eg formyl, acetyl, propionyl, etc.), alkoxy (C - ^ - Cß) -alkanoyl (C2-Cg) (eg methoxy-acetyl, ethoxy-acetyl, etc.), alkyl (C1-Cg) -carbamoyl-alkanoyl (C2-Cg) (eg methyl-carbamoyl-acetyl, etc.), aryl (C6) "C12 ^ -alkanoyl (C2-Cg) (eg phenylacetyl, tolylacetyl, etc.), alkenoyl (C3-C7) (eg acryloyl, crotonoyl, etc.), cycloalkyl (C3-Cg) -carbonyl (eg cyclopropylcarbonyl, cyclohexylcarbonyl, etc.), (C5-C7) cycloalkenylcarbonyl (eg cyclohexenylcarbonyl, etc.), alkoxy (C ^^ - Cj) -carbonyl (p. (eg methoxycarbonyl, ethoxycarbonyl, etc.), aryloxy (Cg-C12) -carbonyl (eg phenoxycarbonyl, etc.), aroyl (Cg-C12) (eg benzoyl, naphthoyl , etc.), (C1-C3) alkoxy-aroyl (C8-C12) (eg methoxy-benzoyl, etc.), halogen-aroyl (Cg-C12) (eg chloro-benzoyl etc.) , aryl (Cg-C12) -alkenoyl (C3-C8) (eg cinnamoi) it, alokinamoyl, a-methyl-cinnamoyl, 4-methyl-cinnamoyl, etc.), (C 1 -C 3) alkoxy-(C 6 -C 12) -alkeneoyl (C 3 -Cg) (p. ex. methoxycinnamoyl, ethoxy cinnamoyl, dimethoxy cinnamoyl, etc.), alkylenedioxy (C ^ pC-jJ-aryl (Cg-C12) -alkenoyl (C3-Cg) (eg methylenedioxy cinnamoyl, etc.), nitro-aryl (Cg-C12) -alkenoyl (C3-Cg) (eg nitro-cinnamoyl, etc.), cyano-aryl (C6-C12) -alkenoyl (C3-C8) (eg cyano- cinnamoyl, etc.), halogen-aryl (Cg-C12) -alkenoyl (C3-Cg) (eg chloro-cinnamoyl, dichloro-cinnamoyl, etc.), halogen-alkyl (C ^ pC-j) -aryl (Cg-C12) -alkenoyl (C3-Cg) (eg trifluoromethyl-cinnamoyl), hetero-cycloalkyl (C3-C8) -aryl (Cg-C12) -alkenoyl (C3-Cg) (eg morpholino-cinnamoyl, etc.), amino-aryl (Cg-C12) - alkenoyl (C3-Cg) (eg amino-cinnamoyl), alkyl (C ^ pC ^ -amino-aryl (Cg-C12) -alkenoyl (C3-C8) (eg methyl-amino-cinnamoyl, dimethyl) -amino-cinnamoyl, etc.), acyl (C2-C5) -amino-aryl (Cg-C12) -cinamoyl, (eg acetyl-amino-cinnamoyl, cyclopropyl-carbonyl-amino-cinnamoyl, etc.), alkoxy (C-jpC-j) -carbonyl-amino-aryl (Cg-C12) -cinnamoyl (eg methoxy) -carbonyl-amino-cinnamoyl, etc.), alkyl (C ^ C ^ -amino-carbonyl-amino-cinnamoyl (eg ethyl-amino-carbonyl-amino-cinnamoyl, etc.), hetero-aryl (Cg- C12) -alkanoyl (C2-Cg) -amino-aryl (Cg-C12) -alkenoyl (C3-C8) (eg pyridyl-acetyl-amino-cinnamoyl, etc.), aroyl (Cg-C12) -amino -aril (Cg-C12) -alkenoyl (C3-Cg) (eg benzoyl-amino-cinnamoyl, etc.), hetero-aryl (Cg-C12) -carbonyl-amino-aryl (Cg-C12) -alkenoyl (C3-C8) (eg, pyridyl-carbonyl-amino-cinnamoyl, etc.), alkyl ^ l "c5 ^ -sulfonyl-amino-aryl (Cg-C1) -alkenoyl (c3_c6 ^ (P- eJ • ethyl -sulfonyl-amino-cinnamoyl, etc.), alkyl (C ^ Cg) -ureido-aryl (C8-C12) -alkenoyl (C3-Cg) (eg ethyl-ureido-cinnamoyl, etc.), alkanoyl ( C2-Cg) -aryl (Cg-C12) -alkenoyl (C3-Cg) (eg acetyl-cinnamoyl), alkoxy (C ^ pCg) -carbonyl-aryl (Cg-C12) -alkenoyl (C3-Cg) (p. eg methoxy-carbonyl cinnamoyl, etc.), alkyl (C-L-CC) -carbamoyl-aryl (Cg-C12) -alkenoyl (C3-Cg) (p. ex. ethyl carbamoyl-cinnamoyl, etc.), aryl (Cg-C12) - carbamoyl-aryl (Cg-C12) -alkenoyl (C3-C8) (eg phenyl-carbamoyl-cinnamoyl, etc.), aryl (Cg) -C12) - alkoxy (C-jpCg) -carbonyl (eg benzyl-oxocarbonyl, etc.), alkyl (C ^ Cg) -carbamoyl (eg ethyl-carbamoyl, etc.), aryl ( C8-C12) -carbamoyl (eg phenyl-carbamoyl), aroyl (Cg-C12) -carbamoyl, (eg, benzoyl-carbamoyl, etc.), alkyl (Cj ^ -Cg) -sulfonyl (eg. eg methanesulfonyl, ethyl-sulfonyl, etc.), aryl (Cg-C12) -sulfonyl (eg phenylsulfonyl, etc.), aryl (C8-C12) -alkyl (C ^ Cg) -sulfonyl (eg benzyl sulfonyl, etc.) and phthaloyl (for R6 = R7), as well as their physiologically compatible salts. Alkyl, alkenyl and alkynyl can be straight chain or branched. The corresponding is valid for radicals derived from them, such as p. ex. alkoxy Aryl (Cg-C12) preferably means phenyl, naphthyl or biphenylyl. Correspondingly, radicals derived from these, such as aryloxy, aralkyl or aroyl, can be formulated. Heteroaryl is understood to mean radicals with up to 9 carbon atoms, which form a monocyclic or bicyclic aromatic ring, in which one or more CH groups are replaced by N, O and / or S. These are, for example. ex. , thienyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, indolyl, quinolyl and imidazopyridyl. Halogen represents fluoro, chloro, bromo and iodo, preferably chloro. Physiologically compatible salts of compounds of the formula (I) are understood to mean both their organic and inorganic salts, as described in the work Remington 's Pharmaceutical Sciences (AR Gennaro (compiler), Mack Publishing Co., Easton, PA, 17th edition, page 1. 418 (1985)). On the basis of physical and chemical stability and solubility, sodium, potassium, calcium and ammonium salts are preferred for acidic groups, - for basic groups, other salts with hydrochloric acid, sulfuric acid, acid are preferred phosphoric, or salts of carboxylic acids or sulfonic acids, such as p. ex. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid. Preferred are compounds of the formula (I), in which the symbols have the following meanings: R1, R2, R3 equal or different 1. hydrogen, 2. alkyl (C-L-C-J); R4, R5 halogen; R6 1. hydrogen, 2. methyl, ethyl, 3. benzyl; . and the other radicals and variables are defined as above. Especially preferred are the compounds of the formula (I), in which the symbols have the following meanings: R7 l. hydrogen, 2. an acyl radical, such as alkanoyl (C2-C6), aryl (C6-C12) -alkanoyl (C2-Cg), aryl (Cg-C12) -cycloalkanoyl (C2-C8), alkyl (C-jpCg) ) -aminocarbonyl, (C3-C7) alkenyl-aminocarbonyl, alkoxy (C ^ pC-j) -carbonyl, aryl (Cg-C1) -alkyl (C-jpCg) -aminocarbonyl, aryl (Cg-C12) -alkenoyl (C3) -C6), (C1-C3) alkoxy-aryl (Cg-C12) - alkenoyl (C3-Cg), halogen-aryl (C8-C12) - alkenoyl (C3-Cg), halogen-alkyl (C1-C3) - alkenoyl (C3-Cg), amino-aryl (Cg-C12) - alkenoyl (C3-C8), alkyl (C1-Cg) -amino-alkenoyl (C3-Cg), and hetero-aryl (Cg-C12) - alkenoyl (C3-Cg) and phthaloyl (for R6 = R7), and the other radicals and variables are defined as above.

Especially preferred are the compounds of the formula (I), in which the symbols have the following meanings: R1, R2, R3 equal or different l. hydrogen, 2. methyl, ethyl, propyl; R4, R5 chloro, -n from 1 to 4; R6 hydrogen; R7 i. hydrogen, 2. alkanoyl (C -C5), 3. alkenoyl (C3-C5), 4. alkyl (C - ^ - Cg) -aminocarbonyl, 5. aryl (Cg-C10) -alkyl (C ^ Cj) -aminocarbonyl 6. alkyl (C-jpCg) -oxycarbonyl, 7. aryl (Cg-C10) -alkyl (C-jpCrj) -oxocarbonyl, 8. aryl (Cg-C10) -cycloalkyl (C3-C7) -carbonyl, 9. a radical of trans-cinnamic acid, whose phenyl ring is substituted with up to 2 radicals, the same or different, taken from the series consisting of a) hydrogen, b) alkyl (Cj C ^, c) amino, d) mono- and di-alkyl (C ^ pC-j) -alkylamino, e) halogen, f) halogen-alkyl (C ^ pC-j), g) acyl (C2-C5) -amino and h) (C1-C3) alkoxy. The invention also relates to a process for the preparation of compounds of the formula (I), which is characterized in that a) a compound of the formula (II) is reacted (ll) wherein R1, R2 and R3 are defined as above, with a compound of the formula (III) wherein R4, R5 and n are as defined above, in the presence of metal hydrides, such as lithium, potassium or sodium hydride, or alkali metal carbonates, such as sodium, potassium or cesium carbonate, within an inert solvent, such as DMF or DMSO, at temperatures from 0 ° C to 60 ° C, to form a compound of the formula (IV) the symbols and variables being defined as above, -b) a compound of the formula (IV) is transformed by hydrazinolysis in refluxing ethanol, in a compound of the formula (la) (la) wherein R1, R2, R3, R4, R5 and n are defined as above, -c) optionally, the compounds of the formula (la) are acylated and / or alkylated according to known methods, and d) optionally, the compounds obtained from the formula (I) are converted according to known methods into their physiologically compatible salts. The acylation of the compounds of the formula (la) is effected by reaction with the correspondingly substituted carboxylic acids and sulfonic acids, or their activated derivatives and isocyanates. As activated acid derivatives, acid chlorides, acid anhydrides and active esters, for example, are involved in this case. ex. chlorides and bromides of carboxylic acids, mixed anhydrides, symmetrical anhydrides, p-nitrophenyl esters and hydroxy-succinimide esters. The choice of one of these activated derivatives is dependent on the acyl group that has been introduced. In the case of free acids, the acylation is carried out in the presence of the condensation reagents used in the chemistry of the peptides, see p. ex. Houben-Weyl, Methoden der Organischen Chemie, Volume 15/2, Georg Thieme Verlag, Stuttgart 1974, but especially carbodiimi-das such as p. ex. N, N '-dicyclohexyl-carbodiimide, N, N'-diisopropyl-carbodiimide and N-ethyl-N' - (3-dimethylamino-propyl) -carbodiimide or uronium salts such as 0- [cyano- (ethoxycarbonyl) tetrafluoroborate] -methylamino] -1, 1, 3, 3-tetramethyl-uronium (TOTU) and O-benzotriazol-1-yl-N, N, N ', N' -tetramethyl-uronium hexafluorophosphate (HBTU). The acylation and respectively the activation of the acid derivatives are carried out in conventional organic solvents, such as CH2C12, dioxane, THF or DMF. The acylation is carried out in the presence of an inorganic or organic base, at temperatures of 0 ° C to reflux. The processes for the preparation of the compounds of the formula (II) are known, inter alia, from H.

Fiedler, J. Prakt, Chemie, volume 13, 1961, pages 86 et seq. The compounds of the formula (III) are prepared by halogenation of the corresponding methyl compounds of the formula (V) wherein R 4, R 5 and n are as defined above, preferably with N-bromo-succinimide or 1,3-dibromo-5,5-dimethylhydantoin in refluxing chlorobenzene. The preparation of the compounds of the formula (V) is carried out by alkylation of the phenols of the formula (VI) wherein R 4 and R 5 are as defined above, with N- (bromoalkyl) -phthalimides obtainable commercially, in the presence of alkali metal carbonates such as sodium carbonate, potassium or cesium in DMSO as solvent at room temperature and in Reaction time periods of 10 min up to 1 h. The compounds of the formula (I), according to the invention, individually or in combination have an antagonistic effect of bradykinin, which can be tested in different models (see Handbook of Exp. Pharma, volume 25, Springer). Verlag, 1970, pages 53 -55), so p. ex. in the isolated uterus of a rat, in the ileum of a guinea pig, in the isolated pulmonary artery of a guinea pig or in the jugular vein of a rabbit. The effects of the compounds of the formula (I) on bradykinin-induced bronchoconstriction and on foot edema, induced by carrageenan, can be determined analogously to the procedure described in Br. J. Pharma-col. , 102, 774-777 (1991). The determination of the affinity of the compounds of the formula (I) with the B2 receptor of bradykinin was carried out in membrane preparations of the ileum of a guinea pig (R.B. Innis et al., Proc. Nati. Acad. Sci. USA; 17 (1981) 2 630) according to the following procedure: 1. Ligand: 3H-BRADIQUININE (from NEN Du Pont) 2. Packers: a) TES TES buffer 25 mM (SIGMA, order no .: T-4152) 1, 10-phenanthroline 1 M (SIGMA, order no .: P-9375) b) 25 mM TES incubation buffer (SIGMA, custom no .: T-4152) 1, 10 M-phenanthroline (SIGMA, custom nr: P-9375) 0.1% bovine albumin (SIGMA; of order: A-7906) Bacitracin 140 μg / ml (SIGMA, order no. B-0125) 1 mM Dithiothreitol (SIGMA, custom no .: D-0632), Captopril 1 μ - 1- [(2S) - 3-mercapto-2-methyl-propionyl] -L-proline.

Both buffers were adjusted to pH 6.8 with 5 molar NaOH. 3. Preparation of guinea pig ileum membranes are released, by careful rubbing, roughly from the contents of the intestine and cleaned in a 0.9% NaCl solution. The pieces of ileums, with a length of 2 cm, are transferred to an ice-cold TES buffer (approximately 1 g / 10 ml) and homogenized in the ice bath for approximately 30 s with the Ultraturrax. The homogenized material is then filtered through 3 layers of gauze and the filtrate is centrifuged at 50,000 xg / 10 minutes. The supernatant is discarded, the pellet is rehomogenized in the same volume of TES buffer and centrifuged again at 50,000 xg / 10 minutes. The sediment is rehomogenized in the incubation buffer (approximately 1 g / 5 ml) and frozen at -70 ° C, in 2 ml portions, inside cryogenic tubes. The protein concentration of the finished membrane suspension is determined according to LOWRY and should be about 15 μg / 100 μl. 4. Assay binding: All incubations are carried out at room temperature for 60 minutes on microtiter plates (96 x 300 μl) in a volume of 200 μl. All batches are made in the incubation buffer. For this, 50 μl of the radioligand, 50 μl of the preparation to be tested and 100 μl of the membrane suspension were consecutively pipetted into the microtiter plate cavities. a) Saturation experiments (hot saturation): Preparation of the 3H-bradykinin solution: For the saturation experiments the concentrations 0.05, 0.1, 0.2, 0.4, 0.6, 0 are used. , 8, 1.0, 1.5, 2.0, 2.5 and 3.0 nmol / 1, which corresponds to 0.05 to 3.0 pmol / ml. After the preparation of the corresponding dilutions, 50 μl of each of them per sample is previously arranged per sample. Non-specific binding: For each concentration of the radioactive ligand, non-specific binding should be determined. This can be achieved by adding a high concentration (1-100 μmol) of the unlabeled ligand, other antagonists or agonists of the bradykinin receptor. In this test HOE 140 (10 μmol / 1) is used. For this, 1,862 mg in 1 ml of dimethylsulfoxide (DMSO) are dissolved, diluted 1:25 with the incubation buffer and 50 μl is added to the samples in the microtiter plate. The reaction is started by the addition of 100 μl of the membrane suspension. b) Competency experiments (IC50): In this case a fixed size of the radioactive ligand (from 0.25 to 0.3 nmol / 1 of 3H-bradykinin) and different concentrations of unlabeled agonists or antagonists are used. In each case, 50 μl of the 3H-bradykinin solution is added with 50 μl of the preparations or standards to be tested, in the concentrations of 10 ~ 5 to 10"10 mol / 1, and the reaction is started. by the addition of 100 μl of a membrane suspension, also in this assay determinations are carried out in triplicate and three samples are incubated, for the determination of non-specific binding, with 10 μmol / 1 of HOE 140. which are to be tested for competence are primarily dissolved in a concentration of 1 mmol / l in dimethylsulfoxide (DMSO) and then further diluted with DMSO, then this solution is diluted 1:25 with the incubation buffer. of the incubation, the samples are separated by filtration in the Skatron cell harvester through a Whatmann GF / B filter paper strip, previously wetted with 0.1% PEI (poly (ethylenimine)) and subsequently washed with 10 ml, for each sample, TES buffer cooled by ice. The still wet filters are die cut and separated into mini-scintillation tubes and loaded with 3 ml of a scintillator. After a soaking time of about 12 hours, the samples are briefly shaken and measured in a beta counter. c) Exploration: In the primary scan, only 1-2 concentrations of the test preparation (10 ~ 5 and 10"6 mol / l) are used in general, if a 50% radioligand displacement can be detected at the highest concentration. or more, a complete analysis (competition experiment) is carried out with at least 8 concentrations. 4. Evaluation: The evaluation is carried out through the LIGAND program package (Me Pherrson, Minson &Rodbard, sale: Elsevier-BIOSOFT), which carries out the necessary calculations to determine the IC50 and K¿ values. This program also produces graphical representations of the saturation or displacement curves as well as the SCATCHARD graph, the HILL graph or the HOFSTEE graph.

. Test results: According to the aforementioned procedure, the following values were determined for the compounds of Examples 2, 5 and 6, as representative compounds of the described aminoalkyl ethers and acylaminoalkyl ethers of the formula (I). i = Example K¿ [nM] 2 20 5 61 6 32 Furthermore, for the determination of the bradykinin antagonist effect of the compounds of the formula (II), their effect on the contraction of the ileum of a guinea pig induced by bradykinin can be measured according to the following protocol: Guinea pigs weighing approximately 300 g (Morioth race, 69) are killed by beating on the neck and bleed. The ileum is extracted and prepared in a length of approximately 20 cm, rinsed with a solution of Tyrode (Record syringe) and is thus released from the contents of the intestine. Then it is subdivided into segments with a length of 1.5 cm. These are fixed in organ baths that have a capacity of 10 ml, which are filled with a Tyrode solution, and are joined with strips measuring the elongation (isometric measurement of the contraction). The preload is 1 g. The Tyrode solution is heated in a 37 ° C water bath and bubbled with pressurized air. After an interval of 30 min., The experiment is started. After tracing the biological zero line, for each organ bath, bradykinin is added to a final concentration of 4 x 10"8 mol / 1 and the concentration is recorded graphically, after which it is rinsed for 3 min with a solution of Tyrode and after a rest pause of 20 min new bradykinin is added.The maximum of the contraction (control) has been reached.It is necessary to rinse again and make a rest pause.Then the bradykinin antagonist is added (time 10 min.) After that, bradykinin is added again and the contraction that then occurs is compared with that of the control.The graphic record of the experiment is carried out on an ink writer stylus.

Tyrode solution (M): NaCl 137 Glucose 5.05 KC1 2.68 NaHCO3 11.9 NaH2P04 0.47 MgCl2 x 2H20 0.49 CaCl2 x 2H20 0.68 Amplifier: TF6 V3 Fleck entity, Mainz Ink stylus writer: Goerz Metra att SE 460, BBC Bradiquinina: entity Bachem.

Thus, for example, the compound according to Example 1 has the following IC50 value, determined according to the above procedure: IC50 = 1.8 x 10"6 M. For the form of application orally or for the application on the mucous membranes, the active compounds are mixed with the usual additive materials for this, such as vehicle materials, stabilizers or inert diluents and are brought by customary methods to suitable forms of presentation and administration, such as tablets, dragees, nestable capsules, suspensions aqueous, alcoholic or oily, or aqueous, alcoholic or oily solutions, eg inert carriers, eg gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially In this case, the preparation can be made to the form of both a dry granulate and a wet granulate, such as vehicle materials or solvents. oils, for example, vegetable or animal oils are considered., such as sunflower oil and cod liver oil. A preparation for topical administration can be presented as an aqueous or oily solution, lotion, emulsion or jelly, fat ointment or ointment or, if possible, in the form of a spray, the adherence possibly being improved by the addition of a polymer. For the intranasal application form, the compounds are mixed with the usual additive materials for this, such as stabilizers or inert diluents and are brought by customary methods to appropriate forms of presentation and administration, such as aqueous, alcoholic or oily suspensions. or aqueous, alcoholic or oily solutions. Aqueous intranasal preparations can be admixed with chelating agents, ethylenediamine-N, N, N ', N' -tetraacetic acid, citric acid, tartaric acid or its salts. The application of the nasal solutions can be done by dosing sprayers, or in the form of nasal drops with an increasing portion of the viscosity, or a nasal gel or a nasal cream. The compounds of the formula (I) which have been described, and their pharmacologically appropriate salts, are potent antagonists of bradykinin. Therefore, its therapeutic utility lies in the treatment and / or prevention of all disease states, which are mediated, provoked or sustained by bradykinin or bradykinin-like peptides. This involves, among other conditions, allergies, inflammations, autoimmune diseases, shock, pain and, more especially, asthma, cough, bronchitis, rhinitis, chronic obstructive pulmonary diseases, pneumonitis, septic shock, endotoxic shock, anaphylactic shock, disseminating intravascular coagulopathy , arthritis, rheumatism, osteoarthritis, lumbago, bone resorption induced by inflammation, conjunctivitis, iritis, headache, migraine, migraine, toothache, back pain, pain caused by cancers, postoperative pain, traumas (wounds, burns, etc.) ), rash, rash, erythema, edema, eczema, dermatitis, zoster, herpes, pruritus, psoriasis, dermatomycosis, inflammatory bowel diseases, hepatitis, pancreatitis, gastritis, esophagitis, nutrition allergies, ulcers, irritable bowel, angina, cerebral edema, blood hypotension, thrombosis, cranio-encephalic and spinal traumas, premature labor, abo rto, atherosclerosis, ascites in the case of a malignoma, tumor metastasis, cerebral edema in the case of tumors, thermal brain injuries and diseases caused by viruses. Since it is also known that bradykinin is linked to the release of mediators, such as prostaglandins, leukotrienes, tachykinins, histamine, thromboxanes, the compounds of formula (I) therefore also have the potential to carry out the treatment and / or the prevention of diseases that are caused by these mediators. The invention therefore also concerns the use of compounds of the formula (I) as pharmaceuticals and pharmaceutical preparations containing these compounds. The pharmaceutical preparations and medicaments contain an effective amount of the active substance of the formula (I) - individually or in combination - together with a vehicle material, organic or inorganic, pharmaceutically usable. The application can be carried out enterally, parenterally - such as p. ex. subcutaneous, intramuscular (i.m.) or intravenous (i.v.) -, sublingual, epicutaneous, nasal, rectal, intravaginal, intra-oral or by inhalation. The dosage of the active substance depends on the species of warm-blooded animal, body weight, age and mode of application. The pharmaceutical preparations of the present invention are produced according to known methods of dissolution, mixing, granulation and / or dragee-making. For the application by inhalation, nebulizers or containers with gas under pressure can be used, using inert carrier gases. For application by an intravenous, subcutaneous, epicutaneous or intradermal route, the active compounds or their physiologically compatible salts can be carried, if desired together with the usual pharmaceutically acceptable excipients, for example for isotonization or pH adjustment as well as the solubilizers, emulsifiers, or other adjuvants, to the form of a solution, suspension or emulsion. If the semi-disintegration times of the medications described in body fluids are insufficient, the use of delayed injectable preparations is appropriate. As drug forms can be used p. ex. oily suspensions of crystals, microcapsules, rods or implanted ones, the latter ones being constituted from polymers compatible with the tissues, especially biodegradable polymers, such as p. ex. based on copolymers of poly (lactic acid) -poly (glycolic acid) or human albumin.

An appropriate dose range for topical and inhalative administration forms is for solutions of 0.01-5 'mg / 1, and in the case of systemic application forms, 0.01-10 mg / kg. As a general rule, amounts between 0.1 mg / body and 1,000 mg / body can be applied.

List of abbreviations: CH2C12 dichloromethane DCI desorption-chemical ionization DIP diisopropyl ether DMF N, N-dimethyl-formamide AE ethyl acetate FAB bombardment with fast atoms h hour (s) MeOH methanol min minute (s) MS mass spectrum TA room temperature TOTU O- [cyano (ethoxycarbonyl) -methyleneamino] -1,1,3,3-tetramethyl-uronium tetrafluoroborate Desc. decomposition.

The invention is explained by the following Examples. Example 1 8- [3- (2-Amino-ethaxy) -2,6-dichloro-benzyloxy] -2-methyl-quinoline a) 2,6-Dichloro-3- (2-phthaloyl-ethoxy) -toluene. 5.0 g (28.2 mmol) of 2,4-dichloro-3-methyl-phenol were stirred for 10 min at RT. , 2 g (28.2 mmol) of Cs C03 in 100 ml of DMSO. 7.5 g (28.2 mmol) of N- (2-bromoethyl) phthalimide was added and the resulting reaction mixture was stirred for 16 h at RT. It was mixed with H20 and the reaction solution was extracted multiple times with EA. The organic phases were combined, washed with 1 N NaOH, 1 N HCl, H 2 O and saturated NaCl solution, and dried over Na 2 SO 4. Filtration, removal of the solvent and chromatography on silica gel with a 1: 4 mixture of EA and n-heptane yielded 2.9 g of the title compound. P.f .: 148 ° C Rf (Si02, AE / n-heptane 1: 4) = 0.15 MS (DCI): 350 (M + H) b) 2,6-dichloro-3- (2-phthaloyl-ethoxy) -benzyl bromide A solution of 1.9 g (5.4 mmol) of the compound of Example la), 1.0 g (5.4 mmol) ) of N-bromo-succinimide and 50 mg of benzoyl peroxide in 20 ml of chlorobenzene was heated for 2 h at reflux. It was concentrated to dryness and the residue was taken up in CH2C12. The CH2C12 solution obtained was washed with a saturated solution of NaHCO3 and H20 and dried over Na2SO4. It was concentrated to dryness and the residue was recrystallized from EA. Filtration with suction and drying of the crystals in high vacuum afforded 1.9 g of the title compound. P.f .: 171 ° C Rf (Si02, AE / n-heptane 1: 2) = 0.19 MS (DCI): 428/430 (M + H) c) 8- [2,6-Dichloro-3- (2-phthaloyl-ethoxy) -benzyloxy} -2-methylquinoline To a suspension of 207.0 mg (4.3 mmol) of a 50% dispersion of NaH in mineral oil in 30 ml of absolute DMF, it was added in portions at 700 ° C. mg (4.3 mmol) of 8-hydroxy-2-methyl-quinoline. It was stirred at 0 ° C for 30 min and 1.85 g (4.3 mmol) of the compound of Example Ib) were added in portions as well. After stirring for 1 h at 0 ° C, the reaction solution was concentrated to dryness, the residue was suspended in a little H20 and extracted several times with CH2C12. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated. The residue obtained was recrystallized from AE. Filtration with suction and drying of the white crystals afforded 2.0 g of the title compound.

P.f. : 176 ° C Rf (SiO 2, AE / n-heptane 1: 2) = 0.13 MS (DCI) = 507 (M + M). d) 8- [3- (2-Amino-ethoxy) -2,6-dichloro-benzyloxy] -2-methyl-quinoline A solution of 1.8 g (3.5 mmol) of the compound of Example le) and 350 μl (7.2 mmol) of hydrazine hydrate in 30 ml of ethanol was heated to reflux for 1.5 h. It was concentrated to dryness, the obtained residue was suspended in water, and the suspension, after adding 2N NaOH (pH ~ 12), was extracted multiple times with CH2C12. Drying over Na 2 SO 4, removal of the solvent and purification by chromatography on silica gel with AE / MeOH / NH 4 OH = 8: 2: 0.1 gave 1.3 g of the title compound. P.f .: 123-125 ° C Rf (AE / MeOH / NH 4 OH 8: 2: 0.1) - 0.16 MS (DCI) = 377 (M + H) Example 2 8- [3- (2-N- (trans-4-Amino-cinnamoyl) -amino-ethoxy) -2,6-dichloro-benzyloxy] -2-methyl-quinoline a) 8- [3- (2- (trans-4- (N-tert -Butyloxycarbonyl) amino-cinnamoyl) -amino-ethoxy) -benzyloxy] -2-methyl-quinoline A solution of 120.0 mg ( , 32 mmol) of the compound of Example la), 83.5 mg (0.32 mmol) of trans-4- (N-tert-butyloxycarbonyl) -amino-cinnamic acid, 56.0 μl of N-ethyl-diiso -propylamine and 106.3 mg (0.32 mmol) of TOTU in 5 ml of absolute DMF were stirred at RT for 3 h. It was concentrated to dryness under high vacuum, the residue was taken up in a mixture of CH2C12 and water, and the organic phase was separated. It was washed with a 10% solution of KHS04 and with a 10% solution of NaHCO3 and dried over Na2SO4. Filtration, removal of the solvent and purification by chromatography on Si02 with EA / heptane 2: 1 yielded 130 mg of the title compound.

P.f .: 116-118 ° C Rf (AE / n-heptane 4: 1) = 0.27 MS (FAB): 622 (M + H) b) 8- [3- (2-N- (4-trans-Amino-cinnamoyl) -amino-ethoxy) -2,6-dichloro-benzyloxy] -2-methyl-quinoline A solution of 65.0 g ( , 10 mmol) of the compound of Example 2a) and 260 μl of trifluoroacetic acid in 5 ml of CH2C12 was stirred for 5 h at RT. It was concentrated to dryness and the residue was taken up several times in toluene and concentrated again to dryness. The remaining residue was taken up in a little MeOH and the title compound was separated by crystallization by the addition of diisopropyl ether. 60 mg of the title compound were isolated as bis-trifluoroacetate. P.f. : 158 ° C (dec.) Rf (EA / n-heptane 10: 1) = 0.18 MS (FAB): 522 (M + H).

Example 3 8- [2,6-Dichloro-3- ((2-N-ethyl-aminocarbonyl) -amino-ethoxy) -benzyloxy] -2-methyl-quinoline They were stirred at RT for 1.5 h 80.0 mg (0.21 mmol) of the compound of Example Id) and 33.0 μl (0.42 mmol) of ethyl isocyanate in 2 ml of CH C12. It was concentrated to dryness and the residue was triturated with a small amount of EA. The title compound resulted as a white precipitate, which was filtered with suction and washed with a small amount of cold EA. Drying in high vacuum gave 70 mg of the desired compound. P.f .: 153-154 ° C Rf (AE / n-heptane 1: 2) = 0.49 MS (DCI): 448 (M + H).

Example 4 8- [2,6-Dichloro-3- (2- (3-phenyl-propionyl) -amino-ethoxy) -benzyl-oxy] -2-methyl-quinoline They were reacted according to the procedure indicated in the Example 2a), 90.0 mg (0.24 mmol) of the compound of Example Id), 35.8 mg (0.24 mmol) of 3-phenyl-propionic acid, 42.0 μl (0.24 mmol) of N ethyl-diisopropylamine and 80.0 mg (0.24 mmol) of TOTU in 5 ml of absolute DMF. After chromatography on Si02 with EA / n-heptane 2: 1 as eluent, 60.0 mg of the title compound were obtained. P.f. : 112-114 ° C Rf (SiO 2, EA / n-heptane 2: 1) = 0.12 MS (DCI): 509 (M + H).

Example 5 8- [2,6-Dichloro-3- (trans-2-N-cinnamoyl-amino-ethoxy) -benzyloxy] -2-methyl-quinoline They were reacted, according to the procedure set forth in Example 2a), 100 , 0 mg (0.26 mmol) of the compound of Example Id), 39.3 mg (0.26 mmol) of trans-cinnamic acid, 46.6 μl (0.26 mmol) of N-ethyl-diisopropylamine and , 8 mg (0.26 mmol) of TOTU in 5 ml of absolute DMF. After chromatography on Si02 (EA / n-heptane 2: 1) 90 mg of the title compound resulted. P.f .: 170-171 ° C Rf (AE / n-heptane 2: 1) = 0.13 MS (DCI): 507 (M + H).

Example 6 8- [2,6-Dichloro-3- (2-N- (trans-4-methoxy-cinnamoyl) -amino-ethoxy) -benzyloxy] -2-methyl-quinoline They were reacted analogously to the procedure set forth in Example 2a), 100.0 mg (0.26 mmol) of the compound of Example id), 47.2 mg (0.26 mmol) of trans-p-methoxy-cinnamic acid, 46.6 μl (0.26 mmol). mmol) of N-ethyl-diisopropylamine and 88.8 mg (0.26 mmol) of TOTU in 5 ml of absolute DMF. They resulted 69 mg of the title compound.

MP: 182 ° C Rf (AE / n-heptane 2: 1) = 0.12 MS (DCI): 537 (M + H).

Example 7 8- [2,6-Dichloro-3- ((2-N- (trans-2-phenyl-cyclopropane-1-carbonyl) -amino-ethoxy) -benzyloxy] -2-methyl-quinoline Reacted, corresponding to the procedure set forth in Example 2a), 100.0 mg (0.26 mmol) of the compound of Example Id), 43.0 mg (0.26 mmol) of trans-2-phenyl-cyclo-ropano-1 acid carboxylic acid, 46 μl (0.26 mmol) of N-ethyl-diisopropylamine and 88.8 mg (0.26 mmol) of TOTU. 65 mg of the title compound were obtained. P.f. : 108 ° C (dec.) Rf (SiO 2, EA / n-heptane 2: 1) = 0.15 MS (DCI): 521 (M + H).

Example 8 8- [2,6-Dichloro-3- (2-N- (trans-3-methoxy-cinnamoyl) -amino-ethoxy) -benzyloxy] -2-methyl-quinoline They were reacted, corresponding to the procedure set forth in Example 2a), 100.0 mg (0.26 mmol) of the compound of Example Id) with 47.2 mg (0.26 mmol) of trans-m-methoxy-cinnamic acid. They were 55.0 mg of the title compound. P.f .: 158-159 ° C Rf (SiO 2, EA / n-heptane 2: 1) = 0.10 MS (DCI): 537 (M + H).

The following compounds of Examples 9-14 can be prepared analogously to the procedures set forth in Examples 1 and 2 by using N- (bromomethyl) -phthalimide, N- (3-bromo-propyl) -phthalimide and N- (4- bromo-butyl) -phthalimide in place of the N- (2-bromo-ethyl) -phthalimide in Example la): "3R - The compounds of Examples 15-20 can be prepared analogously to the procedures set forth in Examples 1 and 2 by using 2,5-dimethyl-8-hydroxy-quinoline-2,7,7-dimethyl-8-hydroxy. -quinoline and 2, 5, 7-trimethyl-8-hydroxy-quinoline, synthesized according to H. Fiedler, J. Prakt, Chemie, volume 13, 1961, pages 86 et seq. - instead of 8-hydroxy-2-me in Example le):

Claims (9)

CLAIMS Compounds of the formula (I), wherein the entities mean: R1, R2, R3 equal or different 1. alkyl (^ -05), 2. aryl (Cg-C10), 3. alkyl (C-jpC ^ -aryl (Cg-C10), 4 halogen, 5. hydrogen, 6. (C3-C3) cycloalkyl, 7. CHO, 8. CO-O-alkyl (C - ^ - C ^), 9. COOH, R4, R5 equal or different 1. hydrogen, 2. halogen, 3. (C1-C3) alkoxy, 4. nitro, 5. cyano, 6. S-alkyl (C ^ pCj), -n a number of 8, R6

1. hydrogen, 2. alkyl (C ^ pC ^, 3. (C3-C5) alkylalkenyl, 4. Alkylaryl (Cg-C10), R hydrogen and the following substituted or unsubstituted acyl radicals: alkanoyl (C-jpCg), alkoxy (C ^ pC ^ - alkanoyl (C2-Cg), alkyl (C1-Cg) -carbamoyl-alkanoyl (C2-Cg), aryl (Cg-C12) -alkanoyl (C2-C8), alkenoyl (C3-C7), cycloalkyl (C3-C8) -carbonyl, (C5-C7) cycloalkenylcarbonyl, (C1-C3) alkoxycarbonyl, aryloxy (Cg-C12) -carbonyl, aroyl (C8-C1), alkoxy-arylloyl (Cg-C12), halogen-aroyl (Cg-C12), aryl (Cg-C12) -alkenoyl (C3-Cg), alkoxy-aryl (Cg-C12) -alkenoyl (C3-Cg), alkylenedioxy (CjpC ^ - aryl (Cg-C1) -alkenoyl (C3-Cg), nitro-aryl (C8-C12) -alkenoyl (C3-Cg), cyano-aryl (Cg-C12) -alkenoyl (C3-Cg), halogen-aryl (Cg-C12) -alkenoyl (C3-Cg), halogen-alkyl (C-jpC ^ -aryl (Cg-C1) -alkenoyl (C3-Cg), hetero-cycloalkyl (C3) -C8) -aryl (Cg-C12) -alkenoyl (C3-C8), amino-aryl (Cg-C12) -alkenoyl (3_6) '(C1-C4) alkyl-amino-aryl (Cg-C12) -alkenoyl (C3-Cg), acyl (C2-C5) -amino-aryl (Cg-C12) -cinamoyl, alkoxy (C1-C3) -carbonyl-amino-aryl (Cg-C12) -cinnamoyl, alkyl (C1-C4) -amino-carbonyl-amino-cinnamoyl, hetero-aryl (Cg-C12) -alcanoyl (C2-Cg) -amino-aryl (Cg-C12) -alkenoyl (C3-C6), aroyl (Cg-C12) -amino-aryl (Cg-C12) -alkenoyl (C3-Cg), hetero-aryl (Cg-C12) -carbonyl-amino-aryl (Cg-C12) -alkenoyl (C3-Cg), alkyl (C ^ pCg) -sulfonyl-amino-aryl (Cg-C12) -alkenoyl (C3-C6), alkyl (C ^ pCg) -ureido-aryl (Cg-C12) -alkenoyl (C3) -Cg), (C2-Cg) alkanoyl-aryl (Cg-C12) -alkenoyl (C3-Cg), alkoxy (C-jpCg) -carbonyl-aryl (Cg-C12) -alkenoyl (C3-Cg), alkyl carbamoyl -aril (Cg-C12) -alkenoyl (C3-Cg), aryl (Cg-C12) -carbamoyl-aryl (Cg-C1) -alkenoyl (C3-Cg), aryl (Cg-C12) -alkoxy (C ^^ -Cg) -carbonyl, alkyl (C ^ Cg) -carbamoyl, aryl (Cg-C12) -carbamoyl, aroyl (Cg-C12) -carbamoyl, alkyl (C ^^-C) -sulfonyl, aryl (Cg-C12) -sulfonyl, aryl (6"ci2) - ^ F" -1 (? -c6> -sulfonyl and phthaloyl (for R6 = R7), us physiologically compatible salts.

2. - Compounds of the formula (I) according to claim 1, in which the symbols have the following meanings: R1, R2, R3 equal or different 1. hydrogen, 2. alkyl (C-pC-j); R4, R5 halogen; R6 l. hydrogen, 2. methyl, ethyl,

3. benzyl. 3. Compounds of the formula (I) according to claims 1 or 2, wherein R7 is hydrogen or 2. an acyl radical.

4. Compounds of the formula (I) according to claims 3, in which the symbols have the following meanings: R1, R2, R3 equal or different 1. hydrogen, 2. methyl, ethyl, propyl, -R4, R5 chlorine; n from 1 to 4; R ° hydrogen, -R7 l. hydrogen, 2. alkanoyl (C2-C5), 3. alkenoyl (C3-C5), 4. alkyl (C - ^ - Cg) -aminocarbonyl,

5. aryl (Cg-C10) -alkyl (C1-C3) -aminocarbonyl

6. alkyl (C - ^ - Cg) -oxocarbonyl,

7. aryl (Cg-C10) -alkyl (C1-C3) -oxycarbonyl,

8. aryl (Cg-C10) -cycloalkyl (C3-C7) -carbonyl,

9. a radical of trans-cinnamic acid, whose phenyl ring is substituted with up to 2 radicals, the same or different, taken from the series consisting of a) hydrogen, b) (C1-C3) alkyl, c) amino, d) mono- and di (C1-C3) alkyl-alkylamino, e) halogen, f) halogeno-alkyl, g) acyl (C2-C5) -amino and h) alkoxy. 5. Process for the preparation of compounds of the formula (I) according to claims 1 to 4, characterized in that a) a compound of the formula (II) is reacted OH wherein R1, R2 and R3 are as defined above, with a compound of formula (III) wherein R4, R5 and n are as defined above, in the presence of metal hydrides, such as lithium, potassium or sodium hydride, or alkali metal carbonates, such as sodium, potassium or cesium carbonate, within an inert solvent, such as DMF or DMSO, at temperatures from 0 ° C to 60 ° C to give a compound of the formula (IV), defining the symbols and variables as before; b) a compound of the formula (IV) is converted by hydrazinolysis in refluxing ethanol, into a compound of the formula (la), wherein R, R ?, R, R, Rb and n are defined as above; c) optionally the compounds of the formula (la) are acylated and / or alkylated according to known methods, and d) optionally the compounds of the formula (I) which have been obtained are converted according to known methods into their physiologically compatible salts. 6. Use of the compounds of the formula (I) according to claims 1 to 4, as medicaments. 7. Medicaments containing at least one compound of the formula (I) according to claims 1 to 4.