MXPA97002028A - Heterociclic bradiquinin antagonists, replaced with fluoroalquilo and fluoroalcoxi, procedures for its preparation and its use - Google Patents

Abstract

Heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) are described with a bradykinin antagonist effect (See Formula) wherein X1-X3 signifies N6CR5, R1 and R2 signify H or halogen, R3 and R4 signify H, halogen, alkyl or alkenyl, R5 signifies H, halogen, alkyl (substituted), O-R6, S-R6, NHR6, aryl (substituted), aryl (substituted) -alkyl, -C (O) -OR6o-C (O) -H , R6 and R8 mean H, alkyl, alkenyl or aryl-alkyl, R7 means (substituted) alkyl or (substituted) alkoxy, B means an aminocarboxylic acid, D means alkenodiyl, alkanediyl or (CH2) n-Yp- (CH2) m- E means oxygen or sulfur, Y means oxygen, sulfur or NR8, n and m mean a number of 0-3, or means a number of 1-3 and p means 0 or 1, as well as their physiologically compatible salts and a process for their preparation

Description

Heterocyclic bradykinin antagonists, substituted with fluoroalkyl and fluoroalkoxy, procedures for their preparation and use The invention relates to fluoroalkyl substituted and fluoroalkoxy substituted heterocyclic compounds, which have a bradykinin antagonist effect. From the European patent documents EP-A 622. 361 and from US Pat. No. 5,218,182, US-5,216,165 and US-5,438,064, quinolines substituted in O and N and their use as antagonists of bradykinin receptors. Surprisingly, it was found that the introduction of fluoroalkyl groups provides compounds that have a clearly longer duration of effect. The present invention concerns heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) in which the symbols have the following meanings: a) x1-x3 are, same or different, N or CR5, -b) R1 and R2 are, same or different, 1 H 2. halogen, -O R3 and R4, equal or different, they mean 1. H 2. halogen 3. (C1-C5) alkyl 4. (C2-C5) alkenyl; d) R5 means 1. H 2. halogen 3. (C1-C6) alkyl 4. O-R6 5. S-R6 6. NHR6 7. (C6-C12) aryl 8. aryl (Cg-C12) -alkyl ( c1-c3) 9. -C (0) -0Rβ 10. -C (0) -H; the meanings 3, 7, 8 can be possibly substituted with one or several groups, such as p. ex.

OR6, SR6 N02, CN, NHR6, halogen; e) RR66 and and RR ° 8, equal or different, denote 1. H 2. alkyl (CJ-CJ) 3. (C3-C5) alkenyl 4. aryl (C6-C12) -alkyl (C1-C3); f) RR7 'ssiiggnifica 1. alkyl (C ^ -Cg), the hydrogens being partially or totally replaced by fluoro or chloro 2. (C1-C5) alkoxy, the hydrogens being partially or totally replaced by fluoro or chloro, -g) B means an aminocarboxylic acid, e.g. ex. methionine, alanine, phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyltyrosine, β- (2-thienyl) alanine, glycine, cyclohexylalanine, leucine , isoleucine, valine, norleucine or phenylglycine, serine or cysteine, aminopropionic acid, aminobutylic acid, -h) D means 1. alkenodiyl (C2-C5) 2. alkanediyl (C1-C5) 3. - (CH2) n-Yp - (CH2) m-; i) E means l. OR 2. S; j) Y means 1. or 2. S 3. NR8; k) n and m, equal or different, mean a number 0-3; 1) or means a number 1 - 3; m) p means a number 0 or 1; as well as its physiologically compatible salts. The alkyl and alkenyl can be straight chain or branched. The corresponding is valid for radicals derived from them, such as p. ex. alkoxy The aryl (C6-C12) is for example phenyl, naphthyl or biphenylyl, preferably phenyl. The corresponding is also valid for radicals derived from them, such as p. ex. aralkyl. Halogen (Hal) represents fluoro, chloro, bromo or iodo, preferably chloro. Physiologically compatible salts of compounds of the formula (I) are understood to mean both their organic salts and also their inorganic salts, as described in Re's Pharmaceutical Sciences (AR. Gennard (compiler), Mack Publishing Co., Easton PA , 17th edition, page 1. 418 (1985)). Due to the physical and chemical stability and the solubility, the sodium, potassium, calcium and ammonium salts are preferred among the acid groups; for the basic groups, the salts of hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acids or sulfonic acids, such as p. ex. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluene sulfonic acid. Preferred are compounds of the formula (I), wherein a) x? _x3 mean CR5; b) R3 and R4, equal or different, mean i. H 2. alkyl (C ^ -C-j) 3. (C3-C5) alkenyl; c) R5 means 1. H 2. alkyl ('-L-Cg) 3. 0-R6 4. S-R6 5. NHR6 6. aryl (Cg-C12) 7. aryl (Cg-Cl) -alkyl (C1 -C3) 8. -C (0) -0R6 9. -C (0) -H.

Especially preferred are compounds of the formula (I), in which a) B means leucine, isoleucine, valine, alanine, methionine, glycine, serine, aminopropionic acid or aminobutyric acid, -b) R7 means OCF-c) or means 1-2 The invention also relates to a process for the preparation of compounds of the formula (I), which is characterized in that a compound of the formula (II) is deprotonated, wherein X? ~ X3 and Rj as well as R4 are defined as above in formula (I), with Cs C0 or K2C03 in an inert solvent, preferably DMF or N-methyl-pyrrolidine, and reacted to room temperature with a compound of the formula (III) wherein R1 and R2 are defined as above in formula (I), • the compound thus obtained of formula (IV) is reduced wherein R, 4 X- and X3 are defined as above in formula (I), with the aid of transition metal halides, preferably SnCl2, FeCl3 to form a compound of formula (V), wherein R1, R2, R3, R4, X1 # X2 and X3 are defined as above in formula (I); a compound of the formula (V) is reacted with appropriately protected activated derivatives of aminocarboxylic acid derivatives of B (B-Prot), preferably with the acid chlorides of the aminocarboxylic acid derivatives of B protected with phthaloyl, the sine of inert solvents, such as NMP, possibly by the addition of DMAP, and in this way a compound of the formula (VI) is obtained, wherein B, R 1, R 2, R 3, R 4, l t X 2 and X 3 are defined as above in formula (I); and Prot represents an amino protecting group, as described in T. W. Greene, "Protective Groups in Organic Synthesis", edi torial John Wiley, 2? 1991 edition, p. ex. phthaloyl, benzyl or para-methoxybenzyl; d) a compound of the formula (VI), after the action of alkali metal hydrides, alkali metal carbonates or alcoholates, has been reacted in inert solvents, preferably DMF or NMP, followed by a treatment with R6X, R6 being defined as above in formula (I) and X denoting a leaving group, p. ex. halogen, methanesulfonate (mesylate) or toluenesulfonate (tosylate), obtaining a compound of the formula (VII), wherein B, R1, R2, R3, R4, R6, X1 # X2 and X3 are defined as above in formula (I) and Prot is defined as above in formula (VI); e) for the removal of the protective group (Prot) of the compound of the formula (VII), in the case of the phthaloyl group, it is preferably reacted with hydrazine in alcohols as solvents, at temperatures ranging from room temperature to the point of boiling, preferably at room temperature, obtaining a compound of the formula (VIII), wherein B, R1J1, R2, R3, R4, R6 X-, 2 and X3 are defined as above in formula (I) and Prot is defined as above in formula (VI), • a compound of the formula (VIII) with activated carboxylic acid derivatives of the formula (IX), wherein R, o and D are defined as above in formula (I), preferably their acid chlorides or carboxylic acids of formula (IX), activated by reagents, such as those used in the synthesis of peptides, or f2) a compound of the formula (VIII) is reacted with an amine or with an alcohol of the formula (X) wherein R7, o and D are as defined above and Z means OH or NH2, the compound of the formula (VIII) being reacted first of all or (X) with a doubly activated carbonyl compound for the formation of the urea or urethane group, e.g. ex. with carbodiimides, phosgene or esters of chlorocarbonic acid, preferably phosgene and carbonyldiimidazole, preferably at temperatures ranging from 0 ° C to room temperaturein the case of inert solvents, preferably dichloromethane or dimethoxyethane, or f3) a compound of the formula (VIII) is reacted with a corresponding isocyanate or isothiocyanate, preferably at temperatures ranging from 0 ° C to room temperature in the Inert solvents, preferably dichloromethane or dimethoxyethane and g) the compound obtained of the formula (I) is optionally converted according to known methods into its physiologically compatible salts.

The conversion to the bromoethyl compound is effected by reaction of the corresponding methyl derivative with N-bromo-succinimide, dibromohydantoin or bromine in inert solvents, preferably bromobenzene or cyclohexane at temperatures from 60 ° C up to the boiling point. tion. As a coupling reagent, all possible activation reagents used in peptide synthesis are considered, see p. ex. Houjben-Weyl, ethoden der organischen Chemie, volume 15/2, ed. Torial Georg Thieme Verlag, St ttgart 1974, but especially carbodiimides such as p. ex. N, N '-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide or N-ethyl-N' - (3-dimethylamino-propyl) carbodiimide. The coupling can be carried out in this case directly by reaction by addition of a carboxylic acid derivative with the activation reagent and optionally with an addition such as p. ex. 1-hydroxy-benzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103, 2. 054 (1970)), or, also, the previous activation of the carboxylic acid derivative as symmetrical anhydride or as an ester of HOBt or HOObt can be carried out separately and the solution of the Chemical species activated in an appropriate solvent can be added to the amine. The coupling or activation of the amino acid derivatives with one of the aforementioned activating reagents can be carried out in dimethylformamide, N-methyl-pyrrolidone or methylene chloride, or in a mixture of the solvents mentioned. Protective groups can also be used instead of the phthaloyl group, which protect both protons of the amino group, e.g. ex. 2 benzyl groups. The compounds according to the invention have, individually or in combination, a bradykinin antagonist effect, which can be tested in different models (see Handbook of Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, pages 53-55), p. ex. in the isolated uterus of a rat, the ileum of a guinea pig, the jugular vein of a rabbit or the isolated pulmonary artery of a guinea pig. The effects of the compounds of the formula (I) on bradykinin-induced bronchoconstriction and a carrageenan-induced foot edema can be determined analogously to Br. J. Pharmacol. 102, 774-777 (1991). The measurement of the binding to the B2 receptor of bradykinin of the ileum of a guinea pig is described below (R. B.

Innis et al. , Proc. Nati Acad. Sci. USES; 17 (1981) 2. 630): 1. Ligand: 3H-BRADIQUININE (from NEN Du Pont) 2. Buffer strips: a) Tail 25 mM TES TES (SIGMA, order no .: T-4152), 1 mM 10-phenanthroline (SIGMA, order no .: P-9375) b) Incubation buffer: 25 mM TES (SIGMA, custom no .: T-4152) 1, 1 mM 10-phenanthroline (SIGMA, custom no .: P-9375) 0.1% bovine albumin (SIGMA; custom no .: A-7906) Bacitracin 140 μg / l (SIGMA, order no B-0125) 1 M Dithiothreitol (SIGMA, custom no .: D-0632), Captopril 1 fiM - 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 membranes are released, by careful rubbing, coarsely from the contents of the intestine and cleaned in a 0.9% NaCl solution. The pieces of ileums, with a length of approximately 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 Ultratu -rax. 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 a. -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 fixation: For each concentration of the radioactive ligand the inespe-cific fixation must 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 3 H-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 / l, and the reaction is started by adding 100 μl of a membrane suspension. Also in this test, triplicate determinations are carried out and three samples are incubated, for the determination of non-specific binding, with 10 μmol / 1 of HOE 140. The preparations that are to be tested in terms of competence are essentially dissolved in a concentration of 1 mmol / 1 in di-ethyl sulfoxide (DMSO) and then diluted further with DMSO. Then, this solution is diluted 1:25 with the incubation buffer. After incubation, the samples are separated by filtration in the Skatron cell harvester through a hatmann filter paper strip GF / B, previously wetted with 0.1% PEI (poly (ethylene imine)) and subsequently washed. -te with 10 ml, for each sample, of TES buffer cooled by ice. The still wet filters are stamped 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) Scan: In the primary scan, only 1-2 concentrations of the test preparation (10-5 and 10"6 mol / l) are generally used, 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 procedure indicated above, the compounds of Examples 1, 2, 8, 22 and 29 were determined as representative compounds of the heterocyclic bradykinin antagonists, substituted with fluoroalkyl and fluoroalkoxy, of the formula (I) , the following values of CI5Q and K ^: Example Cl50 tnM] K¡ [nM] 1 9.0 1.0 2 40.0 4.0 8 28.0 3.4 22 95.0 10.0 29 38.0 5.1 Determinations of the antagonist effect on the contraction induced by bradykinin of the guinea pig ileum are carried out according to the following protocol: Guinea pigs weighing approximately 300 g (Morioth breed, 69) are killed by beating on the nape of 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 in., The experiment is started. After tracing the biological zero line, for each organ bath, bradykinin is added in a final concentration of 4 x 10"8 mol / l and the concentration is recorded graphically, after which it is rinsed for 3 min with a Tyrode's solution and after a rest pause of 20 min new bradykinin is added, the contraction maximum has been reached (control), it is necessary to rinse again and make a rest pause, then the bradykinin antagonist is added ( time of action 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 (mM): NaCl 137 Glucose 5.05 KC1 2.68 NaHC03 11.9 NaH2P04 0.47 MgCl2 x 2H20 0.49 CaCl2 x 2H20 0.68 Amplifier: TF6 V3 entity Fleck, Mainz Stylus writer with ink: Goerz Metrawatt SE 460, BBC Bradykinin: entity Bachem. So, p. ex. the compounds of Examples 1 and 2 possess the following IC 50 values, determined according to the above procedure Example C15Q [nM] 1 44.2 1,500.0 The clearly prolonged duration of the effect of the compounds of the formula (I) was checked in the jugular of a rabbit and is described below: The compounds of Examples 1 were compared. , X and Y. Examples X and Y are described in EP-A-622,361.

R Example 1 4-CF3 Example X 4-CH 3 Example Y 3-OCH 3 Comparison of the duration of the in vitro effect of heterocyclic bradykinin antagonists in the jugular vein isolated from a rabbit.

Description of the method: Male rabbits (New Zealand white rabbits, breeder: Mollegaard, Denmark, 2.5-3.0 kg) are slaughtered by injection of an overdose of sodium pentobarbital (1 ml of Narcoren + 0.5 ml of heparin). Both jugular veins are extracted and prepared, cut into a spiral shape, and longer pieces of approximately 1.5 cm are hung in buffered organ baths (Krebs-Henseleit buffer) with a pre-tension of 0.5 g. After a resting time for 30 min, contractions are provoked by the addition of bradykinin (10 ~ 7 M), which serves as a starting value. The substances under test are then added at a concentration of 10"5 M. The shown values of inhibition are average values (n = 6) .The values indicated at the time 15 min show the inhibition of the contraction induced by bradykinin, still in the presence of the substances under test, in the bath liquid after an incubation for 15 minutes, after which the contraction induced by bradykinin is terminated by rinsing with a simple buffer solution, at each of the other times indicated it was stimulated again with bradykinin (in the absence of the test substance in the bath fluid) and for the termination of the contraction, the bath fluid is replaced by a mere buffer solution.

Results: Compared with the compounds of Examples Y and X the compound of Example 1 shows superiority in the form of a clearly longer duration of effect of the effect. This is a measure of the mechanical strength of the attachment to the receiver. The compounds of Examples Y and X no longer show any inhibition after 4 h, while the compound of Example 1 still exhibits a strong inhibitory effect with a value of 68% after 6 h. For the form of application by oral route 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 presentation forms and appropriate administration, such as tablets, dragees, nestable capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. As inert vehicles, p. ex. gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. In this case, the preparation can be carried out in the form of both a dry granulate and a wet granulate. Suitable vehicle materials or oily solvents are, for example, vegetable or animal oils, 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, ointment or fat ointment or, if possible, in the form of a spray, the adhesion 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, ab ortho, 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 prevention of the 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 preparations farm <The chemicals and medicaments contain an effective amount of the active substance of the formula (I) individually or in combination - together with a carrier 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 excnts, 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 being able to be 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. A suitable 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: AIBN a, a '-azobis-isobutyronitrile DEI desorption-impact of electrons DCI desorption-chemical ionization AE ethyl acetate FAB bombardment with fast atoms DME dimethoxyethane DMF dimethylformamide DMAP dimethylaminopyridine NMP N-methyl-pyrrolidone nH n -heptane RT ambient temperature CH2C12 dichloromethane h hour (s) ESI ionization by electron spray The invention is explained by the following Examples.

Example 1 8- [3- (N- (4-trans-Trifluoromethyl-cinnamoylglycyl) -N-methylamino) -2,6-dichloro-benzyloxy] -2-methyl-quinoline a) 2,6-dichloro bromide -3-nitro-benzyl A 2,6-dichloro-3-nitro-toluene (100 g, 0.48 mol) in chlorobenzene (400 ml) was added in portions at 150 ° C a mixture of dibromohydantoin (70 g, 0.24 mol) and AIBN (5 g). After 1 h, a mixture of dibromohydantoin (35 g, 0.12 mol) and AIBN (2.5 g) was added again. After a further 1.5 h, it was allowed to cool and AE (500 ml) was added. This mixture was washed in each case with saturated solutions of Na 2 SO 3, Na 2 CO 3 and NaCl, then dried (over MgSO 4) and concentrated, resulting in the title compound as an amorphous powder.

Rf (AE / H 1/1) = 0.7 MS (DEI) = 283 (M +) b) 8- (2,6-Dichloro-3-nitro-benzyloxy) -2-methyl-quinoline A 8-hydroxy-2-methyl-quinoline (5 g, 33.3 mmol) in DMF (65 ml) was Cs2C03 (10.8 g, 33.3 mmol) was added at room temperature. After 30 min 2,6-dichloro-3-nitro-benzyl bromide (13 g, 45.6 mmol) was added. After 18 h H20 was added and the precipitate was filtered with suction and washed with EA (50 ml), the title compound resulting as an amorphous substance. Rf (AE / n-H 1/2) = 0.3 MS (DEI) = 362 (M) c) 8- (2,6-Dichloro-3-ami: non-benzyloxy) -2-methyl-guiolinine To the title compound of Example ib) (4.5 g, 12.4 mmol) in EA (60 ml) SnCl2-H20 (15 g, 66.6 mmol) was added and the suspension was heated to 70 ° C. After 1 h, it was concentrated in vacuo after cooling to room temperature and a 20% NaOH solution (100 ml) was added and then it was extracted 3 times with CH2C12. The combined organic phases were dried over CaCl2 and concentrated. R? (AE / nH 1/1) = 0.4 MS (FAB) = 333 (M + l) d) 8- (2,6-Dichloro-3-phthaloylglycylamino-benzyloxy) -2-methyl-quinoline To the title compound of Example le) (3.2 g, 10 mmol) and DMAP (1.2 g, 10 mmol) in NMP (30 mL) and pyridine (10 mL) was added phthaloylglycyl chloride (3.4 g, 15 mmol). ). The mixture was heated at 50 ° C for 1.5 h, cooled to 0 ° C and H20 (30 mL) was added. The precipitate was filtered with suction and washed with EA (100 ml), the title compound resulting as an amorphous powder. R1 (AE / n-H l / l) = 0.2 MS (FAB) = 520 (M + l) e) 8- [3- (N-Phthaloylglycyl-N-methylamino) -2,6-dichloro-benzyl-oxy] -2-methyl-quinoline To the title compound of Example Id) (3.7 g, 7.1 mmol) in DMF (40 mL) was added at 0 ° C sodium hydride (313 mg, from a 60% suspension, ~ 8 mmol). After 30 min, methyl iodide (0.5 ml, 0.8 mmol) was added by injection. The cooling was then removed and after 1 h cooled again to 0 ° C and H20 (75 ml) was added. The title compound was filtered with suction and washed with cold CH3OH (30 mL). R1 (AE / n-H 1/1) = 0.2 MS (FAB) = 534 (M + l) f) 8- [3- (N-Glycyl-N-methylamino) -2,6-dichloro-benzyloxy] -2-methyl-quinoline The title compound of Example le) (1.5 g, 2.8 mmol) and hydrazine hydrate (0.54 ml, 11.2 mmol) in ethanol (60 ml) were stirred for 12 h at room temperature. It was then concentrated and CH2C12 (40 mL) was added and filtered, and then the solid residue was washed with CH2C12 (40 mL). Concentration of the solution in CH2C12 afforded the title compound as a pale yellow foam. Rf (AE / CH3OH 1/1) = 0.25 MS (FAB) = 404 (M + l) g) Trans-4-trifluoromethyl cinnamic acid chloride To 4-trifluoromethyl-E-cinnamic acid (1 g, 4) , 6 mmol) and pyridine (375 μL, 4.6 mmol) in dry CH2C12 (11 mL) was added at 0 ° C thionyl chloride (335 μL, 4.6 mmol). It was then stirred for 1 h without cooling, cooled again to 0 ° C and filtered while excluding the wet. The filtered material (10 ml) contained the title compound and was used in aliquots for the next reaction step. h) 8- [3- (N- (4-trans-Trifluoromethyl-cinnamoylglycyl) -N-methylamino) -2,6-dichloro-benzyloxy] -2-methyl-quinoline To the title compound of Example 1 f) ( 250 mg, 0.6 mmol) in CH2C12 (3 mL) was added an aliquot of the solution of the title compound of Example 1 g) (2 mL, 1.5 eq., 0.9 mmol) at the temperature ambient. After 18 h a saturated solution of Na 2 CO 3 (10 mL) was added and extracted 3 times with CH 2 C 12 (3 x 20 mL). The organic phases were dried (on CaCl2) and concentrated. Chromatography on Si02 with EA as eluent afforded the title compound of Example 1 as an amorphous powder. Rf (EA) = 0.4 MS (ES) = 602 (M + l) Analogously to Example 1, the compounds of Examples 2 to 13 were obtained (Tables 1 and 2).

Table 1 Table 2 Example MS (M + H) 576 EXAMPLE 14 8- [2,6-Dichloro-3- (N- (4-trifluoromethyl-benzyloxycarbonyl-amino-acetyl) -N-methylamino) -benzyloxy] -2-methyl-quinoline They were stirred at room temperature for 6 h 4-trifluoromethyl-benzyl alcohol (65 mg, 0.37 mmol), 1,1-carbonyl-diimidazole (60 mg, 0.37 mmol) and DMAP (10 mg) in dichloromethane (5 ml). Then the title compound of Example lf) (150 mg, 0.37 mmol) was added and after a further 18 h, ethyl acetate (40 ml) was added. The mixture was washed in each case 1 × with saturated Na 2 CO 3 and a NaCl solution, dried with MgSO 4 and concentrated. The title compound resulted as a colorless foam. lf (AE) = 0.5 MS (FAB) = 606 (M + l) The compounds of Examples 15 to 24 were obtained analogously to Example 14 (Table 3) Table 3 Example 25 8- [3- (N- (4-Trifluoromethyl-phenylureidoacetyl) -N-methylamino) -2,6-dichloro-benzyloxy] -2-ethyl-quinoline To the title compound of Example 1 f) (200 mg, 0.49 mmol) in DME (10 mL) was added 4-trifluoromethyl-phenyl-isocyanate (93 mg, 0.49 mmol). After 3 h at room temperature, the solvent was removed from the solvent in vacuo.

Chromatography on Si02 with EA as eluent afforded the title compound Rf (AE) = 0.4 MS (ES) = 591 (M + l) Examples 26 to 28 were obtained analogously to Example 25 (Table 4) Table 4 Example 29 8- [3-N- (3-Trifluoromethyl-phenyl-thioureido-acetyl-N-methyl-amino) -2,6-dichloro-benzyloxy] -2-methyl-quinoline To the title compound of Example 1 f) (100 mg, 0.24 mmol) in DME (4 mL) was added at room temperature 3-trifluoromethyl-phenyl-isothiocyanate (50 mg, 0.24 mmol). After 2 hours, it was concentrated in vacuo and chromatographed on Si02 with EA as eluent, resulting in the title compound. Rf (AE) = 0.5 MS (FAB) = 607 (M + l)

Claims (10)

1. CLAIMS i.- Heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) in which the symbols have the following meanings: a) xr -X; 3 are, the same or different, N or CR; b) R1 and R2 are the same or different, 1. H 2. halogen; c) R3 and 4, equal or different, mean 1. H 2. halogen 3. alkyl (C ^ -Cg) 4. (C2-C5) alkenyl; d) R5 means 1. H 2. halogen 3. alkyl (C ^ -Cg) 4. O-R6 5. S-R6 6. NHR6 7 aryl (Cg -C12) 8. aryl (C6-C12) -alkyl (C-L-C-J) 9. -C (0) -OR6 10. -C (0) -H; the meanings 3, 7, 8 can be possibly substituted with one or several groups, such as p. ex. OR6, SR6, N02, CN, NHR6, halogen; e) R6 and R8, which are the same or different, denote 1. H 2. alkyl (C ^ Cg) 3. (C3-C5) alkenyl 4. aryl (C6-C12) -alkyl (C ^ C-j); f) R7 means 1. (C1-C5) alkyl, the hydrogens being partially or completely replaced by fluoro or chloro 2. (Cj-Cg) alkoxy, the hydrogens being partially or totally replaced by fluoro or chloro; g) B means an aminocarboxylic acid, h) D means 1. alkenodiyl (C2-C5) 2. alkanediyl (C1-C5) 3. - (CH2) n-Yp- (CH2) m-; i) E means 1. 0 2. S; j) Y means 1. 0 2. S 3. NR8; k) n and m, equal or different, mean a number 0-3; 1) or means a number 1 - 3; m) p means a number 0 or l; as well as its physiologically compatible salts.
2. 2. Heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) according to claim 1, wherein a) x? ~ X3 mean CR5; b) R3 and R4, equal or different, denote 1. H 2. alkyl (C] _-C3) 3. (C3-C5) alkenyl; c) R5 means 1. H 2. alkyl (C - ^ - Cg) 3. O-R6 4. S-R6 5. NHR6 6. aryl (Cg-C12) 7. aryl (Cg-C12) -alkyl (C1 -C3) 8. -C (0) -OR6 9. -C (0) -H.
3. 3. Heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) according to claim 1 or 2, wherein a) B means leucine, isoleucine, valine, alanine, methionine, glycine, serine, aminopropionic acid or aminobutyric acid; b) R means 1. CF3 2. OCF3; c) or means 1-2.
4. 4. Process for the preparation of heterocyclic fluoroalkyl and fluoroalkoxy derivatives of the formula (I) according to claims 1 to 3, characterized in that a) a compound of the formula (II) is deprotonated, di) wherein X1-X3 and Rj as well as R4 are defined as above in formula (I), with Cs2C03 or K2C03 in an inert solvent, and reacted at room temperature with a compound of the formula (III) wherein R1 and R2 are defined as above in formula (I); the compound thus obtained of the formula (IV) is reduced wherein R1, R2, R3, R4, X1 # X2 and X3 are defined as above in formula (I), with the aid of transition metal halides, to form a compound of formula (V), wherein R1, R2, R3, R4, X1 # X2 and X3 are defined as above in formula (I); a compound of the formula (V) is reacted with activated derivatives, appropriately protected, of aminocarboxylic acid derivatives of B (B-Prot), in inert solvents, optionally by the addition of DMAP, and in this way is obtained a compound of the formula (VI), wherein B, RJ xl 'x2 and x3 are defined as above in formula (I); and Prot represents an amino protecting group, a compound of the formula (VI), after the action of alkali metal hydrides, alkali metal carbonates or alcoholates has been effected, it is reacted in inert solvents, followed by a R6X treatment, R6 being defined as above in formula (I) and X denoting a leaving group, obtaining a compound of the formula wherein B, RJ and X3 are defined as above in formula (I) and Prot is defined as above in formula (VI); for the removal of the protecting group (Prot) from the compound of the formula (VII), in the case of the phthaloyl group, it is preferably reacted with hydrazine in alcohols as solvents, at temperatures ranging from room temperature to the point of boiling, obtaining a compound of the formula (VIII), wherein B, R1, R2, R3, R4, R6, X ?, X2 and X3 are defined as above in formula (I) and Prot is defined as and in formula (VI), • f? reacting a compound of the formula (VIII) with activated carboxylic acid derivatives of the formula (IX), wherein R7, o and D are defined as above in formula I), or f2) a compound of formula (VIII) is reacted with an amine or with an alcohol of the formula (X) wherein R7, o and D are as defined above and Z means OH or NH2, the compound of the formula (VIII) or (X) being reacted first with a double activated carbonyl compound for the formation of the group of urea or urethane, or f3) a compound of the formula (VIII) is reacted with a corresponding isocyanate or isothiocyanate, and g) the compound obtained of the formula (I) is optionally converted according to known methods into its physiologically compatible salts.
5. 5. Use of the fluoroalkyl or fluoroalkoxy heterocyclic derivatives of the formula (I) according to claims 1 to 3 as medicaments.
6. 6. Medicaments containing at least one fluoroalkyl or fluoroalkoxy heterocyclic derivative of the formula (I) according to claims 1 to 3.