MXPA99001768A - Acylaminoalkenylene-amide derivatives as nk1 and nk2 antagonists - Google Patents

Abstract

Compounds of formula (I) wherein R is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy;R1 is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl or phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy, R3 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy;or is naphthyl, 1H-indol-3-yl or 1-lower alkyl-indol-3-yl, R4'and R4''are each independently of the other hydrogen or lower alkyl, at least one of the radicals R4'and R4''being hydrogen, and R5 is C3-C8cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl;or a salt thereof, have valuable pharmaceutical properties and are effective especially as NK1 and NK2 antagonists.

Description

DERIVATIVES OF AMIDA ACILAMINOALOUENILENIGA AS ANTAGONISTS OF K1 AND NK2 The invention relates to the compounds of the formula I: (l) wherein: R is phenyl which is unsubstituted or which is substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy, R-j_ is hydrogen or the "lower alkyl" , R 2 is hydrogen, lower alkyl, or phenyl, which is unsubstituted or "which is substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy, R 3 is phenyl which is unsubstituted or substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy; or is naphthyl, lH-indol-3-yl, or 1-lower alkyl-indol-3-yl.

R4 'and 4"are each independently of the other, hydrogen or lower alkyl, where at least one of the radicals R4' and R4" is hydrogen, and R5 is cycloalkyl of 3 to 8 carbon atoms, D-azacycloheptan-2-on -3-yl, or L-azacycloheptan-2-on-3-yl; and salts thereof, to processes for the preparation of these compounds, to pharmaceutical compositions comprising these compounds, to the use of these compounds in the therapeutic treatment of the human or animal body, or in the manufacture of pharmaceutical compositions. The general terms used hereinbefore and hereinafter, preferably have the following meanings within the scope of this application: The term "lower" denotes a radical having up to and including 7, and especially up to and including 4 atoms of carbon. Lower alkyl is, for example, alkyl of 1 to 7 carbon atoms, preferably alkyl of 1 to 4 carbon atoms, especially methyl and ethyl, and more especially methyl. Examples of lower alkyl are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, tertiary butyl, normal pentyl, neopentyl, normal hexyl, and normal heptyl. Halogen is, for example, fluorine, chlorine, bromine, or iodine. Halophenyl is, for example, (fluoro-, chloro-, bromo-, or iodo-) phenyl, preferably fluorophenyl or chlorophenyl, especially 4-fluorophenyl or 4-chlorophenyl, and more especially 4-chlorophenyl. Dihalophenyl is, for example, dichlorophenyl, difluorophenyl, or chlorofluorophenyl, preferably dichlorophenyl or difluorophenyl, especially 3,4-dichlorophenyl or 3,4-difluorophene-nyl, and more especially 3,4-dichlorophenyl. Trihalophenyl is, for example, trifluorophenyl or trichlorophenyl. 1-lower alkyl-indol-3-yl is, for example, 1-methyl-indol-3-yl. Cycloalkyl of 3 to 8 carbon atoms - and in a manner analogous to cycloalkyl of 5 to 7 carbon atoms - is, in each case, a cycloalkyl radical having the number of ring carbon atoms indicated. Accordingly, cycloalkyl of 3 to 8 carbon atoms is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably cyclohexyl. D-azacycloheptan-2-on-3-yl corresponds to the following group: which is derived from D (+) - epsilon-caprolactam; (amino-) substituted at the 3-position [= D-3-amino-epsilon-caprc-lactam = (R) -3-amino-hexahydro-2-azepinone]. In an analogous manner, L-azacycloheptan-2-on-3-yl corresponds to the group: which is derived from L- (-) - epsilon-caprolactam (amino-) substituted at the 3-position [= L-3-amino-epsilon-capro-lactam = (S) -3-amino-hexahydro-2- azepinone]. The salts of the compounds of the formula I sor. especially pharmaceutically acceptable salts. The compounds of the formula I having a basic group, for example, can. forming acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid, or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, sulfate-acids, or phosphates. When the compounds of formula I contain. ur. acid group, corresponding cor-bases salts are also possible, for example the corresponding alkali metal or alkaline earth metal salts, for example scdio, potassium, or magnesium salts, or salts with ammonia or with organic amines, for example salts of ammonium. The compounds of the formula I have valuable pharmacological properties. In particular, they act as neurokinin antagonists (NK antagonists), and therefore, be. able to prevent the symptoms of disease that are caused, among other things, by the production of substance P (NK1 receptor) and neurokinin A [= NKA] (NK2 receptor). The respiratory tract is equipped with sensory nerves containing a number of neuropeptides, especially tachykinins and CGRP (= peptide related to the calcitonin gene). The activation of the sensory nerves results in a local release of neuropeptides into the lungs. More especially, substance P and neurokinin A are produced, which trigger an acute inflammatory reaction called neurogenic inflammation. This inflammation reaction proceeds mainly through the activation of the NK1 receptor, and includes especially vasodilation, microvascular leakage, recruitment of inflammatory leukocytes, and excessive secretion of mucus, and also bronchoconstriction [mainly by activation of the neurokinin 2 receptor (receptor of NK2)]. These tachykinin effects are typical characteristics of asthma. The pharmacological action of the compounds of the formula I is based in particular on the agonization of the NK1 receptor and, in general, also on the antagonism of the NK2 receptor. The compounds of formula I, therefore, are capable of inhibiting neurogenic inflammation and tachykinin-induced bronchoconstriction. The advantageous effects of the compounds of the formula I can be demonstrated by different in vitro or in vivo test methods. For example, in vi tro inhibit the influx of Ca induced by [beta-Ala8] NKA (4-10) into the ovarian cells of transfected Chinese hamsters, which express recombinant human neurokinin 2 receptors, with IC50 values of approximately 10 nM. In addition, in an NK-2 binding assay, where it is tested for its ability to inhibit the binding of 1 -'- "2 NK with hrNK2CHO cells [culture conditions and cell isolation for hrNK2CHO cells, see N. Subramanian and collaborators, Biochem. Biophys, Res. Comm. 200 (1994) 1512-1520], exhibit IC5Q values of approximately 1 nM.In addition, they are effective, for example, in vivo, in the NKI bronchospasm test, in guinea pigs. of Indians with ED50 values of about 0.O5 to 1 milligram / kilogram orally, giving test compounds 2, 4, 12, or 24 hours before intravenous administration of 3.0 micrograms / kilogram of [Sar9, Me (02) 11 ] -substance P [= SarSP] The SarSP stimulation induces an increase in intratracheal pressure in guinea pigs, and some of the compounds of the formula I are also orally effective in the NK2 bronchospasm test in vivo. guinea pigs, in this case, the increase intratrageal pressure is induced by the intravenous administration of 0.8 micrograms / kilogram of [beta-Ala8] NKA (4-10), the test compounds being administered, for example, 2 hours before the stimulation. The compounds of the formula I are effective especially as antagonists of the NK1 receptors. Their action on this class of receptors, and their action on related receptor systems, for example NK2, make "the compounds of the formula I to be therapeutically useful in the prevention, treatment, or diagnosis of a number of diseases, for example diseases of the upper and lower respiratory tract, for example bronchial asthma, allergic asthma, non-allergic asthma, conditions of allergic hypersensitivity and hypersecretion, such as chronic bronchitis and cystic fibrosis; pulmonary fibrosis of different etiologies; diseases of the pulmonary and bronchial circulation, such as high pulmonary blood pressure, angiogenesis, metastasis; diseases of the gastrointestinal tract, such as Crohn's disease, Hirsprung's disease, diarrhea, malabsorption conditions, inflammatory conditions; in affective, traumatic, or inflammatory disorders of the central and peripheral nervous system, such as depression, anxiety states, migraine and other forms of cranial pain, embolisms, emesis; diseases of blood vessels, such as cranial vessels; diseases related to microcirculation in different tissues, such as skin and eyes; diseases of the immune system and the reticulohistiocyto-rio system, such as splenic and lymphatic tissues; conditions of pain and other disorders where the action of neurokinins, tachykinins, or other related substances is involved in the pathogenesis, the pathology, and the etiology.

As already mentioned, the compounds of the formula I act as antagonists of the substance P. Substance P plays an important role in different disorders, for example in conditions of pain, in migraine, and in certain disorders of the central nervous system, such as in states of anxiety, emesis, schizophrenia, and depression, and in certain motor disorders, such as in Parkinson's disease, and also in inflammatory diseases, such as rheumatoid arthritis, iritis, and conjunctivitis, in diseases of respiratory organs. Such disorders as in asthma and chronic bronchitis, in disorders of the gastrointestinal system, such as in ulcerative colitis and Crohn's disease, and in hypertension. The antagonizing effects of substance P can be demonstrated, for example, as follows: in vi tro, for example, the binding of 3 H-substance P with the bovine retina in the radio receiver test according to H. Bittiger, Ciba Foundation Symposium 91 (1982) 196-199, is inhibited with IC 50 values of approximately 0.2 nM. The invention relates preferably to the compounds of the formula I wherein: R is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl. RL is hydrogen or lower alkyl, R2 is hydrogen or phenyl, R3 is phenyl, halophenyl, dihalophenyl, trihalophenyl, 2-naphthyl, lH-indol-3-yl, or 1-lower alkyl-indol-3-yl, R4 'Y R411 are each independently of the other, hydrogen or lower alkyl, where at least one of the radicals R4 'and R4"is hydrogen, and R5 is cycloalkyl of 5 to 7 carbon atoms, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl or salts thereof.

The invention especially relates to compounds of the formula I wherein: R is 3,5-bistrifluoromethyl-phenyl, R-jL is hydrogen, methyl or ethyl, R 2 is hydrogen or phenyl, R 3 is phenyl, 4-chlorophenyl, 4- fluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4,5-trifluorophenyl, 2-naphthyl, lH-indol-3-yl, or l-methyl-indole-3 -yl, R4 'and R4"are each independently of the other, hydrogen or methyl, with at least one of the radicals R4' and R4" hydrogen, and R5 being cyclohexyl, D-azacycloheptan-2-on-3-yl, or L-azacycloheptan-2-on-3-yl; and pharmaceutically acceptable salts thereof.

The invention relates more particularly to compounds of the formula I wherein: R is 3,5-bistrifluoromethyl-phenyl, RL is hydrogen or methyl, R2 is hydrogen or phenyl, R3 is phenyl, 4-chlorophenyl, 3,4-dichlorophenyl , 2-naphthyl, lH-indol-3-yl, or l-methyl-indol-3-yl, R4 'and R4"are hydrogen, and R5 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L -zazacycloheptan-2-on-3-yl, and pharmaceutically acceptable salts thereof.

A special mention must be made of each of the following subgroups of a group of compounds of the formula I: (1) the compounds of the formula I wherein Rs is D-azacycloheptan-2-on-3-yl; (2) the compounds of the formula I wherein R 4 'and R 4"are hydrogen, (3) the compounds of the formula I wherein R is phenyl, 3,5-bistrifluoromethyl-phenyl, or 3,4,5-trimethoxyphenyl (4) the compounds of the formula I in free form, ie not in the form of a salt The invention relates especially to the specific compounds described in the Examples The compounds of the formula I can be prepared from a way known by itself, for example, by: (A) N-acylate a compound of formula II: i ") with a carboxylic acid R-C (= 0) -0H, or with a reactive derivative thereof, or (B) condensing a carboxylic acid of the formula III: or a reactive derivative thereof, with a cycloalkyl amir.a of 3 to 8 carbon atoms, or D (+) - or L (-) - 3-amino-epsilon-caprolactam, or (C) as a last step, synthesizing the double bond by means of a Wittig reaction or a variant thereof, for example from Wittig-Horner; and if desired, converting a compound of the formula I to a different compound of the formula I, and / or, if desired, converting a resulting salt into the free compound or into a different salt, and / or if desired, converting a resulting free compound of the formula I having salt forming properties into a salt, and / or, if desired , separating a resulting mixture of stereoisomers, diastereoisomers, or enantiomers, into the stereoisomers, diastereomers, or individual enantiomers. In the following more detailed description of the processes, unless indicated otherwise, the symbols R, RL-R3, R4 ', R ", and R5 are each as defined for formula I. Process (A) The reaction according to the Process (* 1 corresponds to the N-acylation known per se, of primary and secondary amines, that is, the formation of arylcarboxylic acid amides from the corresponding carboxylic acids, or derivatives of the same, and primary and secondary amines One of the numerous possible methods "which may be mentioned is the N-acylation of a compound of the formula II with a carboxylic acid chloride R ^ -COCl, for example, acid chloride 3, 5-bis-trifluoromethyl-benzoic, for example in the presence of triethyl amine, and optionally 4-dimethyl aminopyridine (DMAP) The compounds of formula II are prepared, for example, as follows: the starting material used is a compound of formula IV: (IV) wherein Pr is an amino protecting group [eg BOC = tertiary butyloxycarbonyl (-COO-tertiary butyl)], and Alk is alkyl of 1 to 7 carbon atoms. The alkyl ester is hydrolysed to obtain the carboxylic acid, the radical -NHRS is introduced by its reaction with the corresponding amine H2NR5 [formation of -C (= 0) -NHRS], and finally the protective group -Pr. A compound of the formula IV can be obtained, for example, by using, as a starting material, an alpha-amino acid derivative of the formula V: (eg R2 = H, R3 = phenyl, D-phenylalanine), protect the free amino group with a "Pr" protecting group [eg, BCC by its reaction with (BOC) 20], optionally introducing the R1 # group for example by N-alkylation, and esterifying the carboxylic acid radical (preferably to form ur., lower alkyl ester, especially the methyl ester). If desired, the introduction of the Rx group and the esterification of the carboxylic acid radical can also be carried out in a single step, for example with methyl iodide and Ag20 in dimethyl form. The carboxylic acid ester is reduced in the corresponding aldehydes Va: (for example, with diisobutyl aluminum hydride in toluene at -78 ° C), and finally reacted to form the compound of formula IV in a Wittig-Horner reaction. This can be effected, for example, by reaction with a trialkyl ester of phosphonoalkanoic acid of the formula (A10) 2P (= 0) - CH2-COOAlk (Alk = alkyl of 1 to 7 carbon atoms). In an advantageous variant of the preparation of the compounds of the formula IV described above, the known esters of the formula Vb are used (with Alk = lower alkyl, especially methyl): as a starting material (instead of the carboxylic acids of the formula V), and then a procedure analogous to that described above is carried out, that is, the free-ring group is again protected by a protective group "? r", optionally, the Rl r group is introduced and the compound is reduced in the aldehyde Va. If the aldehyde Va is reacted in the reaction of Wittig-Horner with a trialkyl ester of phosphonoalkanoic acid of the formula (AlkO) 2 (= 0) -CH (-Alk) -COOAlk (Alk = alkyl of 1 to 7 carbon atoms), then the compounds of Formula IV wherein R 4"is lower alkyl If the compounds of the formula IV are to be prepared, where R 4 'is lower alkyl, then, for example, an aldehyde of the formula Va can be reacted with an alkyl halide. magnesium oxide, for example magnesium magnesium iodide, to form a secondary alcohol, which can then be converted, for example, by Swern oxidation (oxalyl chloride, dimethyl sulfoxide), in a ketone of the formula Ve: The latter is then reacted in a manner analogous to aldehyde Va in a Wittig-Horner reaction, to form a compound of formula IV (wherein R 4 '= lower alkyl).

Process (B): The reaction according to Process (B) corresponds to the formation known per se of carboxylic acid amides from the corresponding carboxylic acids, or reactive derivatives thereof, and primary amines. From the large number of possible methods, the following may be mentioned: (1) the reaction of a carboxylic acid of the formula III with a primary amine H 2 NR 5, for example in the presence of carbodiimide hydrochloride N-ethyl-N '- (3-dimethylaminopropyl) (EDC), and 4-dimethyl aminopyridine (DMAP); (2) the reaction of a carboxylic acid of the formula III first with N-hydroxysuccinimide and carbodiimide hydrochloride N-ethyl-N '- (3-dimethylaminopropyl) in the presence of 4-dimethyl aminopyridine, for forming the corresponding N-hydroxysuccinimide ester, and then with the corresponding amine H2NRc;; (3) the reaction of a carboxylic acid of the formula III with an amine H2N ^ in the presence of 1-propanphosphonic acid anhydride. The compounds of formula III are prepared, for example, as follows: starting from a compound of formula IV, the amino protecting group is removed, for example in the case of BOC, by its reaction with trifluoroacetic acid, the amino group is acylated with a carboxylic acid R-COOH (for example, 3, 5-bistrifluoromethyl-benzoic acid), or with a reactive derivative thereof [analogously to Process (A)], and finally the alkyl ester group is hydrolysed, for example with LiOH in methanol and tetrahydrofuran. Process (C): A possible starting compound for the Wittig- (Horner) reaction is, for example, an aldehyde of the formula Va, wherein the amino protecting group is removed, and which is then N-acylated with a carboxylic acid R-COOH, (for example 3, 5-bistrifluoromethyl-benzoic acid), or with a reactive derivative thereof [in a manner analogous to Process (A)]. For example, this aldehyde can be reacted with a dialkyl phosphonoalkanoic acid ester amide of the formula (AlkO) 2P (= 0) -C0-NHRs, in a Wittig-Horner reaction, to form a compound of the formula I . The compounds of the formula I can also be converted in a manner known per se to other compounds of the formula I. For example, the compounds of the formula I wherein R *. is lower alkyl can be obtained by N-alkylation of a compound of formula I, wherein R? is hydrogen, with a compound Y3-R-., wherein Y3 is hydroxyl, or reactive esterified hydroxyl. The esterified reactive hydroxyl is, for example, halogen, especially bromine, iodine, or chlorine, or sulfonyloxy, for example methylsulfonyloxy or p-toluenesulfonyloxy. Another possible method consists in reacting a compound of the formula I, wherein R-_ is hydrogen, with a compound Y4 -R '', wherein Y4 is formyl, and R-. 'is a radical Rx minus a CH2 group [Rx = -CH2-R ,, 1], under reducing conditions (reductive amination). If any intermediates contain reactive groups that interfere, for example carboxyl, hydroxyl, mercapto, or amino groups, these groups can be protected temporarily by easily removable protective groups. The choice of suitable protecting groups, and the manner in which they are introduced and removed, are known per se, and are described, for example, in J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York 1973. Salts of compounds I can be prepared in a manner known per se. For example, the acid addition salts of the compounds I are obtained by treatment with a suitable acid, or with a suitable ion exchange reagent, and the salts with bases are obtained by treatment with a suitable base or with an suitable ion exchange reagent. The salts of the compounds of the formula I can be converted to the free compounds I in the customary manner: for example, the acid addition salts by treatment with a suitable basic agent, or with a suitable ion exchange reagent, and salts with bases, for example, by treatment with a suitable acid, or with an appropriate ion exchange reagent. The compounds of the formula I, including their salts (of the salt-forming compounds of the formula I), can also be obtained in the form of their hydrates, and / or can include other solvents, for example solvents that may have been used for the crystallization of the compounds in solid form. Depending on the nature of the variables and the corresponding number of centers of asymmetry, and also on the starting materials and selected procedures, the compounds of the formula I can be obtained in the form of mixtures of stereoisomers, for example mixtures of diastereoisomers or mixtures of enantiomers, such as racemates, or possibly also in the form of pure stereoisomers. Mixtures of diastereomers "which can be obtained according to the process, or by some other method, can be separated in the customary manner in mixtures of enantiomers, for example racemates, or in the individual diastereomers, for example based on the differences physicochemical between the constituents in a known manner, by fractional crystallization, distillation, and / or chromatography. Convenient, the most active isomer is isolated. Mixtures of enantiomers, especially the racemates, which can be obtained according to the process or by some other method, can be separated into the individual enantiomers by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms, by chromatography, and / or by its reaction with an optically active auxiliary compound, for example a base, acid, or alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, the separation thereof , and the release of the desired enantiomer. Conveniently, the most active enantiomer is isolated. The invention also relates to those forms of the process according to which a compound that can be obtained as an intermediate at any stage of the process, is used as a starting material, and the remaining steps are performed, or a starting material is used in the form of a derivative or salt, or especially formed under the conditions of the reaction. The invention also relates to the final products "having the (4S) configuration described in the following examples, which likewise have some action as NK1 / NK2 antagonists. In the process of the present invention, it is preferable to use the starting materials and the intermediates, in each case in free form or in salt form, which result in the compounds I, or its salts, described at the beginning as especially valuable. The invention also relates to novel starting materials and intermediates, in each case in free form or in salt form, for the preparation of compounds I or their salts, to their use, and to processes for preparation, the variable R being it is defined for compounds I. The invention also relates to the use of compounds I and their pharmaceutically acceptable salts in the treatment of allergic conditions and diseases, preferably in the form of pharmaceutically acceptable compositions, especially in a method for the therapeutic treatment of the animal or human body, and said method of treatment. The invention relates in the same way to pharmaceutical compositions comprising a compound I or a pharmaceutically acceptable salt thereof as an active ingredient, and to processes for its manufacture. These pharmaceutical compositions are compositions for enteral administration, such as oral and also rectal, for parenteral administration, for local administration, and especially for administration by inhalation to warm-blooded animals, especially humans, the compositions comprising the active pharmacological ingredient alone or together with customary pharmaceutical excipients. The pharmaceutical compositions comprise (in weight percent), for example, from about 0.001 percent to 100 percent, preferably from about 0.1 percent to about 50 percent active ingredient. Pharmaceutical compositions for enteral and parenteral administration are, for example, those in unit dosage forms, such as dragees, tablets, capsules, or suppositories, and also ampoules. These are manufactured in a manner known per se, for example, by means of conventional mixing, granulating, confectionery, dissolving, or lyophilizing processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, after the addition of suitable excipients, to form tablets or dragee cores. Suitable carriers are especially fillers, such as sugars, for example lactose, sucrose, mannitol, or sorbitol, cellulose preparations, and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, and also binders, such as starch pastes, using, for example, corn, crab, rice, or potato starch, gelatin, tragacanth, methyl cellulose, and / or polyvinyl pyrrolidone, and if desired, disintegrants, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. The excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid and their salts, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric coatings, using, among other things, concentrated sugar solutions, which may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and / or titanium dioxide, or solutions of coating in suitable organic solvents or mixtures of solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to tablets or dragee coatings, for example, for identification purposes, or to indicate different doses of the active ingredient. Other orally administrable pharmaceutical compositions are hard gelatin capsules, and also sealed soft capsules comprising gelatin and a plasticizer, such as icerol or sorbitol. Hard gelatine capsules may comprise the active ingredient in the form of granules, for example mixed with fillers, such as lactose, binders, such as starches, and / or brighteners, such as talc or magnesium stearate, and if you want, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as oils «Fatty, paraffin oil, or liquid polyethylene glycols, it being possible in the same way to add stabilizers. The rectally suitable pharmaceutical compositions are, for example, suppositories which consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, or higher alkanols. It is also possible to use rectal gelatin capsules comprising a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. For parenteral administration there are suitable, especially aqueous solutions of an active ingredient in a water-soluble form, and also suspensions of the active ingredient, such as the corresponding oil suspensions for injection, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous suspensions for injection comprising viscosity-increasing substances, for example sodium carboxymethyl cellulose, sorbitol, and / or dextran, and optionally also stabilizers. Pharmaceutical compositions for local administration are, for example, for the topical treatment of the skin: lotions, creams, and ointments, i.e. liquid or semisolid oil-in-water or water-in-oil emulsions; oily ointments that are anhydrous; pastes, that is, creams and ointments that have dust constituents absorbing secretions; gels that are aqueous, have a low water content or do not contain water, and that consist of inflatable gel-forming materials; foams, that is, liquid oil-in-water emulsions in aerosol form that are administered from pressurized containers; and paints that have an aqueous-ethanolic base; each of said compositions may comprise additional customary pharmaceutical excipients, such as preservatives. The pharmaceutical compositions for local administration are manufactured in a manner known per se, by mixing the active ingredient with the pharmaceutical excipients, for example by dissolving or suspending the active ingredient in the base material, or if necessary, in a portion thereof. For the preparation of emulsions in which the active ingredient is dissolved in one of the liquid phases, the active ingredient usually dissolves in that phase before emulsifying; for the preparation of suspensions wherein the active ingredient is suspended in the emulsion, the active ingredient is mixed with a portion of the base material after emulsification, and then added to the rest of the formulation. The dosage of the active ingredient may depend on different factors, such as the activity and duration of action of the active ingredient, the severity of the disease to be treated and its symptoms, the mode of administration, the species, sex, age, and the weight of the warm-blooded animal, and / or its individual condition. In a normal case, the daily dose for administration, for example oral administration, to a warm-blooded animal weighing approximately 75 kilograms, is estimated to be from about 1 milligram to about 1000 milligrams, especially from about 5 milligrams to about 200 milligrams. . This dose can be administered, for example, in a single dose or in several partial doses, for example, from 10 to 100 milligrams. The following examples illustrate the invention described above. Temperatures are given in degrees Celsius; DMSO = dimethyl sulfoxide; THF = tetrahydrofuran; EtOH = ethanol; carbamoyl = -C0NH2; hexane indicates an isomeric mixture of different hexanes (eg, supplied by Fluka); TLC = thin layer chromatography; TA = room temperature.

Example 1; Amide N- [(R> - (3R) -3-ethyl-N '- (3, 5-bistrifluoromethyl-benzoyl) -aminol-5- (1-methyl-indole) -3-ethyl-caprolactam-3-alkyl ester -3-yl) -pent-2-ßnoic 0.525 milliliters of 3,5-bistrifluoromethyl-benzoyl chloride at 0 ° C are added dropwise to a solution of 0.976 grams of N- [(R) -epsilon-caprolactam amide -3-acidic] acid (4R) - (N '-methyl-amino) -5- (1-methyl-indol-3-yl) -pent-2-enoic, and 1.1 milliliter of triethyl amine in 20 milliliters of methylene chloride. The reaction mixture is stirred at 20 ° C for 30 minutes, and concentrated by evaporation. The residue is taken up in ethyl acetate, and extracted once with water and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to chromatography by evaporation (85 grams of silica gel, ethyl acetate / acetone = 3/1). In this way, the title compound is obtained in the form of a colorless solid foam. Rf (ethyl acetate / acetone = 1/1) = 0.4. High performance liquid chromatography: Chiralcel OD, heptane / isopropyl alcohol = 80/20 plus 0.1 percent trifluoroacetic acid, 1 milliliter / minute, Rt = 24.39 minutes [a] D20 - = + 54.2 ° C ± 3.8 ° C ( c = 0.26, EtOH).

The starting materials can be prepared as follows: (a): Amide N- [(R) -ispsylQn-capro-actam-3-yl-lime acid. (4R) - (N '-methyl-amino) -5- (1-methyl-indol-3-yl) -pent-2-enoic: S added 27 milliliters of 4N hydrochloric acid in dioxane at 0 ° C, a 1.24 grams of N- [(R) -ispsilon-caprolactam-3-lyl] amide] (4R) - (N 1 -methyl-N 1 -tertiary butyloxycarbonyl-amino) -5- (1-methyl-indole-3) -il) -pent-2-enoic. The resulting suspension is stirred at room temperature for 15 minutes, and concentrated by evaporation. The residue dissolves in a small amount of ice water; a 2N sodium carbonate solution is added, and extraction is carried out three times with ethyl acetate. The combined organic phases are washed twice with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is dissolved twice in methylene chloride, and again concentrated by evaporation. In this way, the title compound is obtained in the form of a yellow foam. Rf (ethyl acetate) = 0.05. b): Amide (N- \ (R) -epsilon-caprolactam-3-lical acid. (4R) - (N '-methyl-N1-tertiary butyloxy-carbonyl-ano) -5- (1-methyl-indol-3-yl) -pent-2-ene: A mixture of 1.07 grams of acid (4R) ) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (1-methyl-indol-3-yl) -pent-2-ene, 0.42 grams D-3-amino-epsilon-caprolactam, 0.63 grams of carbodiimide N-ethyl-N '- (3-dimethylaminopropyl) hydrochloride, 0.48 grams of 4-dimethyl aminopyridine, and 15 milliliters of methylene chloride, is stirred at room temperature for 4 hours, and then it is concentrated by evaporation. The residue is taken up in ethyl acetate, and extracted twice with water, once with 1N hydrochloric acid, and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. In this way, the title compound is obtained in the form of a colorless foam. Rf (methylene chloride / methanol = 9/1) = 0.45. c) s Acid (4R) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (l-methyl-indol-3-yl) -pent-2-ene: A solution of 4.26 grams of hydroxide of lithium in 27 milliliters of water, is added at 0 ° C to a solution of 5.56 grams of ethyl ester of (4R) - (N-methyl-N-butyloxyl tertiary-carbonyl-amino) -5- (1-methyl) -indol-3-yl) -pent-2-ene in 64 milliliters of tetrahydrofuran and 64 milliliters of methanol, and the mixture is stirred at room temperature for 5 minutes, neutralized with approximately 25 milliliters of 4N hydrochloric acid, and concentrates by evaporation. The residue is taken up in water, acidified to pH = 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The combined organic phases are washed with water and a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is dissolved in methylene chloride three times, and again concentrated by evaporation. The title compound is thus obtained in the form of a solid foam. R '(ethyl acetate / hexane = 1/1) = 0.07. d): (4R) - (N-Methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (l-methyl-indol-3-yl) -pent-2-ene acid ethyl ester: 0. 848 grams of dry LiCl, 1.77 grams of 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), and a solution of 5.75 grams of (R) -N-methyl-N-butyloxy-tertiary-carbonyl -amino-3- (1-methyl-indol-3-yl) -propanal in 100 milliliters of acetonitrile is added at 0 ° C to a solution of 4.86 grams of triethyl phospho-noacetic acid in 50 milliliters of acetonitrile absolute. When the addition is complete, the mixture is stirred at room temperature for 45 minutes. Then the resulting suspension is poured into water and extracted twice using 500 milliliters of diethyl ether each time. The combined organic phases are washed three times with water, and twice with a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is purified by chromatography (330 grams of silica gel, hexane / ethyl acetate = 2/1). In this way, the title compound is obtained in the form of a colorless resin. Rf (hexane / ethyl acetate - 2/1) = 0.25. e): (R) -N-methyl-N-butyloxy-tertiary-carbonyl-amino-3- (1-methyl-indol-3-yl) -propanal: To a solution of 6.28 grams of methyl ester of acid (R) -N-methyl-N-butyloxy-tertiary-carbonyl-amino-3- (l-methyl-indol-3-yl) -propanecarboxylic acid in 117 milliliters of toluene, is cooled to -78 ° C under argon, and added by drip to the same 41.6 milliliters of a solution of diisobutyl aluminum hydride at 20 percent in toluene (40 minutes). When the drip addition is complete, the mixture is stirred at -78 ° C for an additional 90 minutes. Then add 5.9 milliliters of methanol and 200 milliliters of diethyl ether at -74 ° C, and 10 grams of citric acid dissolved in 190 milliliters of water, so that the temperature does not exceed -10 ° C. The mixture is stirred vigorously at 0 ° C for 2 hours. The resulting suspension is filtered with suction. In the filtrate, the phases are then separated, and the aqueous phase is extracted once more with diethyl ether. The combined organic phases are washed with water and a saturated solution of NaCl, dried (sodium sulfate), and concentrated by evaporation. In this way, the title compound is obtained in the form of a viscous oil. Rf (hexane / ethyl acetate = 2/1) = 0.37. f): Methyl ester of (R) -N-methyl-N-bufcyloxy-tertiary-amino-3- (l-methyl-indol-3-yl) -propanecarboxylic acid: 55 grams of silver oxide (I) are added to 5 ° C, with stirring, to a solution of 14.3 grams of methyl tertiary butyloxy-carbonyl-D-tryptophan methyl ester in 90 milliliters of N, N-dimethyl formamide. Then 44 milliliters of methyl iodide, and 2 milliliters of acetic acid (absolute) are added at 5 ° C. The reaction mixture is stirred at room temperature for 72 hours, then diluted with 1 liter of diethyl ether, filtered, and concentrated by evaporation. The residue is taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and concentrated by evaporation. Chromatography of the residue on 1 kilogram of silica gel (hexane / ethyl acetate = 2/1) produces the title compound in the form of a light yellow resin. Rf (hexane / ethyl acetate = 2/1) = 0.27. g); Sterile methyl ester Tertiary butyl-carbonyl-D-tryptophan: Add 10 grams of tertiary butanol, 10.1 grams of BOC anhydride, and 12.27 grams of di-isopropyl-letil amine dissolved in 30 milliliters of tetrahydrofuran, 0 ° C, to a suspension of 12.12 grams of D-tryptophan methyl ester hydrochloride in 80 milliliters of absolute tetrahydrofuran. After stirring for 2 hours at room temperature, the reaction mixture is poured onto ice / 470 milliliters of 0.3N HCl, and extracted three times with ethyl acetate. The combined organic phases are washed once with water and twice with a saturated solution of NaCl, dried (MgSO 4), and concentrated by evaporation. The residue is converted to a slurry in diethyl ether / petroleum ether, and filtered with suction. In this manner, the title compound is obtained in the form of colorless crystals having a melting point of 148-149 ° C. R £ (methylene chloride) = 0.24.

In the same manner as described in Example 1, but using the appropriate amines instead of D-3-amino-epsilon-caprolactam, the following compounds can be obtained: Example 2: Amide N- T (5) - epsilon-capr-olacfcam-3-lical acid (4R) - TN '-methyl-N' - (.5-bistri luoromefcil-benzoyl) -aminol -5- ( 1-methyl-indol-3-yl) -pent-2-ene: L-3-amino-epsilon-caprolactam is used. Solid foam, Rf (ethyl acetate / acetone = l / l) = 0.31, High performance liquid chromatography: Chiralpack OD, heptane / isopropyl alcohol = 80/20 + 0.1 percent trifluoroacetic acid, 1 milliliter / minute, Rf = 29.96 min. [a ^ 20 = + 67 ° C ± 2.3 ° C (C = 0.44, EtOH). Example 3: N-cyclohexyl amide of (4R) -NT '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol-5- (l-methyl-indol-3-yl) -pent-2 acid -enoic: Cyclohexyl amine is used. Rf (ethyl acetate) = 0.41.

Example 4, N-cyclohexyl amide of 4R) -NT 1 -methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -aminol -5- (1-methyl-indol-3-yl) -2-methyl- pent-2 -enoic acid: The title compound can be prepared in exactly the same manner as described in Example 1, but using triethyl 2-phosphonopropionate in place of the triethylphosphonoacetic acid ester in sub-step Id). The title compound is obtained in the form of an amorphous colorless solid. Rf (ethyl acetate) = 0.46.

In an analogous way, it is also possible to prepare the following products: Example 5; Amide N- [(R) -Epsilon-caprolactam-3-lical acid (4R) - TN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -5- (1-methyl-indol-3-yl) -2-yl-pent-2-ene: Foam colorless, Rf (ethyl acetate / acetone = 1/1) = 0.46; [a] D20 = -24.4 ° C ± 2.8 ° C (c = 0.352, EtOH).

Example 6; Amide N- T (S) -epsilon-caprolactam-3-lical acid (4R) - TN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol-5-1-methyl-indol-3-yl ) -2-methyl-pent-2-ene: Colorless foam, Rf (ethyl acetate / acetone = 171) = 0.46. Using L-3-amino-epsilon-caprolactam.

In the same manner as described in Example 5, but using benzoyl chloride instead of 3,5-bistrifluoromethyl-benzoyl chloride, the following product can be prepared: Example 5/1: Amide N- (R) -ispsilon-caprolactam-3-lical acid (4R) -N1-methyl-N'-benzoyl-amino) -5- (l-methyl-indol-3-yl) -2-methyl-pent-2-enoic: Colorless foam, Rf (ethyl acetate / acetone = 1/1) = 0.23; [a] D20 = -10.7 ° C ± 3.5 ° C (c = 0.283, EtOH).

Example 7: Amide N- (R) -ispsilon-caprolactam-3-lical acid (4R) -NT '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naph -2 -il) -pent-2 -enoic 78.3 milligrams of (D) -3-amino-epsilon-caprolactam, 116.9 milligrams of carbodiimide hydrochloride N-ethyl-N '- (3-dimethylaminopropyl), and 88 milligrams of 4-dimethyl aminopyridine, to a solution of 0.275 grams of (4R) - [N-methyl-N- (3,5-bistrifluoromethyl-benzoyl) -amino] -5-amino (naft-2-yl) acid -pent-2 -enoic acid in 6 milliliters of methylene chloride. The reaction mixture is stirred at 20 ° C for 3.5 hours, and concentrated by evaporation. The residue is subjected to chromatography by evaporation (40 grams of silica gel, ethyl acetate). In this way, the title compound is obtained in the form of a light yellow solid. Rf (methylene chloride / methanol = 15/1) = 0.28.

The starting materials can be prepared as follows: a): Acid (4R) - [N-methyl-N- (3,5-bistrif luoromethyl-benzoyl) -aminol-5- (naphth-2-yl) -pent- 2 -enoic acid: A solution of 0.18 grams of lithium hydroxide in 1.18 milliliters of water at 0 ° C is added to a solution of 0.325 grams of ethyl ester of (4R) - [N-methyl-N- (3, 5-bistrifluoromethyl-benzoyl) -amino] -5- (naphth-2-yl) -pent-2-ene in 3 milliliters of tetrahydrofuran and 3 milliliters of methanol, and the mixture is stirred at room temperature for 45 minutes, neutralize with a small amount of 4N hydrochloric acid, and concentrate by evaporation. The residue is recovered in water, acidified to pH = 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The combined organic phases are washed with water and a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is dissolved three times in methylene chloride, and again concentrated by evaporation. In this way, the title compound is obtained in the form of a colorless solid foam. Rf (ethyl acetate / hexane = 1/1) = 0.15. -b) • (4R) - [N-Methyl-N- (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naph-2-yl) -pent-2-enoic acid ethyl ester: Are added drip 0.229 milliliters of 3,5-bistrifluoromethylbenzoyl chloride at 0 ° C to a solution of 0.327 grams of (4R) -N-methyl-amino-5- (naphth-2-yl) ethyl ester - pent-2 -enoic acid, and 0.48 milliliters of triethyl amine in 5 milliliters of methylene chloride. The reaction mixture is stirred at 20 ° C for 60 minutes, and concentrated by evaporation. The residue is taken up in ethyl acetate, and extracted once with water and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to chromatography by evaporation (40 grams of silica gel, hexane / ethyl acetate = 2/1). In this way, the title compound is obtained in the form of a solid orange foam. Rf (hexane / ethyl acetate = 2/1) = 0.59. c): (4R) -N-Methyl-amino-5- (naphth-2-yl) -pent-2-enoic acid ethyl ester: 8 milliliters of hydrochloric acid are added 4N in dioxane at 0 ° C, at 0.30 grams of ethyl ester of acid (4R) -N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) -pent-2-enoic acid. The resulting suspension is stirred at room temperature for 30 minutes, and concentrated by evaporation. The residue is dissolved in a small amount of ice water; a 2N sodium carbonate solution is added, and extraction is carried out three times with ethyl acetate. The combined organic phases are washed twice with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is dissolved twice in methylene chloride, and concentrated n by evaporation. In this way, the title compound is obtained in the form of a yellow foam. R (ethyl acetate) = 0.65. d): (4R) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) -pent-2-enoic acid ethyl ester: «They are added 1. 34 grams of dry LiCl, 4.37 grams of 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), and a solution of 9.0 grams of (R) - (tertiary-N-methyl-N-butyloxy- carbonyl-amino) -3-naphth-2-yl) -propanal in 150 milliliters of acetonitrile, at 0 ° C, to a solution of 7.08 grams of triethyl phosphonoacetic acid ester in 80 milliliters of absolute acetonitrile. When the addition is complete, the mixture is stirred at room temperature for an additional 45 minutes. Then the resulting suspension is poured into water, and extracted twice using 600 milliliters of diethyl ether each time. The combined organic phases are washed three times with water and twice with a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is purified by chromatography (800 grams of silica gel, hexane / ethyl acetate = 8/1). In this way, the title compound is obtained in the form of a colorless resin. Rf (acetate / ethyl acetate = 8/1) = 0.09. High performance liquid chromatography: Chiralcel OJ, hexane / isopropyl alcohol = 90/10 + 0.1 percent trifluoroacetic acid, 1 milliliter / ml, Rt = 15.86 minutes. e): (R) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -3- (naphth-2-yl) -propanal: A solution of 21.8 grams of methyl ester of acid (R) -N- Tertiary-methyl-N-butyloxy-carbonyl-amino-3- (naphth-2-yl) -propanecarboxylic acid in 497 milliliters of toluene, cooled to -78 ° C under argon, and 146 milliliters of triturate are added thereto. a solution of diisobutyl aluminum hydride at 20 percent in toluene (60 minutes). When the dropwise addition is complete, the mixture is stirred at -78 ° C for 60 additional minutes. Then add 17.8 milliliters of methanol at -74 ° C, and 35 grams of citric acid dissolved in 665 milliliters of water, so that the temperature does not exceed -10 ° C. The mixture is stirred vigorously at 0 ° C for 2 hours, and diluted with diethyl ether. The resulting suspension is filtered with suction. In the filtrate, the phases are then separated, and the aqueous phase is extracted once more with diethyl ether. The combined organic phases are washed with water and a saturated solution of NaCl, dried (sodium sulfate), and concentrated by evaporation. In this way, the title compound is obtained in the form of beige crystals having a melting point of 98-100 ° C. Rf (hexane / ethyl acetate = 3/2) = 0.51. f): Methyl ester of (R) -N-methyl-N-butyloxyl tertiary-carbonyl-amino-3- (naph-2-yl) -propanecarboxylic acid: 76.4 grams of silver (I) oxide are added ° C, with stirring, to a solution of 20.1 grams of (R) -N-butyloxy-tertiary-rio-carbonyl-amino-3- (naphth-2-yl) -propanecarboxylic acid (eg, Bachem), in 191 milliliters of formamide N, N-dimethyl. Then add 12.5 milliliters of methyl iodide at 5 ° C. The reaction mixture is stirred at room temperature for 24 hours, then diluted with 1 liter of diethyl ether, filtered, and concentrated by evaporation. The residue is taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and concentrated by evaporation. In this manner, the title compound is obtained in the form of a light yellow oil. Rf (hexane / ethyl acetate = 4/1) = 0.47. High performance liquid chromatography = Chiralcel OJ, hexane / isopropyl alcohol = 90/10 + 0.1 percent trifluoroacetic acid, 1 milliliter / minute, Rt = 11.32 minutes.

In the same manner as described in Example 7, but using benzoyl chloride instead of 3,5-bistrifluoromethyl-benzoyl chloride in Step 7b), the following product is obtained: Example 7/1: Amide N- [(R) -ispsilon-caprolactam-3-lical acid (4R) - (N 1 -methyl-N '-benzoyl) -amino-5- (naphth-2-yl) -pent -2 -nic: Rt (ethyl acetate / acetone = 9/1) = 0.13.

Example 8: Amide N-I "(R) -psylon-caprolactam-3-yl-1-acid (4R) -rN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol-5- (naphtha- 2-yl) -2-methyl-pent-2-enoic 0.153 milliliters of 3,5-bistrifluoromethyl-benzoyl chloride are added dropwise at 0 ° C to a solution of 0.27 grams of amide N- [(R) - epsilon-caprolactam-3-yl] of (4R) - (N 1 -methyl-amino) -5- (naphth-2-yl) -2-methyl-pent-2-enoic acid, and 0.3 milliliter of triethyl amine in 6 milliliters of methylene chloride The reaction mixture is stirred at 90 ° C. for 90 minutes and concentrated by evaporation, the residue is taken up in ethyl acetate and extracted once with water and twice with brine. The combined organic extracts are dried over magnesium sulfate and concentrated by evaporation, the residue is subjected to chromatography by evaporation (150 grams of silica gel, ethyl acetate / hexane = 4/1). in the form of a solid foam i Ncolora Rf (ethyl acetate) = 0.43. High performance liquid chromatography: AD column, hexane / isopropyl alcohol = 90/10 + 0.1 percent trifluoroacetic acid, 1 milliliter / minute, Rt = 17.87 minutes.

The starting materials can be prepared as follows: a): Amide N- F (R) -epsilon-caprolactam-3-lical acid. (4R) - (N '-methyl-amino) -5- (naphth-2-yl) -2-methyl-pent-2-enoic: 7.0 milliliters of 4N hydrochloric acid are added at 0 ° C, at 0.342 grams of amide N- [(R) -ispsilon-caprolactam-3-lolic acid] (4R) - (N 1 -methyl-N 1 -butyl tertiary-carbonyl-amino) -5- (naphth-2-yl) -2-methyl-pent-2-enoic. The resulting suspension is stirred at room temperature for 20 minutes, and concentrated by evaporation. The residue dissolves in a small amount of ice water; a 2N sodium carbonate solution is added, and extraction is carried out three times with ethyl acetate. The combined organic phases are washed twice with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is dissolved twice in methylene chloride, and concentrated again by evaporation. In this way, the title compound is obtained in the form of a yellow foam. Rf (methylene chloride / methanol = 95/5) = 0.33. b): Amide N- T (R) -epsilon-caprolactam-3-lical acid (4R) - (N '-methyl-N' -butyl tertiary-carbonyl-amino) -5- (naph -2-yl) -2-methyl-pent-2-ene: A mixture of 500 milligrams of acid (4R) ) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) -2-methyl -pent-2-urea, 0.183 grams of D-3-amino-epsilon-caprolactam, 0.265 grams of carbodiimide hydrochloride N-ethyl-N '- (3-dimethylaminopropyl), 0.200 grams of 4-dimethyl aminopyridine, and 16 milliliters of methylene chloride , it is stirred at room temperature for 1 hour, and then it is concentrated by evaporation. The residue is taken up in ethyl acetate, and extracted twice with water, once with IN hydrochloric acid, and twice with brine. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation. The residue is subjected to chromatography by evaporation (80 grams of silica gel, ethyl acetate / hexane = 7/3 - 9/1). In this way, the title compound is obtained in the form of a colorless foam. Rf (ethyl acetate) = 0.39. c): Acid (4R) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) -2-methyl-pent-2-enoic: A solution 2.6 grams of lithium hydroxide in 17 milliliters of water at 0 ° C, to a solution of 3.5 grams of ethyl ester of (4R) -N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) ethyl ester 2-methyl-pent-2-enoic in 40 milliliters of tetrahydrofuran and 40 milliliters of methanol, and the mixture is stirred at room temperature for 45 minutes, neutralized with approximately 15 milliliters of 4N hydrochloric acid, and Concentrate by evaporation. The residue is taken up in water, acidified to pH = 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The combined organic phases are washed with water and a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is dissolved three times in methylene chloride, and concentrated again by evaporation. In this way the title compound is obtained in the form of a solid foam. Rf (ethyl acetate / hexane = 1/1) = 0.26. d): Ethyl ester of (4R) - (N-methyl-N-butyloxy-tertiary-carbonyl-amino) -5- (naphth-2-yl) -2-methyl-pent-2-ene acid: Sa add 1.36 grams of dry LiCl, 4.37 grams of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and a solution of 9 grams of (R) -N-methyl-N-butyloxy-tertiary-carbonyl-amino- 3- (naphth-2-yl) propanal in 150 milliliters of acetonitrile, at 0 ° C, to a solution of 7.52 grams of 2-phosphonopropionic acid triethyl ester in 80 milliliters of absolute acetonitrile. When the addition is complete, the mixture is stirred at 10 ° C for 40 minutes. Then the resulting suspension is poured into water, and extracted twice using 600 milliliters of diethyl ether each time. The combined organic phases are washed three times with water, and twice with a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is purified by chromatography (600 grams of silica gel, hexane / ethyl acetate = 95 / 5-93 / 7). In this way, the title compound is obtained in the form of a colorless resin. R (hexane / ethyl acetate = 7/3) = 0.53.

In the same manner as described in Example 8, but using 3, 4, 5-trimethoxybenzoyl chloride in place of 3,5-bistrifluoromethylbenzoyl chloride, the following product can be prepared: Example 8/1; Amide N- T (R) -epsilon-caprolactam-3-lical acid (4R) - TN '-methyl-N1 - (3 f 4, 5-trimethoxy-benzoyl) -aminol -5- (naf -2-il ) -2-methyl-pent-2-enoic: Rf (methylene chloride / methanol = 95/5) = 0.42.

In the same manner as described in Example 8, but using the appropriate amines instead of D-3-amino-epsilon-caprolactam, the following products can be obtained: Example 9: N-f (S) -epsilon-caprolactam-3-lical amide of (4R) -NT 1 -methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -aminol-5- (naphth-2- il) -2-methyl-pent-2-enoic: Using L-3-amino-epsilon-caprolactam. Rf (ethyl acetate) = 0.44.

Example 10: N-cyclohexyl amide of (4R) -NT'-methyl-N '- (3 r 5 -bistrifluoromethyl-benzoyl) -aminol-5- (naph -2-yl) -2-methyl-pßnt-2 -enoic: Using cyclohexyl amine. Rf (ethyl acetate = 1 / L) = 0.43. High performance liquid chromatography: Chiralcel AD, hexane / isopropyl alcohol = 90/10 plus 0.1 percent trifluoroacetic acid, 1 milliliter / minute, Rt = 6.25 minutes.

Example 11: Amide N- [(S) -ispsilon-caprolactam-3-yl]] (4R) -NT '-methyl-N' - (3 - 5-bistrifluoromethyl-benzoyl) -aminol-5- (1- methyl-indol-3-yl) -pent-2-enoic (Another method of preparation for the compound of Example 2). The title compound can also be prepared starting from racemic D, L-tryptophan methyl ester hydrochloride (in place of D-tryptophan methyl ester hydrochloride). The methyl ester hydrochloride of D, L-tryptophan is reacted in a manner analogous to that described in Example 1. L-3-amino-epsilon-caprolactam is used in Step lb). The resulting mixture of diastereoisomers is then separated in a final step by chromatography on silica gel (ethyl acetate). In this manner, N- [(S) -ispsilon-caprolactam-3-yl] amide is obtained from (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] - 5- (1-methyl-indol-3-yl) -pent-2-enoic (Rf = 0.31, ethyl acetate / acetone = 1 / l), and amide N- [(S) -ispsilon-caprolactam-3-yl]] (S) -4- [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1- methyl-indol-3-yl) -pent-2-ene. { Rf = 0.35, ethyl acetate / acetone = 1 / l; [α] D 0 = -44.3 ° C ± 4.5 ° C (c = 0.221, EtOH)} , in a pure form.

Example 12: N, T (R) -epsilon-caprolactam-3-yl] amide of (4R) -NT '-methyl-N' - (3, 5-bistrifluoromethyl-benzoyl) -aminol -4- (4- chlorobenzyl) -but-2-ene A solution of 0.71 grams of 23.5-bistri-fluoromethylbenzoyl chloride (in 5 milliliters of methylene chloride) is added dropwise at 0 ° C to a solution of 0.9 grams of amide N- [(R) -ispsilon-caprolactam-3-yl]] (4R) - (N '-methyl-amino) -4- (4-chlorobenzyl) -but-2-ene acid, and 0.75 milliliter of triethyl amine in 35 milliliters of methylene chloride. The reaction mixture is stirred at room temperature for 2 hours. Then 3 milliliters of methanol are added, and the reaction mixture is diluted with 50 milliliters of methylene chloride. The solution is washed with 0.1 N HCl, water (twice), and a saturated solution of NaCl, dried (MgSO 4), and concentrated by evaporation. The residue is subjected to chromatography by evaporation (85 grams of silica gel, ethyl acetate / methanol = 98/2). The title compound is obtained in the form of an amorphous white solid. Rf = 0.12 (ethyl acetate), [] D20 = + 42 ° C ± 1 ° C (c = 1, EtOH). Rt = 20.38 minutes (Chiracel-OJ, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: ethanol = 90:10 plus 0.1% trifluoroacetic acid, flow rate 1.0 milliliters / minute, 30 bar).

The starting materials can be prepared as follows: a): Amide N- \ (R) -epsilon-caprolactam-3-lical acid (4R) - (N '-methyl-amino) -4- (4-chlorobenzyl) -but-2-phenyl ester: A solution of 1.2 grams of N- [(R) -ispsilon-caprolactam-3-yl] amide of (4R) - (N'-methyl-N'-tertiary butyloxycarbonyl-amino) -4- (4-chlorobenzyl) amide -but-2-enoic, and 8 milliliters of trifluoroacetic acid in 30 milliliters of methylene chloride, is stirred under argon at room temperature for 2 hours. Then the reaction mixture is concentrated by evaporation and dissolved in 200 milliliters of ethyl acetate. The ethyl acetate solution is washed with a 0.05N sodium hydroxide solution and a saturated solution of NaCl, dried (sodium sulfate), concentrated by evaporation, and further reacted without further purification. b): N-f (R) -epsilon-caprolactam-3-lical amide of áslÚO. (4R) - (N 1 -methyl-N'-tertiary butyloxy-carbonyl-amino) -4- (4-chlorobenzyl) -but-2-ene: A mixture of 1.53 grams of (4R) - (N'-methyl) -N'-tertiary butyloxy-carbonyl-amino) -4- (4-chlorobenzyl) -but-2-enoic, 0.58 grams of D-3-amino-epsilon-caprolactam, 0.94 grams of carbodiimide hydrochloride N-ethyl -N '- (3-dimethylaminopropyl), 0.60 grams of 4-dimethyl aminopyridine, 0.725 grams of hydroxybenzotriazole, and 80 milliliters of methylene chloride, is stirred at room temperature for 16 hours, and then concentrated by evaporation. The residue is passed through chromatography (silica gel, hexane / ethyl acetate = 1/1). In this way, the title compound is obtained, mp .: 154-156 ° C. c): (4R) - (N1 -methyl-N'-tertiary-aminobutyl) -4- (4-chlorobenzyl) -but-2-ene acid: A solution of 1.64 grams of ethyl ester of (4R) - (N '-methyl-N1-tertiary-butyloxy-amino) -4- (4-chlorobenzyl) -but-2-ene, and 1.72 grams of lithium hydroxide in tetrahydrofuran / methanol / water = 3/3/1, is stirred at room temperature for 1 hour, and then poured into 150 milliliters of water. The mixture is acidified to pH = 2 by the addition of IN hydrochloric acid, and the aqueous phases are extracted twice with diethyl ether. The combined organic phases are washed with water and a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation to form a colorless oil. -NMR, 400 MHz, CDC13, d (ppm): 7.30 (d, 2H), 7.20 (d, 2H), 6.80 (d, IH), 5.81 (d, IH), 4.85 (m, 1H), 2.75 ( d, 2H), 2.63 (s, 3H), 1.35 (s, 9H). d): Ethyl aide (4R) - (N '-methyl-N'-tertiary butyloxycarbonyl-amino) -4- (4-chlorobenzyl) -but-2-ene: 0.453 grams of dry LiCl are added and 1.46 grams of DBU at room temperature, to a solution of 2.37 grams of triethyl phosphonoacetic acid ester in 40 milliliters of absolute acetonitrile. Then a solution of 2.86 grams of (R) -N 1 -methyl-N'-tertiary butyloxycarbonyl-4 (4-chlorophenyl) -alaninal (in 10 milliliters of acetonitrile) is added dropwise to the same. When the dropwise addition is complete, the mixture is stirred at room temperature for 2 hours. The reaction mixture is then poured into water, and extracted twice using 100 milliliters of diethyl ether each time. The combined organic phases are washed three times with water and once with a saturated solution of NaCl, dried (magnesium sulfate), and concentrated by evaporation. The residue is purified by chromatography (silica gel, hexane / ethyl acetate = 3/1). In this manner, the title compound is obtained in the form of a colorless oil. -'- H-NMR, 200 MHz, CDC13, d (ppm): 7.35-7.05 (m, 4H), 690 (dd, ÍH), 5.85 (d, ÍH), 5.15 (m, 0.5H), 4.90 ( m, 0.5H), 4.17 (q, 2H), 2.90 (m, 2H), 2.68 (s, 3H), 1.30 (m, 12H). e): (R) -N'-methyl-N7-tertiary butyloxycarbonyl- (4-c-orophenyl) -alaninal: A solution of 2.95 grams of methyl ether of (R) -N '-methyl-N' - tertiary butyloxycarbonyl- (4-chlorophenyl) -alanine in 75 milliliters of toluene is cooled to -78 ° C under argon. At this temperature, 17 milliliters of a 1M DIBAH solution (in toluene) are slowly added dropwise. When the dropwise addition is complete, the mixture is stirred at this temperature for 2 hours. Then 2 milliliters of methanol and 50 milliliters (18 grams) of an aqueous solution of sodium / potassium tartrate are added to the reaction mixture. The mixture is stirred vigorously at 0 ° C for 2 hours. The phases are then separated, and the aqueous phase is extracted once more with diethyl ether. The combined organic phases are washed with water and a saturated solution of NaCl, dried (sodium sulfate), and concentrated by evaporation. The residue is further reacted without purification (colorless oil). - "- H-NMR, 200 MHz, CDCl 3, d (ppm): 7.30-7.05 (m, 4H), 4.16 (m, 0.5H), 3.93 (m, 0.5H, 3.25 (dd, 2H), 2.90 ( m, ÍH), 2.70 and 2.62 (2s, 3H), 1.40 (2s, 9H). f): Methyl ester of (R) -N'-methyl-N '-butyloxyl tertiary-carbonyl- (4-chlorophenyl) -alanine: 9.5 grams of silver oxide (I) are added, with stirring, to a solution of 3.1 grams of methyl (R) -butyloxyl tertiary-carbonyl- (4-chlorophenyl) -alanine methyl ester in 45 milliliters of N, N-dimethyl formamide. Then 23 grams of methyl iodide and 1 milliliter of acetic acid (absolute) are added. The reaction mixture is stirred at room temperature for 72 hours, then diluted with 150 milliliters of diethyl ester, filtered, and concentrated by evaporation. The residue is purified by chromatography (silica gel, hexane / ethyl acetate = 5/1). In this manner, the title compound is obtained in the form of a colorless oil. H-NMR: 7.25 (d, 2H), 7.11 (d, 2H), 4.90 (bs, 0.5H), 4.47 (bs, 0.5H), 3.72 (s, 3H), 3.25 (m, 1H), 3.00 ( dd, ÍH), 2.70 (s, 3H), 1.35 (s, 9H). g): Tertiary-carbonyl- (4-chlorophenyl) -alanine (R) -butyloxyl methyl ester: 4 milliliters' of tertiary butanol, 2.12 grams of BOC anhydride, and 2.57 grams of di-isopropylethyl amine, are added to a suspension of 2.5 grams of D-4-chlorophenylalanine methyl ester (for example, Bachem) in 40 milliliters of absolute tetrahydrofuran. After stirring for 4 hours at room temperature, the reaction mixture is poured into ice / 0.1N HCl, and extracted twice with diethyl ether. The combined organic phases are washed with water (three times), and a saturated solution of NaCl, dried (MgSO 4), and concentrated by evaporation to form an oil, which crystallizes completely upon standing. Rf = 0.19 (hexane: ethyl acetate = 5/1).

Preparation of D-3-amino-epsilon-caprolactatrta: A solution of 12.8 grams of D, L-3-amino-epsilon-caprolactam in 200 milliliters of absolute ethanol is mixed with a solution of 12.9 grams of D-pyroglutamic acid ( in 200 milliliters of absolute ethanol), and allowed to stand at room temperature for 20 hours. The resulting crystals are filtered and dissolved at about 65-70 ° C in ethanol: water = 9: 1.

In the same manner as described in Example 12, but using the appropriate amines (in place of D-3-amino-epsilon-caprolactam) in Step 12b), the following products are also obtained.

Example 13: Amide N- (S) -ispsilon-caprolactam-3-lical acid (4R) -fN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-chlorobenzyl) -but-2-enoic: Rf = 0.12 (ethyl acetate). Using L-3-epsilon-caprolactam (commercially available, for example: Fluka 07257). Rt = 35.2 minutes (Chiracel-OD, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: isopropanol = 80:20 + 0.1 percent trifluoroacetic acid, flow rate 1.0 milliliters / minute, 30 bar). \ Example 14: N-cyclohexyl amide of (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-chlorobenzyl) -but-2-enoic acid: m.p. 183-185 ° C. Using cyclohexyl amine. Rt = 10.5 minutes. Chiracel-AC, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: isopropyl alcohol = 97: 3 + trifluoroacetic acid al 0. 1 percent, flow rate of 1.0 milliliters / minute, 20 bar [CÜ] D20 = + 60.4 ° C + 4.4 ° C (c = 0.227, EtOH).

In a manner analogous to the procedure described in Examples 12 and 14, it is also possible to prepare, starting from the appropriately halogenated phenylalanine derivatives, the following substances: Example 14A: N-Cyclohexyl Amide of (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-eneic acid : Rf = 0.24 (hexane: ethyl acetate = 1: 1).

Example 14B: N-cyclohexyl amide of (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (3, -dichlorobenzyl) -but-2-enoic acid: Rf = 0.28 (hexane: ethyl acetate = 1: 1).

Example 15: N-cyclohexyl amide of (4R) -NT '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -a inol -5- (4-chloro-nyl) -2-methyl-pent-2-acid -neoic: The title compound is prepared in exactly the same manner as described in Example 14 (and in Example 12, respectively), but using triethyl 2-phosphonopropionate instead of triethylphosphonoacetic acid ester in sub-step 12d) . The title compound is obtained in the form of a colorless amorphous solid. Rf = 0.32 (hexane: ethyl acetate = 1: 1).

In a manner analogous to Example 15, it is also possible to prepare the following products: Example 16: Amide N- \ (R) -epsilon-caprolactam-3-lical acid (4R) -NT '-methyl-N1- (3,5-bistrifluoromethyl-benzoyl) -aminol -5- (4-chlorophenyl) -2-methyl-pent-2-enoic: Rf = 0.14 (ethyl acetate). Using D-3-amino-epsilon-caprolactam. Rt = 6.24 minutes (Chiracel-AD, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: ethanol = 98: 2 + 0.1% trifluoroacetic acid, flow rate 1.0 milliliters / minute, 30 bar). [] D20 = -10.7 ° C ± 4.4 ° C (C = 0.225, EtOH).

Example 17: Amide r (S) -espsilon-caprolactam-3-lyl] (4R) -NT '-methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-chlorobenzyl) - 2-methyl-but-2-ene: Rf = 0.14 (ethyl acetate). Using L-3-amino-epsilon-caprolactam.

Amide N- f (S) -ispsilon-caprolactam-3-lical acid (4R) -NT '-ethyl-N' - (3,5-bistrifluoromethyl-benzoyl) - "aminol -5- (4-chlorophenyl-pent -2 -enoic: The title compound is prepared starting from (R) -N-ethyl-N-butyloxy-tertiary-carbonyl- (4-chlorophenyl) -alanine methyl ester in exactly the same way (using L-3) -amino-epsilon-caprolactam) which is described in Example 12. Rf = 0.18 (ethyl acetate).

The starting material, methyl ester of (R) -N-ethyl-N-butyloxyl tertiary-carbonyl- (4-chlorophenyl) -alanine, can be prepared as follows: 118 milligrams of sodium hydride (pure) are added in portions at 0 ° C under argon, to a solution of 1.4 grams of methyl tert-N-butyloxy-carbonyl-4-chlorophenyl-alanine methyl ester in 25 milliliters of N, N-dimethyl formamide. The mixture is stirred at 0 ° C for 30 minutes, and at room temperature for 30 minutes. Then 1.07 grams of ethyl bromide are added, and the reaction mixture is stirred at 50 ° C for 16 hours. The reaction mixture is then poured into 200 milliliters of water, and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are washed with water and a saturated solution of sodium chloride, dried (MgSO 4), and concentrated by evaporation. The residue is passed through chromatography (hexane / ethyl acetate = 5/1). In this manner, the title compound is obtained in the form of a colorless oil. \ Example 19: N-cyclohexyl amide of (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -5- (4-chlorophenyl) -3-methyl-pent-2-acid enoic: The title compound can be prepared in exactly the same manner as described in Example 12, but starting from tertiary butyl ester of (R) - [1- (4-chlorobenzyl) -2-oxo-propyl ] -carbamic instead of (R) -N '-methyl-N' -butyl tertiary-carbonyl-4-chlorophenyl-alaninal. Rf = 0.41 (hexane: ethyl acetate = 1: 1).

The tertiary butyl ester material of (R) - fl- (4-chloro-benzyl-2-oxo-propylcarbamic acid, can be prepared as follows: a solution of 0.77 milliliters of dimethyl sulfoxide is added dropwise ( in 2.5 milliliters of methylene chloride, over the course of 20 minutes, at -60 ° C under argon, to a solution of 0.45 milliliters of oxalyl chloride (in 10 milliliters of methylene chloride), and then the mixture is stirred for 15 minutes In the same way, at -60 ° C, a solution of 1.4 grams of tertiary butyl ester of (R) - [1- (4-chloro-benzyl) -2-hydroxy acid is added dropwise to the same. -propyl] -carbamic acid (in 4 milliliters of methylene chloride) The reaction mixture is stirred for 1 hour, triethyl amine is added, and the mixture is heated to room temperature, at which temperature 25 milliliters of water are added. The organic phase is separated, and the aqueous phase is extracted twice more with \ methylene. The combined organic phases are washed with water and a saturated solution of sodium chloride, dried (MgSO 4), and concentrated by evaporation. The residue is subjected to chromatography by evaporation (toluene / methylene chloride / ethyl acetate = 4/4 '2). In this manner, the title compound is obtained in the form of a colorless oil.

Tertiary butyl ester of (R) - [1- (4-chloro-benzyl) -2-hydroxy-propyl] -carbamic acid: 10 milliliters of a Grignard solution (prepared from 0.64 milliliters of methyl iodide and 0.244 grams of magnesium chip in 20 milliliters of diethyl ether), to a solution of 1.19 grams of (R) -N'-methyl-N'-butyloxy-tertiary-carbonyl- (4-chlorophenyl) -alaninal in 25 milliliters of tetrahydrofuran, and the mixture is then stirred for 30 minutes. The reaction mixture is then poured into 100 milliliters of water, and extracted twice with diethyl ether. The combined organic phases are washed with water and a saturated solution of sodium chloride, dried (MgSO 4), and concentrated by evaporation. The residue is chromatographed by evaporation (hexane / ethyl acetate - 1/1). In this manner, the title compound is obtained in the form of a colorless oil.

In a manner analogous to Example 19, using D-3-amino-epsilon-caprolactam in place of cyclohexyl amine, it is also possible to obtain the following compound: Example 20: Amide f (R) -epsilon-caprolactam-3-lical acid (4R) - TN '-methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-chlorobenzyl) -3-methyl-but-2-enoic. Using L-3-amino-epsilon-caprolactam. Rf = 0.16 (ethyl acetate).

Example 21: Amide N- T (R) -pepsilon-caprolactam-3-lical acid (4R) -fN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-chlorobenzyl) ) -but-2 -enoic acid (another method of preparation for the compound of Example 12).

The title compound can also be prepared starting from racemic 4-chlorophenylalanine methyl ester (instead of D-4-chlorophenylalanine methyl ester). The racemic 4-chlorophenylalanine methyl ester is reacted in a manner analogous to that described in Example 12. In step b), D-3-amino-epsilon-caprolactam is used, as in step 12b). The resulting mixture of diastereoisomers is then separated in a final step by chromatography on silica gel (ethyl acetate). In this manner, N- [(R) -ispsilon-caprolactam-3-yl] amide is obtained from (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] - 4- (4-chlorobenzyl) -but-2-enoic [Rf = 0.12, ethyl acetate, Rt = 20.38 minutes (Chiracel-OJ, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: ethanol = 90:10 + acid trifluoroacetic at 0.1 percent, flow rate of 1.0 milliliters / minute, 30 bar)], and N- [(R) -pepsilon-caprolactam-3-yl] amide of (4S) - [N1 -methyl-N1 - (3, 5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic [Rf = 0.09, ethyl acetate, Rt = 23.6 minutes (Chiracel-OJ, 0.46 x 25 centimeters, detection at 210 nanometers, hexane: i-sopropanol = 80:20 + 0.1 percent trifluoroacetic acid, flow rate 1.0 milliliters / minute, 30 bar)], in a pure form.

Example 22: In a manner analogous to the preparation of the compounds described in Example 21, it is also possible to prepare N- [(R) -epsilon-caprolactam-3-yl] amide of (4R) -4-fN1 -me 1-N '- (3, 5-bistrifluoroethyl.-bp.nzoi.1) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic: The title compound is prepared starting from of racemic 3,4-dichlorophenylalanine methyl ester. The racemic 3,4-dichlorophenylalanine methyl ester is reacted in a manner analogous to that described in Example 12 [12 g)]. In step b), D-3-amino-epsilon-caprolactam is used, as in step 12b). The formed diastereoisomer mixture is then separated in a final step by chromatography on silica gel (ethyl acetate). In this way, N- [(R) -ispsilon-caprolactam-3-yl] amide is obtained from (4R) -4- [N '-methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic, Rf = 0.12, ethyl acetate, mp 115-120 ° C, [o]] 20 = + 39.4 ° C (c-0.97, ethanol); and N- [(R) -ispsilon-caprolactam-3-yl] amide of (4S) -4- [N 1 -methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3, 4-dichlorobenzyl) -but-2-enoic, Rf = 0.09, ethyl acetate, in a pure form.

In a manner analogous to the procedure described in Examples 21 and 22, it is also possible to prepare, starting from the appropriately halogenated phenylalanine derivatives, the following substances: Example 22A: N-f (R) -epsilon-caprolactam-3-lical acid amide C4R) - and (4S) -4- TN '-methyl-N' - (3,5-bistri luoromethyl-benzoyl) -aminol -4- (3-fluoro-4-chlorobenzyl) -but-2-ene: First diastereoisomer: Rf = 0.24 (ethyl acetate), and second diastereoisomer: Rf = 0.28 (ethyl acetate).

Example 22B: .Amida. N- [(R) -ispsilon-caprolactam-3-yl]] (4R) - and (4S) -4- TN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (3.4 -difluorobenzyl) -but-2-ene: First diastereoisomer: Rf = 0.4 (ethyl acetate: α-ketone = 1: 1), and second diastereoisomer: Rf = 0.34 (ethyl acetate: acetone = 1: 1).

Example 22C: Amide N- T (R) -epsilon-caprolactam-3-lical acid (4R) - and (4S) -4- TN '-methyl-N'- (2,5-bistri luoromethyl-benzoyl) - amino] -4- (3,4-dibromobenzyl) -but-2-enoic: First diastereoisomer: R £ = 0.17 (ethyl acetate), and second diastereoisomer: Rf = 0.11 (ethyl acetate).

Example 22D: N-f (R) -ispsilon-caprolactam-3-lical amide of (4R) - and (4S) -4- fN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4 - (3,4-trifluorobenzyl) -but-2-enoic: First diastereoisomer: Rf = 0.11 (ethyl acetate), and second diastereoisomer: Rf = 0.076 (ethyl acetate).

Example 22E: Amide N- T (R) -psylon-caprolactam-3-1-acid (4R) - and (4S) -4- TN '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -aminol -4- (4-fluorobenzyl) -but-2-enoic: First diastereoisomer: Rf = 0.175 ( ethyl acetate), and second diastereoisomer: Rf = 0.14 (ethyl acetate). Example 23: Amide N- T (S) -epsilon-caprolactam-3-lical acid (4R) - or (4S) - TN '- (3,5-bistrifluoromethyl-benzoyl) -N'-methyl-aminol-5,5-diphenyl-pent-2-ene: [Presumed to be a derivative ( 4R)]. 58 milligrams (0.47 millimoles) of 4-dimethyl aminopyridine (DMAP), 85 milligrams (0.44 millimoles) of N- (3-dimethylaminopropyl) -N'-ethyl carbodiimide hydrochloride (EDC #) are added in succession. HC1), and 58 milligrams (0.44 millimoles) of \ (S) -3-amino-hexahydro-2-azepinone, to a suspension of 207 milligrams (0.40 millimoles) of acid (4R) - or (4S) - [N- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-amino] -5,5-diphenyl-pent-2-enoic acid in 5 milliliters of methylene chloride. After stirring at room temperature for 16 hours, the mixture is concentrated by evaporation, and the residue is chromatographed on silica gel using methylene chloride / methanol. (95: 5). The title compound is obtained in the form of a cream-colored solid. Thin layer chromatography: methylene chloride / methanol (95: 5) Rf = 0.32; ESI (+) -MS (M + H) + = 632; [a.] D20 = + 41.9 ° C (c = 1, methanol).

The starting compound is prepared as follows: (a) 2- (N-butoxy-tertiary-carbonyl-N-methyl-amino) -3,3-diphenyl-propanoic acid methyl ester: To a solution of 34.2 grams (0.10 moles) of tertiary-2-butoxycarbonylamino acid -3,3-diphenyl propanoic acid (J. Med. Chem. 35, 3364, 1992) in 250 milliliters of N, N-dimethyl formamide, 121.9 grams (0.52 moles) of silver oxide (I) are added in succession. in one portion, and 26 milliliters (0.41 moles) of methyl iodide per drip over a period of 20 minutes. After being stirred at room temperature for 26 hours, the mixture is diluted with ethyl acetate; the oxide is filtered over Hyflo, and then washed with ethyl acetate. The organic phase is concentrated by evaporation first using a rotary evaporator, and then under a high vacuum. The residue is dissolved in ethyl acetate, washed three times with water and once with brine, dried over sodium sulfate, and concentrated by evaporation. The title compound is obtained in the form of a beige solid. Thin layer chromatography: methylene chloride / methanol (95: 5) Rf = 0.28; FAB-MS (M + H) + = 370. (b) Tertiary butyl ester of (1-hydroxymethyl-2,2-diphenyl-ethyl) -methyl-carbamic acid: To a solution of 32.0 grams (86.6 millimoles) of 2- (N-butoxy-tertiary-carbonyl) methyl ester -N-methyl-amino) -3,3-diphenylpropanoic acid in 400 milliliters of ether, 3.0 grams 8130.0 millimoles) of lithium borohydride in portions, and 5.3 milliliters are added in succession. (130 millimoles) methanol drip (foam). The reaction mixture is stirred under reflux for 3 hours, then cooled in an ice bath, and 40 milliliters of 0.5N hydrochloric acid (foam) are added. After further dilution with water, the mixture is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate, and concentrated by evaporation, yielding the title compound in the form of a white foam. Thin layer chromatography: methylene chloride / methanol (95: 5) Rf = 0.46; FAB-MS (M + H) + = 342. (c) Tertiary butyl ester of (l-formyl-2,2-diphenyl-ethyl) -methyl-carbamic acid: 17.8 milliliters (127 millimoles of triethyl amine, and a solution of 22.8 grams (127 millimoles) of trioxide complex of sulfur-pyridine in 100 milliliters of dimethyl sulfoxide, are added in succession to a solution of 14.5 grams (42.5 millimoles) of tertiary butyl ester of (l-hydroxymethyl-2, 2-diphenyl-ethyl) -methyl-carbamic acid in 80 milliliters of dimethyl sulfoxide. After 45 minutes, the reaction mixture is poured into ice water, and exhaustively extracted with ether. The combined organic phases are washed twice with 1M potassium hydrogen sulfate, twice with water, and once with 1M sodium hydrogen carbonate, dried over sodium sulfate, and concentrated by evaporation, yielding the title compound in the reaction mixture. shape of a yellow oil. Thin layer chromatography: methylene chloride / methanol (95: 5) Rf = 0.88. (d) 4- (N-butoxy-tertiary-carbonyl-N-methyl-amino) -5,5-diphenyl-pent-2-enoic acid ethyl ester: A solution of 14 milliliters (68 mmol) of triethyl ester of acid Phosphonoacetic acid in 130 milliliters of tetrahydrofuran is added at 0 ° C to a solution of 3.7 grams (84 millimoles) of a dispersion of 55-65 percent sodium hydride (washed three times with pentane) in 130 milliliters of tetrahydrofuran. . After 1 hour, a solution of 13.6 grams (40 millimoles) of tertiary butyl ester of (1-formyl-2, 2-diphenyl-ethyl) -methylcarbamic acid in 130 milliliters of tetrahydrofuran is added dropwise thereto. After 4 hours, the reaction mixture is made neutral with 1M potassium hydrogen sulfate, and then diluted with water and ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel using methylene chloride / methanol (99: 1 to 98: 2). The title compound is obtained in the form of a yellow oil. Thin layer chromatography: methylene chloride / methanol (98: 2) Rf = 0.45. (e) 4-Methylamino-5,5-diphenyl-pent-2-enoic acid ethyl ester: 22 milliliters (0.28 moles) of trifluoroacetic acid are added dropwise to a solution of 14.2 grams (34.7 millimoles) of ethyl ester of ethyl ester. 4- (tertiary butoxycarbonyl-methyl-amino) -5,5-diphenyl-pent-2-ene acid in 100 milliliters of methylene chloride. After 5 hours, the reaction mixture is concentrated by evaporation, and then toluene is added twice, and the mixture is concentrated by evaporation. The residue is dissolved in methylene chloride, washed with a saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and again concentrated by evaporation. The title compound is obtained in the form of a yellow oil. Thin layer chromatography: methylene chloride / methanol (95: 5) Rf = 0.26. (f) 4-fN- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-amino) -5,5-diphenyl-pent-2-enoic acid ethyl ester: A solution of 10.6 grams (34.3 millimoles) of 4-methylamino-5,5-diphenyl-pent-2-enoic acid ethyl ester in 110 milliliters of methylene chloride is added at 0 ° C by means of a cannula to a solution of 6.7 milliliters (36.0 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride in 110 milliliters of methylene chloride. Then 5.8 milliliters (41.1 millimoles) of triethyl amine and 0.4 grams (3.4 millimoles) of 4-dimethyl aminopyridine are added. After 1 hour, the reaction mixture is diluted with ethyl acetate and washed twice with water and once with brine. The aqueous phases are extracted once with ethyl acetate. The combined organic phases are then dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel using methylene chloride / methanol (100: 0 to 98: 2). The title compound is obtained in the form of a light yellow foam. Thin layer chromatography: methylene chloride / methanol (98: 2) Rf = 0.38; FAB-MS (M + H) + = 550. (g) (4R) - and (4S) - [N- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-axaino] -5,5-diphenyl-pent-2-enoic acid ethyl ester: 4.38 grams (7.95 mmol) of 4- [N- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-amino * -5,5-diphenyl-pent-2-enoic acid ethyl ester, are chromatographed on a column Chiralcel® OD-prep using hexane / isopropanol (99: 1). The separated title compounds are obtained in the form of light yellow foams. High performance liquid chromatography (Chiralcel® OD - 250 x 4.6 millimeters): hexane / isopropanol (980: 20), Rt = (enantiomer 1) = 5.28 minutes, Rt (enantiomer 2) = 7.57 minutes. (h.) Acid (4R) - or (4S) - [N- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-amino] -5,5-diphenyl-pent-2-enoic: 6.7 milliliters are added of sodium hydroxide IN to a solution of 2.16 grams (3.93 millimoles) of ethyl ester of (4R) - or (4S) - [N- (3, 5-bistrifluoromethyl-benzoyl) -N-methyl-amino] -5,5-diphenyl-pent-2-enoic (enantiomer 2) in 30 milliliters of tetrahydrofuran / meta-nol (2: 1). After 4 hours, the reaction mixture is concentrated by evaporation, diluted with water, and made acidic with cold 2N hydrochloric acid. The white precipitate is filtered, washed with water, and dried under a high vacuum at 60 ° C. The title compound is obtained in the form of a white solid. Thin layer chromatography: methylene chloride / methanol (95: 5) R = 0.22; ESI (-) - MS (M-H) = 520; ot] D20 = + 38.5 ° C (c = 1, methanol).

In an analogous manner [starting from (4S) - or (4R) - [N- (3,5-bistrifluoromethyl-benzoyl) -N-methyl-amino] -5,5-diphenyl-pent-2-enoic acid , prepared from the enantiomer 1 of Example 23 (g)], it is possible to prepare: N-f (S) -epsilon-caprolactam--lic acid amide (4S) - or (4R) -fN '- (3 , 5-bistri Inoromethyl-benzoyl) -N '-methyl-amino-5,5-diphenyl -pert-2-enoic [is presumed to be the (4S) derivative]; thin layer chromatography: methylene chloride / methanol (95: 5), Rf = 0.36; ESI (+) -MS (M + H) + = 632; [cc] D20 = -31.2 ° C (c = 1, methanol).

Examples A to E: Pharmaceutical Compositions: Example A: Tablets, each comprising 50 milligrams of active ingredient: Composition (10,000 tablets) active ingredient 500.0 grams lactose 500.0 grams potato starch 352.0 grams gelatin 8.0 grams talcum 60.0 grams magnesium stearate 10.0 grams silicon dioxide (highly dispersed) 20.0 grams ethanol cs The active ingredient is mixed with the lactose and 292 grams of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin, and is granulated through a sieve. After drying, the rest of the potato starch, magnesium stearate, talc, and silicon dioxide are mixed, and the mixture is compressed into tablets, each weighing 145 milligrams, and comprising 50 milligrams of ingredient active; if desired, the tablets can be provided with divider notches for a finer dose adaptation.

Example B: Film-coated tablets, each comprising 100 milligrams of active ingredient: Composition (1,000 film-coated tablets) active ingredient 100.0 grams lactose 100.0 grams corn starch 70.0 grams talc 8.5 grams calcium stearate 1.5 grams hydroxypropylmethyl cellulose 2.36 grams shellac 0.64 grams water cs dichloromethane q.s.

The active ingredient, lactose, and 40 grams of corn starch, are mixed together, and the mixture is moistened with a paste prepared from 15 grams of corn starch and water (with heating), and granulated. The granules are dried, and the rest of the corn starch, the talc, and the calcium stearate are mixed with the granules. The mixture is compressed to form tablets (weight: 280 milligrams each), which are then film coated, with a solution of hydroxypropylmethyl cellulose and shellac in dichloromethane (final weight of each film-coated tablet: 283 milligrams).

Example C: Hard gelatin capsules, each comprising 100 milligrams of active ingredient: Composition (1,000 capsules) active ingredient 100.0 grams lactose 250.0 grams microcrystalline cellulose 30.0 grams lauryl sodium sulfate 2.0 grams magnesium stearate 8.0 grams Sodium lauryl sulfate is added through a sieve with a mesh size of 0.2 millimeters, to the lyophilized active ingredient. The two components mix intimately. Then the lactose is first added through a sieve of a mesh size of 0.6 millimeters, and then the microcrystalline cellulose is added through a sieve of a mesh size of 0.9 millimeters. All four components are then intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve of a mesh size of 0.8 millimeters. After further mixing (3 minutes), 390 milligram portions of the resulting formulation are introduced into the size 0 hard gelatin capsules.

Example D: A solution for injection or infusion, which comprises 5 milligrams of active ingredient per ampule of 2.5 milliliters. Composition (1,000 ampoules) active ingredient 5.0 grams sodium chloride 22.5 grams buffer solution of 300.0 grams phosphate (pH: 7.4) demineralized water up to 2,500.0 milliliters The active ingredient and sodium chloride are dissolved in 1000 milliliters of demineralized water, and the solution is filtered through a microfilter. The phosphate buffer is added to the filtrate, and the mixture is brought to 2,500 milliliters with demineralized water. For the preparation of unit dosage forms, 2.5-milliliter portions of the mixture are filled into glass ampules, which then each comprise 5 milligrams of active ingredient.

Example E: A suspension for inhalation, which comprises propellant, and which forms a solid aerosol, comprising 0.1 weight percent of active ingredient: Composition% by weight active ingredient, micronized 0.1 sorbitan trioleate 0.5 propellant A (trichlorotrifluoroethane) 4.4 propellant B (dichlorodifluoromethane and 15.0 1,2-dichlorotetrafluoroethane) 80.0 With the exclusion of moisture, the active ingredient is suspended in trichlorotrifluoroethane, with the addition of sorbitan trioleate, using a conventional homogenizer, and the suspension is introduced into an aerosol container equipped with a metering valve. The container is closed and filled with propellant B under pressure.

Claims (15)

1. A compound of the formula I: R, R or (l) wherein: R is phenyl which is unsubstituted or which is substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy, R- | _ is hydrogen or lower alkyl, R 2 is hydrogen, lower alkyl, or phenyl, which is unsubstituted or which is substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy, R 3 is phenyl which is unsubstituted or substituted by 1, 2, or 3 substituents selected from the group of halogen, lower alkyl, trifluoromethyl, hydroxyl, and lower alkoxy; or is naphthyl, lH-indol-3-yl, or 1-lower alkyl-indol-3-yl. Rd 'and R4"are each independently of the other, hydrogen or lower alkyl, where at least one of the radicals R4' and R4" is hydrogen, and R5 is cycloalkyl of 3 to 8 carbon atoms, D-azacycloheptan-2-on -3-yl, or L-azacycloheptan-2-on-3-yl; or a salt of it.

2. A compound of the formula I according to claim 1, wherein: R is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl. R- | _ is hydrogen or lower alkyl, R2 is hydrogen or phenyl, R3 is phenyl, halophenyl, dihalophenyl, trihalophenyl, 2-naphthyl, lH-indol-3-yl, or 1-lower alkyl-indol-3-yl, R4 'and R4"are each independently of the other, hydrogen or lower alkyl, with at least one of the radicals R' and R" hydrogen, and Rc is cycloalkyl of 5 to 7 carbon atoms, D-azacycloheptan-2-on -3-yl, or L-azacycloheptan-2-on-3-yl; or a salt of it.

3. A compound of the formula I according to claim 1, wherein: R is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl. R-j_ is hydrogen or lower alkyl, R 2 is hydrogen or phenyl, R 3 is phenyl, halophenyl, dihalophenyl, 2-naphthyl, 1 H-indol-3-yl, or 1-lower alkyl-indol-3-yl, R 4 ' and R4"are each independently of the other, hydrogen or lower alkyl, where at least one of the radicals R4 'and R4" is hydrogen, and R5 is cycloalkyl of 5 to 7 carbon atoms, D-azacycloheptan-2-on-3 -yl, or L-azacycloheptan-2-on-3-yl; or a salt of it.

4. A compound of the formula I according to claim 1, wherein: R is 3,5-bistrifluoromethyl-phenyl, R- * _ is hydrogen, methyl or ethyl, R 2 is hydrogen or phenyl, R 3 is phenyl, 4-chlorophenyl , 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4,5-trifluorophenyl, 2-naphthyl, 1H-indole-3-yl, or 1-methyl- indol-3-yl, R4 'and R4"are each independently of the other, hydrogen or methyl, with at least one of the radicals R4' and R4" hydrogen, and R5 being cyclohexyl, D-azacycloheptan-2-on-3 -yl, or L-azacycloheptan-2-on-3-yl ?; or a pharmaceutically acceptable salt thereof.

5. A compound of the formula I according to claim 1, wherein: R is 3,5-bistrifluoromethyl-phenyl, R * j_ is hydrogen, methyl or ethyl, R 2 is hydrogen or phenyl, R 3 is phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2-naphthyl, lH-indol-3-yl, or l-methyl-indol-3-yl, R4 'and R4"are each independently of the other , hydrogen or methyl, with at least one of the radicals R4 'and R4"hydrogen, and Re being cyclohexyl, D-azacycloheptan-2-on-3-yl, or L-azacycloheptan-2-on-3-yl; or a pharmaceutically acceptable salt thereof.

6. A compound of the formula I according to claim 1, wherein: R is 3,5-bistrifluoromethyl-phenyl, R-] _ is hydrogen or methyl, R 2 is hydrogen or phenyl, R 3 is phenyl, 4-chlorophenyl, , 4-dichlorophenyl, 2-naphthyl, lH-indol-3-yl, or l-methyl-indol-3-yl, R4 'and R4"are hydrogen, and R5 is cyclohexyl, D-azacycloheptan-2-on-3 -yl or L-azacycloheptan-2-on-3-yl or a pharmaceutically acceptable salt thereof.

7. Amide N- [(R) -ispsilon-caprolactam-3-yl] acid (4R) - [N 1 -methyl-N 1 - (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid according to claim 1.

8. N- [(S) -pepsilon-caprolactam-3-yl] amide of (4R) - [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (l) -methyl-indol-3-yl) -pent-2-enoic according to claim 1.

9. Amide N- [(R) -ispsilon-caprolactam-3-yl]] (4R) - [N 1 -methyl] -N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid according to claim 1.

10. Amide N- [(R) -epsilon-caprolactam -3-yl] of (4R) -4- [N '-methyl-N' - (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid according to claim 1.

11. A pharmaceutical composition comprising a compound according to any of claims 1 to 10, and at least one pharmaceutically acceptable carrier.

12. A compound according to any of claims 1 to 10, for use in a method for the therapeutic treatment of the animal or human body.

13. A compound according to any of claims 1 to 10, for use in the treatment of diseases that red to antagonism of the NK1 receptor and / or the NK2 receptor.

14. The use of a compound according to any of claims 1 to 10, in the manufacture of pharmaceutical compositions for the treatment of diseases that red to antagonism of the NK1 receptor and / or the NK2 receptor.

15. A process for the preparation of a compound of the formula I according to claim 1, said process comprises: (A) N-acylating a compound of the formula II: (if) with a carboxylic acid R-C (= 0) -OH, or with a reactive derivative thereof, or (B) condensing a carboxylic acid of the formula III: (III). or a reactive derivative thereof, with a cycloalkyl amine of 3 to 8 carbon atoms, or D (+) - or L (-) - 3-amino-epsilon-caprolactam, or (C) as a last step, synthesizing the double bond by a Wittig reaction or a variant thereof, for example from Wittig-Horner; and if desired, converting a compound of the formula I to a different compound of the formula I, and / or, if desired, converting a resulting salt to the free compound or to a different salt, and / or if desired, converting a free compound resulting from formula I having salt-forming properties into a salt, and / or, if desired, separating a resultant fraction from stereoisomers, diastereomers, or enantiomers, into stereoisomers, diastereomers, or individual enantiomers.