MXPA97008973A - Diarildiamine erivates and their use as agonistasy delta-opioi antagonists - Google Patents

Abstract

A class of diaryldiamine derivatives of the formula (I): in which R1 and R2 are each hydrogen, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl or furan-2- or 3-yl- alkyl or they can form together an alkyl ring of C3-7 which can be interrupted by an oxygen, R3 and R4 are each hydrogen, alkyl, or R4 is oxygen that forms with the carbon atom to which a C = O group is attached; R5 is hydrogen, hydroxy, alkoxy, thiol or alkylthio, R6 is phenyl, halogen, NH2 or a para- or meta C (Z) -R8 group, in which Z is oxygen or sulfur, R8 is alkyl, alkoxy or NR9R10, wherein R9 and R10 are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, or R6 is a para- or meta-R11-NC (Z) -R12 group in which R11 and R12 are hydrogen, alkyl, cycloalkyl , cycloalkylalkyl, alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is defined as above, and R7 is hydrogen, alkyl or halogen, are potent and selective delta-opioid agonists or antagonists, and are useful as analgesics and to treat pathological conditions that can usually be treated with delta-opioid receptor agonists and antagonists.

Description

DERIVATIVES OF DIARILDIAMINE AND ITS USE AS AGONISTS AND DELTA-OPIOID ANTAGONISTS DESCRIPTIVE MEMORY This invention relates to novel dianldiarnma derivatives, processes for their preparation and their use in medicine. The presence of < The populations of at least opioid receptors (rnu, delta and kappa) are now well established and documented and all three appear to be present in the central and peripheral nervous system of many species, including man (Lord 3. fí. H. et al., Nature 1977, tt ±, 495). The activation of the three subtypes of opioid receptor can lead to antimicrobiation in animals. In particular, studies with delta peptide agonists have indicated that activation of the delta receptor produces antinociception in rodents, primates and can induce clinical analgesia in man (DE Molm et al., Pain, 1985, tt, 213) Evidence exists that suggests a lower propensity of delta agonists to cause the usual side effects associated with mu and kappa activation (Gallmgan et al., 3. Pharrn, Exp. Ther., 1984, 229, 641). Prior descriptions have been described previously as compounds for the synthesis of di-benzodi-cepins, useful as anti-histokinetic and anti-anaphylaptic agents FPat. Brit .. 907646, Dr. fi. Uonder fí. G .; Hunzinker et al., Helv. Chirn ficta 46, 2337, (1963) 3. European Patent 508,334 (Green Cross Corp.) discloses oxygen-substituted diaprammes which are said to be inhibitors of mouse ear edema induced by TPfi. UO 93/15062 (The Uelcorne Foundation Limited) describes derivatives of fempiperap na which are said to be agonists in the t is opiate receptors. We have now discovered a novel class of diary-Idiarnine derivatives that are potent and selective delta-opioid agonists and antagonists that can therefore be of potential therapeutic utility as analgesics, immunosuppressants to prevent rejection in organ transplantation and grafting of skin, anti-allergic and anti-inflammatory agents, protectors of brain cells, agents to treat drug and alcohol abuse, gastritis, diarrhea, cardiovascular and respiratory diseases, cough, mental illness, epilepsy and, more generally, agents for those pathological conditions that can usually be treated with delta-opioid receptor agonists and antagonists. In accordance with the present invention, a compound, or a solvate or salt thereof of the formula (I) is provided: wherein R 1 and R 2, which may be the same or different, are each hydrogen, may be linear or branched C 1 -C e alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylene, C -Ce cycloalkylalkyl, C3-C3 alkenyl, C3-C5 alkenyl, aryl, aralkyl or furan-2- or 3-? -alkyl or can together form a C3-C7 alkyl ring which may be interrupted by an oxy ene; R3 and R-4, which may be the same or different, are each hydrogen, Ci-Ce alkyl straight or branched, preferably methyl, or R1 is oxygen scavenger with the carbon atom to which a C = group is attached 0; Rs is hydrogen, hydroxy, C1-C3 alkoxy, preferably methoxy, mercapto, alkylthio, preferably rnetiitio; Rβ is vinyl, for halide, preferably bromide, para- or rneta-NH2 or a para- or rneta-C (Z) -Rβ group, in which Z is oxygen or sulfur, Rβ is Ci-Cs alkyl, alkoxy of Ci-Cß or NR R10, wherein R9 and Rio which may be the same or different, are hydrogen, straight or branched Ci-Cß alkyl, C3-C7 cycloaicyl, cycloalkyl, 4-Ce, alkenyl C3-e, aplo, aralkyl or together form an alkyl ring of A, R11 I or Re is a group -NC (Z) -Ri2 in which Rn and R12, which may be the same or different, are hydrogen, alkyl of Ci -Ce ect or branched, cycloaikyl C3-C7, cycloalkyl-C4-C6-alkenyl, C3-C6-alkenyl, ring, aralkyl or a heterocyclic ring, or optionally substituted and Z is defined as before; and R7 is hydrogen, straight or branched Ci-Ce alkyl, halogen, preferably chloro. Examples of Ri and R are me, ethyl, cyclopropyl ether Lio, aillo or, together with N, pyrrolidino. Examples of R3 and R "are hydrogen, methyl, ethyl, 1-propyl, or R4 is 0 =. Examples of R5 are hydrogen, hydroxy, inetoxy. Examples of Rβ are COMe, CO-i-Pr, COOEt, CONH2, CONH-n-Pr, C0N (Me) Et, CON (Me) i-Pr, C0NEt2. C0N (? - Pr) 2, CONEt (? - Pr), C0NÍ-CH2, NHC0? -Pr, NH2, bromide, femlo. Examples of R7 are hydrogen and methyl. A first group of preferred compounds of formula (I) is that in which of R 3 and R 1 each is hydrogen or Ci-Cβ alkyl, preferably methyl or ethyl, and Rl. R, R5, Rβ and R7 are as defined above. A second preferred group of compounds of the formula (I) is that in which Rs is a hydroxy or an alkoxy group of Ci-C3, Ri, R2, Rβ and R7 are as defined above for the formula (t) and R3 and Ri each is hydrogen or Ci-C-alkyl. A gruf > or particularly preferred compound of the formula (T) is that in which Rβ is a group -C (Z) -Rs wherein Rβ is Ci-Ce alkyl, OC1-4 alkyl or NR9R10 where R9 and Rio are as defined above for the formula (T), Z is oxygen, Ri, R2 and R7 are as defined above for the formula (T), of R3 and RA each is hydrogen or Ci-Ce alkyl and Re is hydroxy or C? -C3 alkoxy. The compounds of the formula (I) or their salts or solvates are preferably presented in pharmaceutically acceptable or purely substi tional form. By "pharmaceutically acceptable formula" is meant, inter alia, a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives, such as diluents and carriers, and not including material considered to be toxic at normal dose levels. A substantially pure form will generally contain at least 50% (excluding the normal pharmaceutical additives), preferably 75%, most preferably 90% and preferably even 95% of the compound of the formula (I) or its salt or solvate . A preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and soivates, the unique portions and additional solvents must also be non-toxic. Examples of pharmaceutically acceptable salts of a compound of the formula (1) include the acid addition salts with the conventional pharmaceutical acids, for example, rnaleic, hydrochloric, phosphoric, acetic, fumaric, salicylic, citric, lactic, andelic, tartaric, succimic. , benzoic, ascorbic and rnetansul phonic. The compounds of formula (I) may exist in more than one stereoisomeric form and the invention extends to all of these forms as well as mixtures thereof, including racemates. The present invention also provides a process for the preparation of a compound of the formula (I). In general, these compounds can be prepared by the method illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it can be synthesized starting from the desired enantiornero of the starting material and carrying out reactions that do not include racernization procedures and can be prepared by chiral synthesis, or by derivation by a qulal auxiliary, in which the resulting diastereomer mixture is separated and the auxiliary group is divided to provide the desired pure Lomeros enan. Alternatively, the compounds of the formula (I) can be separated into their enantiomers for specific salts with an appropriate optically active acid, followed by resolution by fractional crystallization and the subsequent recovery of the pure enantiomers. The compounds of the general formula (I) can be obtained following the procedure described in Scheme 1. The compounds of the general formula (IT) can be synthesized starting from substituted acetanilides and substituted derivatives of brornobenzene in the presence of Cul and K2CO3, as described in 3. Org. Chem, 43, t \ 975 (1978). The bis-anilic (II) derivatives can be alkylated using substituted orbromine esters in the presence of NaH using DHF as a solvent to obtain compounds of the general formula (III). The ester group of these compounds can be fed using L1AIH4 in THF as a solvent or, alternatively, for compounds in which Rβ is a carbonyl-containing group, using NaBH, in t-BuOH / MeOH as a solvent to obtain compounds of the general formula ( IV). The alcohol derivatives are converted to their corresponding metansulphates and then treated with the appropriate amines obtaining compounds of the general formula (I) together with their regioisomers in which R3 = R '.

SCHEME 1 / N ^ B R. ^ * - sv > L O * 3 * alternatively, the compounds < The general formula (I) can be synthesized following the procedure described in Scheme 2. The esters of the general formula 15 (III), obtained as described in Scheme 1, can be treated with substituted amines under pressure. The corresponding amines can be reduced using BH3-Me2S to obtain compounds of the general formula (I) in which R3 is H.

SCHEME 2 The compounds of the general formula (I), in which Rβ is a CORβ group, where Rs is defined as above, can be obtained starting from the compounds of the general formula (Ilb) and (Ele), obtained at the same time from the compounds of the formula (lia), as outlined in Scheme 3. The amides (Ilb) can be obtained by treating the corresponding carboxylic acids (lia) with the appropriate amines, using DCC / HOBT as condensing agents. Esters (lie) are synthesized by treating the compounds (lia) with the corresponding alcohol in acidic media.

SCHEME 3 (H) The compounds of the general formula (I) wherein R .; is = 0 can be prepared as described in Scheme 4. The compounds of the general formula (II) are treated with boiling chloroacetyl chloride in toluene. The resulting chlorine derivatives are treated with the appropriate amines to obtain the final compounds of the general formula (I).

Lü SCHEME 4 (I) The compounds of the general formula (I ') in which Re is a MeO group, can be de-identified, for example, by using BBr-3 in CH2Cl2 as a solvent or, alternatively, using (CH3) 3S? Cl / NaI in CH3CN in boiling, to obtain other compounds of the generic formula (I) in which R5 is OH. See Scheme 5.

SCHEME 5 The compounds of the general formula (I) can be obtained from phenotiames of the general formula (V) (described in EP0346238fil) by removing the sulfur atom or by using NTCl2 / NaBH «. See Scheme 6.

Ll SCHEME 6 (SAW) The compounds of formula (I) can be converted to their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids. The solvates of the formula (I) can be formed by stabilization or recrystallization from the appropriate solvent. For example, hydrates can be formed by storage or recrystallization from aqueous solutions, or solutions in organic solvents containing water. Also the salts and solvates of the compounds of the formula (T) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. According to the above, such salts or solvates can also form part of this invention. In general, the compounds of formula (I) which act as selective ligands of the delta receptor may be useful as analgesics, immunosuppressants to prevent rejection in organ transplantation and skin grafting, anti-allergic agents and n! inflammatory, protector of the brain cells, for the treatment of drug and alcohol abuse to decrease drastic secretion, for the treatment of diarrhea, cardiovascular and respiratory diseases, cough, mental illness, epileptic seizures and other neurological disorders (in hereinafter referred to as "Conditions"). In particular, the activity of the compounds of the formula (D) as delta antagonists in normal tests indicates that they are of potential therapeutic utility as analgesic agents for the improvement or elimination of pain, According to the above, the present invention also provides a compound The formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance The present invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate. Accept it, in the elaboration of a medication for the treatment of the Conditions., and a composition of this invention, can be prepared by mixing a compound of the invention with an appropriate vehicle. It may contain diluent, binder, filler, disintegrant, sabotage agent, coloring agent, lubricant or preservative in a conventional manner. These conventional excipients can be used, for example, in the preparation of compositions of agents known from the Conditions. Preferably a pharmaceutical composition of the invention is presented in unit dosage form and a form adapted for use in the medical and veterinary fields. For example, such preparations may be obtained in package form, accompanied by written or printed forms for use as an agent in the treatment of The Conditions. The appropriate dose variation of the compounds of the invention depends on the compound to be used and the condition of the patient. It will also depend, among other things, on the relationship of the power with respect to the absorption capacity and the frequency and the route of administration. The compound of the composition of the invention can be formulated for administration by any route and is preferably presented in a unit dose form or in a form that a human patient can administer to himself or herself in a single dose. Advantageously, the composition is suitable for oral, rectal, local, parenteral, intravenous or intramuscular administration. Preparations can be designed to provide slow libration of the active ingredient. The compositions may be presented, for example, in the form of tablets, capsules, small impregnated sacks, flasks, powders, granules, troches, reconstituting powders or liquid preparations, for example solutions or suspensions, or suppositories. 1/.

The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbino, tragacanth, or polyvinyl pyrrole idone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example is magnesium erate; disintegrants, for example starch, poly v nil pyrrolidone, sodium starch or cellulose starch; or pharmaceutically acceptable sedimentation agents such as sodium lauryl sulfate. Solid compositions can be obtained by conventional methods of mixing, filling, tableting and the like. Repeated mixing operations can be used to distribute the active agent in all those compositions using large amounts of fillers. When the composition is presented as a tablet, powder or troche, any suitable vehicle can be used to formulate solid pharmaceutical compositions, some examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and clay. The tablets can be coated according to methods known in normal pharmaceutical practice, in particular with enteric coating. The composition can also be in the form of a capsule and syringe, for example a gelatin containing the compound, if desired with a vehicle or other excipients.

Compositions for oral administration as liquids may be presented, for example, in the form of emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution in water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, etui cellulose, gelatin, hydroxyethylethylcellulose, oarboxirnetiicellulose, aluminum cerate gel, hydrogenated edible fats; emulsifying agents, for example locitin, sorbitan rnonooleate or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, fatty esters, for example esters of glycepine, or propylene glycol, or ethyl alcohol, glycepna, water or normal saline; preservatives, for example methyl p-hydroxybenzoate or prspiLo, or sorbic acid; and if desired flavoring and coloring agents conventional. The compounds of this invention can also be administered by a non-oral route. According to the routine pharmaceutical procedure, the compositions can be formulated, for example for rectal administration as a suppository. It can also be formulated for presentation in injectable form of an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, for example sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants and other preservatives, pH regulators or solutes to make the solution isotomized with the salt, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampules or disposable injection devices or in multiple dose form such as a bottle from which the appropriate dose or a solid form can be extracted to a concentrate which can be used to prepare a injectable formulation. The compounds of this invention can also be administered by inhalation, through the nasal or oral routes. Each administration can be carried out with an excretion formulation comprising a compound of the invention and a suitable vehicle, oxidically suspended therein, for example, a hydrocarbon-blowing agent. Preferred spray formulations comprise particles of compounds reduced microscopically in combination with a surfactant, solvent or dispersion agent to prevent sedimentation of the suspended particles. Preferably, the decomposed particle size is about 2 to 10 microns. Another mode of administering the compounds of the invention comprises transdermal delivery using a skin patch formulation. A preferred formation comprises a compound of the invention dispersed in a pressure-sensitive adhesive material that adheres to the skin, thereby allowing the compound to diffuse from the adhesive material through the skin for delivery to the patient. For a constant rate of absorption percutanea, pressure sensitive adhesive materials known in the art can be used, such as natural rubber or ilicon. As mentioned above, the effective dose of the compound depends on the particular compound employed, the condition of the patient and the frequency and route of administration. A unit dose will generally contain from 20 to 1000 rnL and will preferably contain from 30 to 500 ml, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 rng. The composition can be administered one or more times per day, for example, 2, 3 or 4 times daily, and the total daily dose for a 70 kg product is again in the range of 100 to 3000 mg. Alternatively, the unit dose will contain from 2 to 20 rng of active ingredient and will be administered in multiples, if desired, to give the preceding daily dose. No unacceptable toxicological effects are expected with the compounds of the invention when administered according to the invention. The present invention also provides a method for the treatment and / or prophylaxis of conditions in mammals, particularly in humans, which comprises administering to the mammal in need of such treatment and / or prophylaxis an effective amount of the compound of the formula (I). ) or a pharmaceutically acceptable salt or solvate of the The activity of the compounds of the present invention as selective delta ligands is determined in the radioligand binding assays as described above. Mouse brain membranes were prepared as described by Kosterlitz (Br. 3. Pharrnacol., 1981 73_, 939.). The binding of the preferential delta ligand [SH-l-CD-flla-, D-Leu = 1-encephaloma (DfiDLE) at its KD concentration (1.3 nM) in the presence of 40 nM of the unlabelled CD-ftla2 ligand was evaluated, MePhe *, Gly-olS] -ence aline (DflMGO). The binding of the ul ligand "H31 -DftMTO (Eur. 3. Pharmacol., 1989, 166, 213) and the kappa ligand [H3] -U69563 (Excerpta Medica, 1990, 211), to 0.5 nM was carried out. determined the nonspecific binding in the presence of naloxone (10 uM) for all ligands threshed.The binding data were expressed as percentage of inhibition and gave the following equation: f (x) = lOOX / IICβ + X) where X are cold drug concentration values The ICso obtained were used to calculate the inhibitory constants (Ki) according to the Cheng and Prusoff relationship (Biochem Pharmacol., 1973, 22, 3099) The delta agonist / antagonist activity The compounds of the present invention are determined in the bioassay of the vas deferens of mice (VDR) as described below: Deferent vessels of CD-1 mice were obtained and suspended in a pH regulator of Krebs free of Mg2 + at 37 ° C. The tissues were stimulated electrically with series of pulses that fear the following parameters - duration of the impulses 50 rns, duration of the stimuli 2 rns, frequency of the stimuli 50 Hz, maximum voltage 60-70 V, frequency of the series 0.1 Hz. Cumulative concentration curves were cumulatively determined for each compound. Linear regression analysis and IC 50 concentrations were evaluated according to Tallarida and Murray (Manual or Pharrnac lo l l Calculations, Sppnger Verlag NY, 1981). The most potent compounds of the present invention showed affinities for the delta receptor ranging from 0.5 to 200 nM, varying the delta selectivity from 10 to 1500 times with respect to the other types of delta-opioid receptors. These compounds also displayed potent properties as delta agonists or antagonists in the preparation of VDR. Selective delta agonists (antagonized by the selective delta antagonist naltrindol) displayed IC50 ranging from 1 to 500 nM. For example, the compound of Example 5 showed a Ki 6 = 3.9 nM and the bioanalysis of VDR an IC50 = 7 nM (30 nM of NTI) caused a 10-fold variation of the dose response curve); the compound of Example 9 showed a Kid = 3.9 nM, Kiμ / Ki? = 148 and Ki / Kio = 153. Abdominal constriction tests of mice (MfiC) (Proc. Soc. Exp. Biol. Med., 1957, 9_5_, 729), tail wag of mice (MTF) were adapted ) (J. Pharm. Exp. Ther-., 1941 72_,) and moderately hot water in the tail wag of mice (MTF-WU) (Ll fe Sci., 1986, 39_, 1795) to assess the activity antinociceptive of the compounds of the present invention. The following preparations illustrate the preparation of intermediates, while the methods illustrate the preparation of compounds of the present invention. These compounds are synthesized in Chemical Table 4 and the analytical data are synthesized in Table 5.

PREPARATION 1 N.N-Diet? L-4-CN- (3-methoxy enyl) amino-lbenza? Nide 3.7 g (2.3 mmol) of N-actyl-m-anisidy, 10.6 g (41.4 mmol) of 4-brorno-N, N-diethylbenzamide and 0.42 g of Cul, were added at 100 ° C, - 3 g (22.3 g) were added. rnmoles) of K2CO3 and the resulting mixture was heated at 250 ° C for 2 hours. The residue was dissolved in CH2CI2 and washed with H2O, the organic layer was dried over Na2 ° and the solvent was removed m vacuo. The resulting residue was dissolved in 20 rnl of absolute EtOH and refluxed for 2 hours. The solvent was removed in vacuo, the residue was taken up in H2O and the aqueous layer was extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent was removed m vacuo. The resulting residue was purified by evaporation chromatography (AcOEt / Hexane 6: 4), yielding 3 g of the title compound.

? L IR cm-i (pure) .- 3300, 1595, 1535. MS (EI) m / z: 297.6 (M-l) The compounds of the general formula (II) described in Table 1 were obtained following the same procedure.

TABLE 1 The compounds of the general formula (II) can also be prepared according to the following procedure: '? ? PREPARATION 1 l- [4 - [[N- (3-methoxy-enyl) -lamino] -benzoyl-3-pyrrolidone 2 g (8.2 rnmoles) of 4 [N- (3-rnetoxifem 1) arn-nobenzoic acid, 2.2 g (16.4 rnmoles) of N-hydroxybenzotriazole and 1 rnL (12.3 mrnol) of pyrrolin were dissolved in 40 rnl of a 7: 3 mixture of THF / CH3CN, under a nitrogen atmosphere. The solution was cooled to 0 ° C and 3.4 g (16.4 rnrols) of di-clohexylcarbodiimate dissolved in 20 ml of CH2C12 were added. The reaction mixture was allowed to warm to room temperature for 1 hour, stirred for another hour, then stirred for 1 hour. the precipitate was separated by filtration and the solvent was removed in vacuo. The residue was combined with water and extracted with AcOEt, the organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The resulting crude mixture was purified by vaporization chromatography (ficOEt), yielding 2.4 g of the title compound. IR cm-1 (KBr): 3280, 1600, 1435; MS (El) m / z: 296.1. N, N-d? Isoprop? L-4- [N- (3-methox? Phen?) Am? No] -benzazide was obtained using the same procedure. IR crn- (KBr): 3280, 1600, 1340; EM (El) rn / z: 326.1.

PREPARATION 3 (t) -N, N-Diethyl-4- [CN- (1-ethoxy-carbonylethyl) -N- (3-methoxy-enyl) -lamino] -benzamide 2 g (5L.6 mmoles) of a suspension of mineral oil at 60% NaH, in the nitrogen atmosphere, in 100 rnl of DMF were placed. The resulting suspension was cooled to 0 ° C and 7.7 g (25.8 mol) of N, Nd? Et? L-4-CN- (3-rnetoxy fem) am? No] benzene was added in 50 g. my DMF. After one hour 8.4 rnl (64.5 nmrnols) of et? I-2-brorno-propionate in 25 ml of DMF were added. The reaction mixture was allowed to warm to room temperature overnight, then H2O was added, the organic layer was combined, dried over Na2SO4 and the solvent removed. The crude reaction mixture was purified by vaporization chromatography (ficOEt / hexane 6: 4), yielding 3.5 g of the title compound. IR cm- (neat): 2980, 1740, 1610. MS (El) rn / z: 398 The compounds of the general formula (III) described in Table 2 were obtained, following the same procedure.

TABLE 2 PREPARATION 4 (±) -N, N-Diethyl-4 - [[N-l-hydroxyprop-2-yl) -N-3-methoxyphenyl)] amino] benzamide 1.13 g (2.8 rnrnoles) of (±) -N, N-d? Et were dissolved? 1 - 4-L 'CN- (1-ethoxycarbomletii) -N- (3-rnetox? Phenyl) Hammolbenzami, in a nitrogen atmosphere in 14 rnl of t-BuOH and f) .27 g (7 in. oles) of NaBH¿. The reaction mixture was heated to distillation and 2.5 ml of MeOH was added over 1 hour. The solution was refluxed for 2 hours, then H2O was added, the solvent was removed in vacuo, the residue was taken up in H2O and extracted with ficOEt. the organic layer was dried over Na 2 SO-; and the solvent was removed m vacuo. The crude reaction mixture was purified by vapor chromatography (ficOEt / hexane 9: 1), yielding 0.5 g of the title compound. IR crn-i (pure): 3350, 2990, 160; EM (El) rn / z: 356.1. The compounds of the general formula (IV) and described in Table 3 were obtained following the same procedure.

TABLE 3 Lü fifteen 7! ^ 30 35 40 45 PREPARATION 5 (±) -Ethyl-2- [N- (-am? Nofen? L) -N- (3-methoxy in? L) mino prop onate 1.5 g (4.3 rnmoles) of (±) -e? L-2-rN- (4-nitrophenyl) -N ~ (3-rnetox? Phenyl) lamino propionate were dissolved in 50 ml of Absolute EtOH; 150 rnG of 10% Pd / C was added and the resulting mixture was hydrogenated in a Parr apparatus at 2.81 Kg / crn2 for 2 hours. The catalyst was separated by filtration and reagent was added in vacuo, yielding 1.2 g of the title product. IR cm- (pure): 3460, 3360, 1730; EM (El) rn / z: 314.2. The compounds of the general formula V can be prepared according to the following procedure: PREPARATION 6 (i) -l- [2 - [[N- (4-Bromophenyl) -N-3-ethoxyphenyl)] amino] propionyl] pyrrolidone 6.2 g (16.4 mmol) of (±) -et? L-2 ~ CN- (4-brornophenyl) -N- (3-methox? Fem) larninopropionate and 100 ml of pyrrolidine were placed in a medium pressure apparatus and They were heated at 200 ° C overnight. The mixture was then separated in vacuo, the residue was taken up in CH 2 Cl 2 and washed with HCl ai 5. The organic layer was dried over Na 2 SO *; and the solvent was removed in vacuo, yielding 6 g of the title compound. TR crn-l (pure): 298b, 1650, 1610; MS (ES) in / Z: 402 (M-L). We obtained 1.-C -CL "N ~ (4-ro ofenyl) -N- (3-h? Drox? -feni 1) lamí nolaceti Hpirrolidina following the same procedure IR crn-i (KBr): 3180, 1630 1590; MS (El) rn / z: 374.1.L-C2-C [N- (4-arn? Nofen? L) -N- (3-metho-fem)] am? No] acet? I will follow the same procedure: IR crn-l (KBr-): 3440, 3340, 1630; EM (El) rn / z: 339.1.

PREPARATION 7 N.N-Diethyl-4-C [N-chloroacetyl-N- (3-methoxy enyl) amino] benzamide 3.7 g (12.4 mrnoles) of N, Nd? Et? L-4-CN- (3-rnetox? Phen? L) am? No] benzene and 1.2 rnl (14.9 rnmoles) of chloroacetyl chloride were heated to reflux. in 40 rnl of toluene for 2 hours under nitrogen atmosphere. The solvent ij vacuo was removed, the residue was combined with H2O and extracted with ficOEt. The organic layer was dried over Na 2 O 4 and the solvent was removed in vacuo. The crude reaction mixture was purified by vaporization chromatography (ficOEt / hexane ai 8: 2), yielding 2.9 g of the title compound. IR crn-l (pure): 2980, 1695, L635; MS (El) rn / z: 374. Was N, N-D obtained? Sodyl-4-CN-chloroacetyl-N- (3-rnetoxifeni 1) lammolbenzarnide following the same procedure. TR cm-1 (pure): 3280, 1690, 1620. The compounds of the examples described in Table 4 were prepared, whose spectroscopic data are synthesized in Table 5, for procedures analogous to those described in standard procedures. I, which are described in detail for some selected examples.

PROCEDURE A (±) -N, N-Diethyl-4- [CN-C3-methoxyphenyl) -N- (2-pyrrolidinyl-1-butyl)] amino] benzamide Hydrochloride -Example 39- and Hydrochloride of (±) - N, N-diethyl-4- [CN- (3-methoxyphenyl) -N-l-pyrrolidinyl-2-butyl) lamino] enzamide -Example 38- fi a solution of 1.0 g (2.7 rnmoles) of (±) ~ N , Nd? Et? L ~ 4- [CN- (lh? Drox? But-2-? L) -N- (3-rnetox? Phen? L)] arn? No] benza-rnide in 10 rnl of CH2CI2 they added, in a nitrogen atmosphere at 10 ° C, 0.6 rnl (4.3 mmoles) of Et3N and 0.3 ml (4.3 mrnoles) of methanesulfonyl chloride dissolved in 4 rnl of CH2CI2- After 90 minutes the reaction mixture was poured into water, The layers were separated and the organic layer was washed with a saline solution, dried over Na 2 O and the solvent was removed in vacuo. The residue was dissolved in 50 ml of toluene, 5 ml of pyrrolidine was added and the solution was heated overnight at 90 ° C. The solvent was removed m vacuo, the residue was taken to an acid pH with 5% HCl and the aqueous layer was extracted with Et-2 ?, a pH 14 was then taken with 15% NaOH and extracted with ficOE < . The organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by vaporization chromatography C (? -Pr) 20 /? - PrOH / NH "OHconc. to 98: 2: 0.5] producing, after acidification with Et2? / HCl, 200 rng of the product showing the highest Rf, corresponding to the hydrochloride of (±) -N, Nd? et? i-4-C TN- (3 -rnetoxifeniD-N- (1-p? rrolídini1-2-butil)] am? no] benza? n? da and 170 ng of the product showing the lowest Rf, corresponding to the hydrochloride of (±) -N, Nd? et? l-4-CCN ~ (3-rnetox? phen? 1) -N- (2-p? rrol? d? n? ll-but? l) lamino] enzarm da.

PROCEDURE B (±) -N, N-Diethyl-4-EEN- (3-dimethylaminoprop-2-yl) -N- (3-methoxy-enyl)] amino] -benzamide -Example 31- and (±) -NN- diethyl-4- [EN- (2-dimethylaminoprop-1-yl) -N- (3-methoxyphenyl)] amino] benzamide -Example 30- fi a solution of 2.0 g (5.6 nm) of (±) -N, Nd ? et? i-4- [CN- (lh? drox? rop-2-? l) -N- (3-rnetox? phen? l)] arn? no] ben-zamide in 20 rnl of CH2Cl2 were added , under a nitrogen atmosphere at 10 ° C, 1.25 ml (9..0 mol) of Et3N and 0.69 ml (9.0 min) of rnet ansulfoni chloride dissolved in H mi of CH2CI2. After 90 minutes the reaction mixture was poured into water. The organic layer was washed with saline solution, dried over N 2S0-; and the solvent was removed m vacuo. The residue was dissolved in 10 ml of ethanol solution at 33% dirnethylamine, the reaction mixture was placed in an intermediate reaction apparatus and heated overnight at 80 ° C. The solvent was removed in vacuo, the residue was taken to an acid pH with HCl at pi% and the aqueous phase was extracted with Et20, then brought to pH 14 with 15% NaOH and extracted with ficOEt. The organic layer was dried over Na2SO3; and the solvent was removed m vacuo. The crude reaction mixture was purified by vaporization chromatography (CH2Cl2 / MeOH / NH-; HCl 94.5: 5: 0.5), yielding 790 rnl of the product showing the highest Rf, corresponding to (±) -N, N ~ d? et? i-4-CCN- (3- irnet? larn? noprop-2 -Ll) -N- (3-rnetox? phen? l)] am? no] benzarn? da and 645 rnl of the product showing the lowest Rf, corresponding to (±) -N, Nd? et? i-4-CCN- (2-d? rne? larn? no? rop-l-? l) -N - (3-rnetox? Phen? L) larninol enzarnide.

PROCEDURE C - Example 3- Citrate of ±) -N- (4-Bromophenyl) -N- (3-methoxy phenyl) -a-methyl-1- pyrrolidinoethanamine A solution of 2.6 g (6.4 rnrnoles) of (±) -l- 2- CN- (4-brornofeml) -N- (3-rnetox? Phen? L) lamino was refluxed; Micronutrient in 80 ml of dry ß in a nitrogen atmosphere, then 4.2 ml (41.6 mmol) of a LO M solution of BH3-Me S was slowly added. After 4 hours a solution to 0 was cooled ° C and 15 mL of H2O, 15 mL of 10% HCl and 15 mL of 37% HCl were added respectively. The reaction mixture was refluxed for 4 hours, then cooled and the volatile substances were removed m vacuo. The residue was taken up in water, brought to pH 14 with 40% NaOH and extracted with Et 2? The organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo. The crude reaction mixture was purified by evaporation chromatography (CH2Cl2 / MeOH / NH-; HCl 98: 2: 0.4), yielding 1.5 g of the title compound as a free base. 150 g of the product were dissolved in MeOH, an equirnolar amount of anhydrous synthetic acid was added, the solvent was removed m vacuo and the resulting solid was triturated with Ft. 0, yielding 100 mg of the title compound.

PROCEDURE D - Example 2 - (±) -N- (4-Bromophenyl) -N- (3-hydroxy enyl) -oc-methyl-1-pyrrolidinoethanamine hydrochloride 0.85 rnl (9 mmoles) of boron tribulus were dissolved in 15 rnl of dry CHCl3 under a nitrogen atmosphere. At room temperature, 1.6 g (1.5 mmol) of (±) -N- (4-brornophen? L) -N- (3-rnetox? Phen?) -or-rnet? L-1-rroll were added. d? noetanarn? na dissolved in 7 i of dry CHCI3. After 2 hours the solution was poured onto 15 g of crushed ice containing 1.5 nrn of concentrated NH 4 OH and stirred for 20 minutes. The layers were separated and the organic phase was dried over Na 2 O 'and the solvent was removed in vacuo. The crude reaction mixture was purified by vaporization chromatography (CH2Cl2 / MeOH / NH¿OHconc. To 94.5: 5: 0.5). The resulting solid was dissolved in MeOH, the solution was brought to a solid pH with Et "2? / HCl and the solvent was removed in vacuo. A solid product obtained in Et2? Was filtered, yielding 365 rng of the title compound.

PROCEDURE E - Example 1 - (-) - 3- [N- (3-pyrrolidinoprop-2-yl) phenylamino] -N-propylbenzamide Bromohydrate fi a solution of 130 rng (0.33 rnrnoles) of (+) - N-propyl-10- (3-p? rrol? d? nopro? -2-? l) phenot? az? n ~ 2-carboxam? da ( EP0346238A1) and 1.1 g (4.62 mmoles) of N? Cl2-6H2? in 16 ml of a mixture of MeOH: THF: H2? at 1: 2: 1 respectively, 524 rngs (13.86 rnmoles) of NaBH were added at room temperature. After 3 hours the reaction mixture was poured onto a pad of Celite, the solvent was removed in vacuo and the resulting residue was taken up in H2O and extracted with CH2Cl2. The organic phase was dried over Na 2 O * and the solvent was removed m vacuo. The crude reaction mixture was purified by vaporization chromatography (ficOEt / MeOH / NI-OHconc 95: 5: 0.5). The resulting solid was dissolved in acetone, the solution was brought to an acid pH with 24% HBr and the solvent was removed in vacuo. The resulting solid was triturated with d- Pr) 2 ?, yielding 50 rng of the title compound. Co;] 25D = -96 (c-0.1, MeOH) PROCEDURE F - Example 17 - N, N-Diethyl-4-CCN- (dimethylamine-acetyl) -N- (3-pethoxyphenyl)] mino citrate] enzyme A solution of 1.4 g (3.9 rnrols) of N, Nd? Et? I-4-C N-chloraacetyl-N- (3-rnetox? Phen?) Laminolbenzarnide was placed in 30 ml of a 33% ethanolic solution of direthylamine in a medium pressure apparatus and was heated overnight at 80 ° C. The solvent was removed m vacuo, the residue was taken to a solid pH with 5% HCl and the aqueous phase was extracted with Et 2 ?, then brought to pH 14 with 15% NaOH and extracted with AcOEt. The organic layer was dried over Na 2 SO 3 and the solvent was removed in vacuo. The crude reaction mixture was purified by vaporization chromatography (CH2Cl2 / MeOH / NH4 → Hc to 90: 7: 0.7), yielding 1.7 g of the title compound as a free base. 50 mg of the product were dissolved in MeOH, the equirnolar amount of anhydrous citric acid was added and the solvent was removed in vacuo. The resulting solid was triturated with Et2? producing 30 rng of the title compound.

PROCEDURE 6 -Example 43- (±) -N- CE4- [N- (3-Methoxy phenyl) -N-Cl-methyl-2- (1-pyrrolyl) et? L] amino] phen?] -2- methylpropanamide a solution of 0.98 g (3.0 mrnoles) of (t) -N- -ammophenyl) -N- (3-rnet ox i femi) -or-? net? l-1-prroi? d? noetana? na in 25 rnl of dry CH2Cl2, 1 g (7.5 mrnol) of K2CO3 was added. The reaction mixture was cooled to 0 ° C and, under a nitrogen atmosphere, 0.8 g (7.5 mrnol) of isobutyryl chloride dissolved in 10 rnl of dry CH2Cl2 was added dropwise. After 15 hours at room temperature, water was added, the phases were separated and the organic phase was dried over Na 2 SO 4 and the solvent was removed m vacuo. The resulting residue was purified by vaporization chromatography (CH2Cl2 / MeOH / NH; HCl: 94: 5: 5: 0.5) yielding 1.0 gram of the title compound.

PROCEDURE H (-) - N, N-Diethyl-4-CCN- (3-dimethylaminoprop-2-yl) -N- (3-hydroxyphenyl) -lamino] -benzamide-Example-45- and (+) -N-trifluoroacetate trifluoroacetate , N-Diethyl-4-C N- (3-dimethylaminoprop-2-yl) -N- (3-hydroxy enyl) lamino] benzamide - Example 46- The corresponding racemate was resolved by performing HPLC on chiral stationary phase Chiradex (Mer). Column: Lichrocart 250x21 rnrn; eluent: KH2 P0 (75 mM). TEA (0.2%), pH = 4 / MeCN-8Q / 12Q PROCEDURE I -Example 55- N, N-Diethyl-4-CCN- (diethylaminoacetyl) -N- (3-hydroxyphenyl) -lamino] -hydrochloride a solution of 2 g (5.6 mmol) of N, N-diethyl-4-CCN-chloroacet? iN- (3-methox? phen? 1) larnmolbenzarnide in 20 ml of toluene was added, 2.7 ml (25.8 nm) of The resulting solution was heated at 60 ° C for 5 hours. The solvent was removed by vacuum, the residue was taken up in water and extracted with CH 2 Cl 2, then the organic phase was dried over N 2 SO and the solvent was removed in vacuo. The resulting residue was purified by vaporization chromatography (CH2Cl2 / MeOH / NH-; HCl 94.5: 5: 0.5), yielding 1.9 g of the title compound.

TABLE 4 TABLE (- (continued) TABLE Hcontin-tion) TABLE 4- (continued) TABLE Hconnution) TABLE H continued) TABLE 4- (continued) TABLE 4- (continued) TABLE - (continued) TABLE 4- (continued) TABLE 5 TABLE 5- (continued) TABLE 5- (continued) TABLE 5- (continued) TABLE 5- (continued) TABLE 5- (continued) TABLE 5- (continued) TABLE 5-Icon) TABLE 5- (cont'd)

Claims (4)

1. NOVELTY OF THE INVENTION CLAIMS A compound, with solvate or salt thereof, of the formula (I) wherein Ri and R2, which may be the same or different, are each hydrogen, Ci-alkyl & linear or branched, C3-7 cycloalkyl, C3-7 cycloalkyl, cycloalkenyl C3-7 cycloalkylalkyl of C '-β, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2- or 3-yl-alkyl, or they can form an alkyl ring of C3-7 between them which may be interrupted by oxygen; R3 and R-v, which may be the same or different, are each hydrogen, linear or branched Ci-β alkyl, or R * is oxygen that forms with the carbon atom to which a C = 0 group is attached; R5 is hydrogen, hydroxy, C1-3 alkoxy, mercapto or alkylthio; Re is phenyl, parahalogen, para- or rneta-NH2 or a para- or rneta-C (Z) -Rβ group, in which Z is oxygen or sulfur; Rβ is Ci-β alkyl, C?-8 alkoxy or NR 9 R 10, wherein R 9 and Rio, which may be the same or different, are hydrogen, C-β rec-t or branched alkyl, C 3-7 cycloalkyl, cycloalkyl C4-6alkyl, C3-6alkenyl, aplo, aralkyl, or each other form an alkyl ring R11 of CA, or Rs is a para-o-net group -NC (Z) -R12 in the which Rn and R12, which may be the same or different, are hydrogen, straight or branched Ci-βalkyl, C3-7 cycloalkyl, JCc doalkyl of 0 * 4-6, C3-6 alkenyl, aplo, aralkyl or an optionally substituted heterocyclic LCO ring, and Z is defined as before; and R7 is hydrogen, rec- or branched Ci-β alkyl, or halogen.
2. 2. A compound in accordance with the claim 15 1, further characterized in that Ri and R2 each is methyl, ethyl, cyclopropylcell 1, alkyl or, together with the N-atom, pyrrolidone.
3. 3. A compound according to claim 1 or 2, further characterized in that of R3 and R each is Hydrogen, methyl, ethyl, isopropyl or R4 is oxo.
4. 4. A compound according to any of claims 1 to 3, further characterized in that R5 is hydrogen, hydroxy or rnetoxy.- 5.- A compound according to any of the 25 claims 1 to 4, further characterized in that R & is COtle, CO-i-Pr, COOEt, CONH2, CONH-n-Pr, C0N (Me) Ft, CON (Me) i-Pr, CONE + -2, C0N (l-Pr) 2, C0NE + (? - Pr ), C0N (-CH2-, NHCO? -Pr, NH2, bromide or renny) 6. A compound according to any of claims 1 to 5, further characterized in that R7 is hydrogen or methyl. - A compound selected from: (~) -3- N- (3 ~ pi rrol.?d?no?rop-2- l) fem larn? No] ~ N-prop l.benzarn? Da; (±) - N- (4-oinophenyl) -N- (3-hydroxy-phenyl) - "- methyl-1-β-r-rolidino-phenamine; (±) -N- (4-brornofeml) -N- (3-rne or? Teni) 1) -w-rneti 1 -1 -pi rol dmo-ethanarm na (±) -N, Nd? Et? 1 -? ~ C [N- (3-rnetox fen?) -N- (3-? rroli-d? noprop-2-? l) lamino] enzyme; (±) -N, Nd? et? l-4 ~ C CN-- (3 -hydro-x? phen?) -N- (3 ~ p rrol? d? opro? -2-? l)] arn? o] benzam? da; N- (4-brorno (- "eml) -N- (3-h? rox? f ml) -1- p? ol? d? noetana? n? na; N, Nd? et? l-4-C N- (2-d? rnet? larn? noet l) -N- (3-h? drox? feml) lamino ! gone benz; (±) ~ N, N ~ d? et? l-4-CCN- (2-dimet i lamí noprop-1 - 11) -N- (3-hydrox phenyl) lami no] be nzami da; (±) -N, Nd? Et? L-4-C CN- (3-d? Rne-t? Larn? Noprop-2-? L) -N- (3-h? Drox? Phen? L) lami or! benzarn ida; N, N-d? Et? L-4-T-CN- (3-hydroxyl) -N- (2-β-r? R? D? Oet? L) l mi o] en-zarnide; N, N-d? Et? L-4-CCN- (3-rneto? Phen? L) -N- (2-p? Rrol? D? No-et? L) larninolbenzarni a; N, N-d? Et? L-4- N- (2-d? Rnet? Larn? Noet? L) -N- (3-methox? Phen?) Lammolbenzarnide; (±) -N2 - (4-b? Feml? L) -Ni, N -d? Met? L-N2- (3-h? Drox? Phen? -1), 2-propand? Arn? Na; (±.}. -N * - (4-b? Phen? L?) -N2, N2-d? Rnet? L-Ni- (3-h? Drox? Phen? L) -1, 2-pro ? and? am? na; (±) -N2- (4-b? phen? l?) -Ni, Ni-d? rnet? l-N2- (3-rnetox? phen? l) -1, 2 ? ro-pandiarnin; (±) -N1- (4-b? feml? l) -N2 ^ S-dirnethyl-N1- (3-rnetox? -phenyl) -1, 2-propand? arn? na; N, Nd? Et? L-4-C CN- (dirneti 1 arninoace-t? L) -N- (3-rnetox? Phen? L) larninolbenzarnide; (±) -l-C4-CCN- (3- dirnet il? N? No? Ro? -2-? L) -N- (3-rne or ife? 1) l me -nol benzol 11 irro -11 dina; () - L-T -C N- (2 ~ dirnet i ami no rop-1- 11) -N- (3-methoxy-fem 1) lam nolbenzoylpyrrolidine; (±) -1-t 4-1"CM- (3-d? Rne +? L -arn? No? Rop- - 1) N- (3-h? Drox Lfom L) -aminolbenzoiyl-pi rroli tJma; ( ±) -1-C4 - C CN- (2-? Rne? Lamí no? Ro? -1 - Ll) -N- (3-h? Drox? Erul) lamí -nol benzol i lp? Rrol idina; ( ±) -N, Nd? Et? L -3- N- (3 ~ d? Met? Larn? .no-prop-2-? L) -N- (3 -hydro ifeml) laininolbenzarnide; (±) -N , N ~ d? E? 1-3 ~ C CN- (2-d ?? net? Am? Noprop-1-l) -N- (3-h? Drox? -fen? L) larninolben-zarn; (±) -M, N-? I opropyl -4- CN- (3- imet i L-ammoprof) - 2- il) -N- (3 ~ h? Drox? Phenyl) lamino! E nzarn ida; (± ) -N, Nd? I sopropí 1 -4- [N- (2-d ?? net? Larn? Nopro? -1-? L) -N- (3-h? Drox -feml) larnmolbenzarnide; (±) -N, Nd? Et? 1-3- CN- (3-h drox? Phenyl) -N- (3-?? rrol? D? No? Ro? -2-íl) lamino! Benzarm da; (±) -N, Nd? E? I-3-C N- (3-h? Drox? Phenyl) -N- (2-pyrrolidine di-n-propyl) l -ninol en-zarnide; (±) -N, Nd? Et? L-4-N- (3-hydroxy feml) -N- (1-pyrroli-di n? L-2-but? L) arn? Nolbenzarn? -da; (±) -N , Nd? Et? L-4-CN- (3-hydrox? PhenL) -N- (2-p? Rrol? D? N? Ll-butyl) larninolbenzarnide; (±) -N, Nd et? I ~ 4-C CN- (2-d? Met? Larn? No-? Rop-1-? L) -N- (3-rnetox? Feml) 1-arn? Nolbenzarn ?gives; (±) -N, N-d? Et? L-4-CN-? 3- dirnet i lammopro? -2-? L) -N- (3-rnetox? Phen? L) l m nolbenza-mida; (±) -N, N ~ d? Et? L-3-C CN- (3-d? Rne? Lam? Nopro? -2 ~?) -N- (3-rnetoxy feni 1) lamino] enzarní da; (±) -N, Nd? Et? L -3- CN- (2-d? Rnet? L-ammopro? -i-? L) -N ~ (3-methox? -fen? L) lm no] benzarní gives; (±) -N, N-d ??? soprop? L-4-CCN- (3-d? Rnet? L-arn? Noprop-2-? L) -N- (3-rnetox? Fe-nil) lammolbenzamide; (±) -N, N-d ??? soprop? L-4-C CN- (2-dirnetyl-arn? Noprop-1-? L) -N- (3-rnetox? Ferul) 1- animo] be nzarn ida; (±) -N, N-d? Etn-3-C CN- (3-methox? Phen?) -N- (3-p? Rrol? Dmopro? -2-? L) lamino! -bO benzaiiuda; (±) -N, N-d? E? 1-3-C N- (3-rne or? Phen? 1) -N- (2-?? rrol? -d? Nopro? -1-? L) lamino! benzarní da; (±) -N, N- Let L1 - 4 - C M- (3-ine xi fem 1) -N- (1- ?? rroli d? N? L-2-but? L) la no 1 be nzarn gone; (+) -N, Nd? Et? L-4- CCN- (3-rnetoxifen? L) ~ N- (2-? Rol? D? Ml ~ L -bu- »il)] - ar inol enzaini da; (±) -4- CN-Cl- (N-allyl-N-rnetyl) a? N? No-2-? Rop? 11- N ~ (3- h? Drox? En?) Arn? No] ~ N, N-d? -et.? Lbenzarn? Da; (±) -4-CN-C2- (N-al? L ~ N-? Net? I Ja ino- 1 -f > rop l 1-N- (3-h? Drox? Fen? L) a? n? no! - N, Nd? -e +? lbenzarn? da; N, Nd? e? 1- k -CCN- (dirne il rninoacetil) -N- (3-hi droxifeml) l mino "I benzarní da; *) -N - C ~ k - M- (-me »oi Ion 1) -N-Cl-rnetyl -2- (1- pyrro 1 Ldirul) et? Ll 1-arn? Nol phenyl 1-2-rnet ? 1 clothing-nylon; (±) -N- 4-CN- (3-h? Drox-fenxl) -N-Cl-rnet Ll-2- (1-p? Rrol? -diml) et? Ll lamino! fen? l 1-2-rnet? l-? panpan? da; (-) -N, Nd? et? l-4-CCN ~ (3-d? met? lar? noprop? 2-? l) -N - (3-h? Drox? Phen?) Lamino! Enza -mida; (+) -N, Nd? Et? L-4-C CN- (3-d? Met? Lar? No? Ro? -2 - 11) -N- (3-hydroxy-phenyl) -amino] -benzardnide; N, Nd? Et? L-4 ~ C N- (diethylamine-acetyl) -N- (3-h? Drox? Fen? l) l rninol en-zarni a; N, Nd? et? l-4-C CN- (3-h? dro? phen? l) -N- (pyrro? dm-1-? lace? i) larni ol enzanide; N, Nd? sopro? l-4-C CN- (dirnetyl-naphnoacetyl) -N- (-h? drox? fe-nil) lamino! benzarn; 4-CCN-CC (N-allyl-) N-rnethyl) amino] acetyl-N- (3-hydrox? Phen?) Lamino-N, Nd? -et? Lbenzarn? Da; N, Nd? Et? 1-4 - CCN- (3-h? Drox? Phen?) -N- (rnet? L-arn? Noacet? L) larninolbenzarnide; N, N-d? So? Rop? L-4-CCN ~ am? No-acet? L-N- (3-h? Drox? Femi) larninol-benzamide; (±) -4- N-Cl- (N-al? LN-met? L) arn? No-2-prop? Ll-N- (3-rnetoxy phenyl) arn nol -N, N- di -e ii benzarní da; (±) -4-CN-C - (N-al? LN-rnetyl) am? No-l-? Rop? Ll-N- (3-rnetox? Feml) am? Nol-N, Nd? Et? Iben -zarnida; N, N-d? Et? L-4-C CN- (diethylaminoacetyl) -N- (3-rnetox? Fen- Bl LÍ) the inolbenzarní da; N, N-d? Et? L-4-C CN- (3-rnetox? Phenyl) -N- (pyrroli i n-l ~ i l cet i J) J rní no] -benza? N? gives; N, N-d? So? Rop? 1-4- I CN- (dunethylarninoacetl) -M- (3-? Netox i f-enyl) lamino! benzarní da; 4-CCN-CCN-allyl-N -me »11) am? do not! -aceti 11- N- (3-rnetox? fe i 1) l i o! -N, N-d? E til benzar í da; N, N- diethyl-11-CN- (3-methyl) or i-pheni 1) -N- (rne ilarninoacetyl) larnmolbenza-rni a; N, N-? So? RopLl -4-C N-ammoacet 1-N- (3-? Netox? Ten? L) 1-a? N? no] benzarní da; (±) -N- (4-ani ofem 1) -N- (3-rneto? Ten? L) -a-met? I-1- ?? rroLidinoe-t ana i a. 8. A composition of the invention comprising a compound of conformity with any of the claims 1 to 7 and a pharmaceutically acceptable vehicle. 9. The use of a compound according to any of claims 1 to 7 and the preparation of a drug for use as an analgesic, immunosuppressant to prevent rejection in organ transplantation and skin grafting, antiallergic agent and antimicrobial agent. Amatory, protective of brain cells, for the treatment of drug and alcohol abuse, to decrease gastric secretion, for the treatment of diarrhea, cardiovascular and respiratory diseases, cough and respiratory depression, mental illness, epileptic seizures and other disorders neurological 10. The use according to claim 9, further characterized in that the use of the composition is for the treatment and / or prophylaxis in mammals, particularly humans, of the therapeutic conditions as defined in said claim. FI 2 SUMMARY OF THE INVENTION A calendar of daily diary derivatives of the fo rmu (I) wherein Ri and R2 are each hydrogen, alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryio, aralkyl or furan-2- or 3-? -alkyl or can form a ring of C3-7 alkyl which may be interrupted by an oxygen; R3 and R- are each hydrogen, alkyl, or R4 is oxygen that forms with the carbon atom to which a C = 0 group is bound; R5 is hydrogen, hydroxy, alkoxy, alkyl, or alkylthio; Rβ is halo, halogen, NH2 or a para- or rneta-C (Z) -R8 group, in which Z is oxygen or sulfur, Rβ is alkyl, alkoxy or NR9R10, wherein R9 and Rio are hydrogen, alkyl, cycloalkyl , cycloalkylalkyl, alkenyl, aryl, aralkyl, or Rβ is a para- or rneta- R11 -NC (Z) -Ri2 group in which Rn and R12 are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is defined as b3 like before; and R7 is hydrogen, alkyl or halogen, are potent and selective delta-opioid agonists or antagonists, and are useful as analgesics and for treating pathological conditions that can usually be treated with delta-opium receptor agonists and antagonists. GC / lss * blm * elt- * rnrnrn P97 / 1127F