PL148274B1 - Method of obtaining novel derivatives of aminophenol - Google Patents

Description

The subject of the invention is a process for the preparation of new aminophenol derivatives of general formula I, in which X represents a C 1-7 alkylene chain, Y represents a C 1-6 alkylene chain, the sum of carbon atoms in both X and Y chains being 5. , 6 or 7, R1 and R2 are each hydrogen or a methyl group, Q is HCO-, NH2CO-, (CH8 / 2NSO2- or CH8SO2-) and Ar is a phenyl group substituted with groups such as amino, dimethylamino, morpholino, group - (CH2) qNHCOR6 (where R8 is C1-4alkyl, e.g. n-butyl and q is equal to zero or more preferably 1), -NHSO2R7 (where R7 is C1-4alkyl e.g. butyl), -COR8 (where R8 is C1-4 alkoxy, e.g. propoxy) or NR8R4 (where each of R8 and R4 is C1-4alkyl / or - / CH2 / rR10 (in where r is equal to 3 and R10 is C 1-4 alkoxy, e.g. methoxyl), or Ar is 3,5-dihydroxyphenyl or 3-methoxy-4-hydroxyphenyl, and their physiology salts and solvates, e.g. hydrates. These derivatives have a stimulating effect on β2-adrenoreceptors to a much greater degree than compounds of similar structure as 1- (3,4-dihydroxyphenyl) -2-isopropylaminoethanol, known commercially the name Isoprenaline or 2- (tert-butylamino) -1- (4-hydroxy-3-hydroxymethylphenyl) -ethanol, known under the trade name Salbutamol or Ventolin. The compounds of general formula I have one or two asymmetric carbon atoms, namely the atom next to the -CH (OH) group and, when R1 and R2 are different, the carbon atom to which they are attached. The compounds of the invention include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH / OH / - group is in the R configuration are preferred. When defining the compounds of general formula I, the term alkenylene group includes both cis and trans structures. A preferred group of compounds of the formula I are those in which X is a Ca-4alkylene group and Y is a C 1-4 alkylene group. Most preferably, X is - (CH2) 4- and Y is - (CH2) 8-. Another preferred group of compounds of formula I are those in which both R1 and R2 are hydrogen. A further preferred group of compounds of formula I are compounds in which Q is CH3SO2. A still further preferred group of compounds of formula I is there are compounds in which Ar is a phenyl group containing a single substituent, most preferably a -CON (CH2-CH8) group. A particularly preferred compound according to the invention is N, N-diethyl-4- [4- [[ 6- [[2-hydroxy-2- [4-hydroxy-3H [/ methylsulfonyl / amino] phenyl] ethyl] amino] hexyl] oxyJbutyl] benzamide and its physiologically acceptable salts and hydrates. Compounds of general formula I, in which Q, X, Y, Ar, R1 and E2 are as defined above, are prepared by reduction. Certain reactions may affect other groups in the starting materials that are desired in the final product. This applies in particular to the reduction processes described, especially when hydride is used as the reducing agent and end-products are desired in which Q is the group HOO- or CH8CO- and when in the production of compounds having an ethylene bond or Acetylene hydrogen and a metal catalyst are used. Therefore, care must be taken, in accordance with normal practice, to use reagents which will not affect such groups, or to carry out a sequence of reactions which would be redundant if such groups were present in the starting material. In general, in the processes described below for the preparation of both intermediates and end products, the last step of the reaction involves deprotection. The corresponding protecting groups and their removal are described below. In accordance with the invention, compounds of general formula I are prepared by reducing an intermediate product of general formula II in which R15 is hydrogen or a protecting group and at least one X1 , X2 and X8 are reducible groups and / or Y and / or Ar contains a reducible group and the other substituents have the following meanings: X1 is -CH / OH) -, X2 is -CH2NR16, where R1 * represents a hydrogen atom or a protective group, and X * represents a -COX or -CR1R2X group, in which R1, R2 and X are as defined above, with the optional removal of the protective groups. Suitable reducible groups. include groups where X1 is C = 0, X2 is -CH2 / NY'- (where Y 'is a group converted to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl, or thi-methylbenzyl or imino group / -CH = = N / or -CONH- group, X8 is -COX- or CR1! ^ - group (where X is C2-7alkylene or C * -alkynylene group) or -X2-X8- is -CH2N = CRaX-, Y is a C2-ealkynylene group and Ar is a phenyl group substituted with nitro group. In one preferred aspect of the reduction process, the R 15 group may be a group that converts to hydrogen under the reducing conditions used, and may, for example, be an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl. Reductions may be performed using reducing agents. commonly used for the reduction of ketone, imine, amide, protected amine, alkene, alkyne and nitro groups. So, for example, when the phenyl group of Ar contains an n-tro substituent it can be reduced to an amine group with hydrogen in the presence of a catalyst such as such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium on a carrier such as activated carbon, using an alcohol e.g. ethanol or an ester e.g. ethyl acetate or an ether e.g. tetrahydrofuran, or water as a reaction solvent or solvent mixture 5 solvents, e.g. mixtures of two or more of the solvents described only, under pressure and at normal or elevated temperatures e. g. 20 - 100 ° C and a pressure of about 0.1 - 1 MPa. When X 1 in general formula 2 represents the group C = 0, this group may be reduced to the group -CH (OH) - with hydrogen in the presence of the catalyst described above. Alternatively, for example, a hydride such as a boroethane or a metal hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy aluminum hydride, sodium borohydride or aluminum hydride) may be used as the reducing agent. Reactions can be performed in a solvent. A suitable solvent is an alcohol, for example methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrogen gas such as dichloromethane. When X2 in general formula 2 is the group -CH2NY1- or the group _CH = N-, or -X2-Xs- is the group -CH2N = 25 = OR2X-, they can be reduced to the groups -CH2NH- or -CH2NHCHR2X- using hydrogen in the presence of a catalyst as described above. Alternatively, when X2 is the group -CH = N- or -X2-Xs- is the group -CH2N = CR2X- they may be reduced to the groups -CH2NH- or -CH2NHCHR2X- using a reducing agent and under the conditions described above for the reduction of X1 when it is C = 0. When X2 or X8 in general formula II is a -CONH- or -COX- group, they can be reduced to a -CH2NH- or -CH2X- group with using a hydride such as boroethane or a complex metal hydride such as lithium aluminum hydride or sodium bis (2-methoxyethoxy) 40 aluminum hydride in a solvent such as an ether, for example tetrahydrofuran or diethyl ether. of general formula 2 represents the group -CR1R2X- in which X is a C2-7 alkynylene or C2-7 alkenylene group, or Y is a C2-6 alkenylene group and or the C2-ealkynylene, X and / or Y may be reduced to the C2-6alkylene using hydrogen in the presence of the catalyst described above. Alternatively, when X and / or Y is a C2-7 alkynylene group it may be reduced to a C2-7 alkenylene group using, for example, hydrogen and palladium poisoned with lead to calcium carbonate as a catalyst, in a solvent such as pyridine. or lithium aluminum hydride in a solvent such as diethyl ether at low temperature, e.g. 0 ° C. In the case where at least one of R1 ** or R16 is protecting the compound of general formula I is obtained by removal of the o-groups protecting groups of the intermediate of general formula III, in which R 1 * and R 16 are as defined above. Any conventional protecting groups may be used as protecting groups, for example as described in "Protective Groups in Organic Chemistry "ed. JFW McOmie (Plenum Press, 1973). 5 148 274 6 Examples of suitable R 1 * groups protecting the hydroxyl group are arylmethyl groups such as benzyl, diphenylmethyl, or triphenylmethyl groups. Iowa and tetrahydropyranyl. Examples of suitable R 16 protecting amino groups are arylmethyl groups such as benzyl, β-methylbenzyl, diphenylmethyl or triphenylmethyl groups, and acyl groups such as trichloroacetyl or trifluoroethyl groups. using traditional techniques; Thus, for example, when R1 and / or R1f are arylmethyl groups, it can be cleaved by hydrogenolysis in the presence of a metal catalyst (eg palladium on carbon). When R 1 * is a tetrahydropyranyl group it can be cleaved by hydrolysis under acidic conditions. The acyl groups represented by R 16 can be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl can be removed by reduction with, for example, zinc and acetic acid. It is also possible to interconvert one compound of general formula I into another compound of general formula 1. For example, a compound of formula I in which Ar is a phenyl group and a nitro substituted group can be converted to corresponding compound in which Ar is a phenyl group substituted with an amino group, by reduction. Conventional reducing agents may be used, for example, hydrogen in the presence of a catalyst such as platinum or palladium on a carrier such as activated carbon in a solvent such as alcohol, such as ethanol. Formula I, wherein X and / or Y represents an alkenylene or alkynylene chain, may be reduced to a compound of the general formula I, wherein X and / or Y is an alkylene chain using hydrogen in the presence of a metal catalyst as described above. In a further example, a compound of formula I wherein X and / or Y is an alkenylene chain may be prepared by reduction of a corresponding compound wherein X and / or Y is an alkynylene chain as described above in Reduction Processes. In the general processes described above, the compounds of general formula I can be obtained in the form of salts, conveniently in the form of physiologically acceptable salts. Where desired, such salts may be converted to the corresponding free acids by conventional methods. Suitable physiologically acceptable salts of compounds of formula I include inorganic and organic acid addition salts such as hydrochlorides, hydrobromides, sulfates. , phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfonates, methanesulfonates, sulfamylates, ascorbates, salicylates, fumarates acetates, succinates, mils Acetates, glutarates, tricarbalylates, hydroxynaphthalenecarboxylates, for example 1-hydroxy or 3-hydroxy-2-naphthalenecarboxylates or oleates. These compounds can also form salts with suitable bases. Examples of such salts are the salts with alkali metals, for example, sodium and potassium, and with alkaline earth metals, for example, calcium or magnesium. Physiologically acceptable salts of compounds of general formula I can be prepared by reacting a compound of general formula I with a suitable acid. or a base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, for example methanol, ethanol or isopropanol. Physiologically acceptable salts may be prepared from other salts, including other physiologically acceptable salts of compounds of Formula I, using conventional methods. When a specific enantiomer of a compound of Formula I is required, it can be prepared by separation into isomers of the corresponding racemate of the compound of general formula I by conventional methods. Alternatively, the enantiomers of a compound of formula I may be synthesized from the corresponding optically active intermediates by any of the processes described above. Individual diastereoisomers of the compound of formula I may be obtained by conventional methods, for example by synthesis from a suitable asymmetric starting material with any suitable of the processes described above, or by the conversion of the isomer mixture of the compound of formula I into the corresponding diastereomeric derivatives, for example salts, which can be separated by traditional means, for example by means of fractional crystallization. The compounds of the invention are known compounds or can be produced by methods analogous to known ones. Corresponding methods are described in British Patent Nos. 2,140,800 A and 2,159,151A and are exemplified below. The compounds obtained according to the invention have a selective stimulatory action / fo-adrenoceptor with a particularly advantageous profile. The stimulating effect was demonstrated on the isolated guinea pig trachea, where it was shown that the compounds loosened the contraction of the PGF20 released. The compounds obtained according to the invention show a particularly long-lasting effect in this test. The compounds obtained can be used in the treatment of diseases associated with reversible airway obstruction, such as asthma or chronic bronchitis. These compounds can also be used in the prevention of preterm labor, depression and congestive heart failure, and are recommended. also in the treatment of inflammatory and allergic skin diseases, glaucoma, and in the treatment of conditions in which it is beneficial to reduce acidity, especially in gastric or digestive ulcers. The compounds of the invention of general formula I and their physiologically permissible 10 15 20 29 30 35 40 45 50 55 60 148 274 7 8 Salts and solvates are used primarily in the treatment and prevention of diseases associated with reversible obstruction of the respiratory tract in humans and animals. The stimulatory effect of the compounds according to the invention on the adrenergic / α receptors was determined by examining the prepared sections of guinea pig trachea. The thoracic sections of the trachea were placed in a superfusion apparatus, and the Krebs oxygenated physiological solution containing indomethacin (2,4 X KM m) and atropine (4 X 1Q ~ 7 m) at 37 ° C, flow rate 2ml / min. The changes in tension in the sections were measured with an isometric strain gauge. The contraction of the sections during the test was induced by the addition of prostaglandin Fta (2.9 X 10 m) to the superfusion fluid. At the beginning of each trial, 2 dose-effect curves were determined with respect to the isoprenaline used as standard (1 X 1012 - IX 10 m), each time waiting for the maximum relaxation to be reached before increasing the dose again. After this dose-effect curve was obtained, the tissue was allowed to recover for a period of time sufficient to return to its initial state (15-30 minutes). After this time elapsed, the concentration-effect curves were determined, first for isoprenalin, and then for the test compound. This was done as follows: the compound was administered at a low concentration (isoprenaline 3 X 10 ~ 8 m; test compound 1 X 10 ~ 10 m) until the maximum response was reached, then the infusions were stopped and the tissue was allowed to recover. within 30 minutes at most. After this period of time had elapsed, the above operations were repeated with gradually increasing concentrations of the agonist. Thus, complete concentration effect curves were obtained. The power was determined by comparing the concentration effect curve thus obtained with the curve obtained previously for isoprenaline. The potency was expressed as the ratio of the concentrations producing the same effect (assuming the value determined for isoprene as 1), thus the ratio (ECse of the test compound) was calculated; (EC50 of isoprenaline). For each reaction, the duration of action was also measured, defined as the time from stopping the infusion to returning to 50% of the previous state. Relationships between the magnitude of the reaction and the duration of drug action were plotted and the time periods in which 50% of the maximum reaction was obtained. The table below shows the potential (expressed as the molar concentration equivalent to Insoprenaline-1) of the compounds according to the invention and the commonly known stimulant, Salbutamol. From the compounds obtained according to the invention, preparations for administration may be made. By any known * way. Such pharmaceutical preparations contain at least one compound of formula I or a physiologically acceptable salt or solvate thereof in a form suitable for use in human or veterinary medicine. The composition of such preparations may include physiologically acceptable carriers or excipients, possibly with additional pharmaceuticals. Table 1 Compound according to Potential example (Isoprenaline = 1) 10 I Ha Ilb lic Ud III IV V itamol 0.09 1, 8 0.04 0.62 0.19 0.67 0.03 0.11 2.0 Pharmaceutical preparations suitable for administration by inhalation or insufflation, or by oral, buccal, parenteral or external administration, can be prepared. including nasal, and rectal. Administration by inhalation or insufflation is preferred. The proposed daily dose of the active compound for human treatment is in the range from 0.005 mg to 100 mg, conveniently administered in one or two portions. The exact dose will of course depend on the age and condition of the patient and the route of administration. The starting materials and intermediates for the preparation of the compounds of the invention were prepared as follows, and the terms used herein also apply to the embodiments of the compounds of the invention. The term "dried" refers to drying over sodium sulfate or magnesium sulfate unless otherwise indicated. SiO2 was used for thin layer chromatography (tlc). Merck 9385 silica was used in flow column chromatography (FCC). the following abbreviations: THF - tetrahydrofuran, EA - ethyl acetate, ER - ethyl ether, CX - cyclohexane, H - hexane, DMF - dimethylformamide, T - toluene, ET - ethanol, MC - methylene chloride, CF 50 - chloroform , DEA - diisopropylethylamine, BTPC - bis / triphenylphosphine / palladium (II) chloride, A - 0.88 ammonia solution, DCC - dicyclohexylcarbodiimide, TAB - tetra-n-butyl ammonium sulfate, Pt-C = "platinum on carbon , Pd-C = 55 palladium on carbon, PtO-C = platinum oxide on carbon, PdO-C = palladium oxide on carbon. Intermediate 1. (E) -li [[4- (6-bromohexyl) - - oxy] -2-butenyl] -4-fluorobenzene. A mixture of 5.73 g of intermediate 9, 25.2 g of 60 1,6-dibromohexane, 1.5 g of TAB and 45 ml of a 40% sodium hydroxide solution and mixed with for 18 hours, diluted with 200 ml of water and extracted with 2 x 150 ml of EA. The organic phase was washed with 100 ml of water, 100 ml of brine, dried and evaporated in vacuo to give a yellow oil. Purification on FCC148 274 9 10 eluting with CX-EA (10: 0 over a 9: 1 step transition gave 8.59 g of the title compound as a yellow oil. Thin layer chromatography (CX-EA 9: 1) showed Rf 0.34 Intermediate products 2 and 3 were similarly prepared. Intermediate 2. 1-Bromo-5 - [(3-butynyl) oxy] pentane as a colorless oil (43.5 g). It was formed from 50.0 g of 3-butyn-1-ol, 414 g of 1,5-dibromopentane, 250 ml of 50% (w / v) aqueous sodium hydroxide and 5.0 g of TAB, after dilution with water the mixture was extracted with ER. The dried extract was then evaporated and dibromopentane (20 cm Vigreux column, 85 ° C, about 6.67 mbar) was distilled from the mixture before purification on FCC. A liquid chromatograph column was eluted with CX and then OX-ER mixture (9: 1) Thin layer chromatography (OX ^ ER 9: 1) showed Rf 0.65 Intermediate 3. 4- [4- [4- [(4-bromobutoxy) - 20 - butyl] phenyl] morpholine in the form of a colorless solid (6.7 g) mp 33-35 ° C was made from 6.0 intermediate 12, 22.1 g 1,4-dibromobutane, 40 ml 50% aqueous sodium hydroxide and 0.85 g TAB, with The reaction mixture was stirred under a nitrogen atmosphere for 20 hours prior to dilution with water and ER extraction. The product was purified on FCC eluting with CX followed by ER-CX (1: 3). A pale yellow oil was obtained which solidified on standing. Intermediate 4. / E / -N- [6- [4 - [(4-hydroxy-3-methoxyphenyl) -3-butenyl] oxy] hexyl] benzenetanamine 1 g / E / -4- [4 - [(6-bromohexyl] oxy] -1-butenyl] -2-methoxyphenol and 1.5 g of benzylamine were stirred together for 2 hours at 120 ° C under nitrogen atmosphere. The mixture was allowed to cool, diluted with 40 ml of MC and washed with 2 x 20 ml of 2N hydrochloric acid. The organic extract was washed with 2 x 20 ml of 8% sodium bicarbonate solution, dried and evaporated in vacuo to give 0.93 g of the title compound as brown oil. Thin layer chromatography (T - RT - A 39: 10: 1) showed Rf 0.51. Intermediate 5. 4- [4 - [(5-bromopentyl / oxy] - 45 -l-butynyl] benzoate. Mixture 10.0 g of intermediate 10.7 g of intermediate 2, 0.35 g of BTPC, 0.035 g of CuI, 50 ml of DEA and 50 ml of THF were stirred at room temperature under nitrogen for 18 hours, filtered and evaporated. The residue was purified on FCC eluting with CX-ER (19: 1). 5.8 g of a colorless oil were obtained. Thin layer chromatography (CX - ER 19: 1) showed Rf 0.3. Intermediate 6. 4- [4 - [(6-Bromohexyl / oxy] butyl] -N, N-diethylbenzamide. Solution 12.0 g 4- [4 - [(6-bromohexyl / oxy] -1-butyl) The] -N, N-diethylbenzamide in 300 ml of ET was hydrogenated with 2 g of 10% Pd-C and 2 g of 5% Pt-C, filtered and evaporated. The residue was purified on FCC eluting with ER - CX (1: 1). 7.5 g of the title compound was obtained in the form of a colorless oil. Thin layer chromatography (ER - CX 1: 1) showed Rf0.3. Intermediate 7. N, N-Dipropyl-4-iodobenzamide 10.0 g 4-iodobenzoyl chloride was added portionwise to 4.10 g dipropylamine in 40 ml triethylamine at 20 ° C. The resulting slurry was stirred at room temperature for 1 hour, diluted with 150 ml of ER, filtered and evaporated to give 11.51 g of the title compound as an orange oil. Thin layer chromatography (ER) showed a Rf of 0.48. Intermediate 8. N - [(4-Iodophenyl) methyl] pentanamide 3.7 g of valeric anhydride were added dropwise to 4.2 g of 4-iodobenzenemethanamine and 3.2 g. pyridine in 50 ml MC at 0 ° C. The solution was stirred for 10 minutes at this temperature and then for 2 hours at room temperature, washed with an aqueous sodium hydrogen carbonate solution, dried and evaporated. The residue was crystallized from ER at -78 ° C to give 3.7 g of the title compound in the form of a white solid, mp 80-81 ° C. Intermediate 9. / E / -4- / 4- Fluorophenyl) -3-butyl-1-ol 100 ml of n-butyllithium (1.6 m in H) was added dropwise to a stirred suspension of 32.1 g of (3-hydroxypropyl) triphenylphosphonium bromide in 200 ml of dry THF cooled to 0 ° C., under a nitrogen atmosphere. A solution of 9.93 g of 4-fluorobenzaldehyde in 100 ml of dry THF was added dropwise and the mixture was stirred under nitrogen at 0 ° C for 30 minutes and at room temperature for a further 1.5 hours. The mixture was carefully diluted with 25 ml of water, the solvent was evaporated under vacuum at 40 ° C and the residue was partitioned between 200 ml of EA and 200 ml of water. The aqueous phase was re-extracted with 200 ml of EA, the organic phases were combined, dried and evaporated. under vacuum to obtain a brown oil. Purified by FCC eluting with CX - ER (1: 1) to yield 6.33 g of the title compound as a colorless oil. Thin layer chromatography (CX - ER 1: 1) showed Rf 0.13. Intermediate 10. Propyl 4-iodobenzoate 13.4 g of DCC was added in one portion to 15.0 g of 4-iodobenzoic acid, 7.2 g of n -propanol and 0.6 g 4- (dimethylamino) -pyridine in 50 ml MC at 0 ° C under nitrogen atmosphere. The mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 3 hours, diluted with 50 ml ER, filtered and evaporated. The residue was treated with 50 ml of CX, filtered and the filtrate evaporated to give 16.2 g of the title compound as a pale yellow oil. Thin layer chromatography (CX-ER 3: 1) showed a Rf 0.8, Intermediate 11. N - [[4 [4 - [[6- [(phenylmethyl) amino] hexyl] oxy] -1-butynyl ] phenyl] methyl] pentanamide A mixture of 3.5 g intermediate 8, 2.85 g N- [6- {(3-butynyl) oxy] hexyl] benzenemethanamine, 0.2 g BTPC, 0.02 g Cul and 50 ml of diethylamine was stirred at room temperature under nitrogen for 18 hours and evaporated. The residue was partitioned between 50 mL of 1M aqueous water, 274 L, and 12 sodium hydrogencarbonate and 2 X 100 mL of EA. The organic phase was dried and evaporated. The residue was purified with FCC eluting with EA. 2.3 g of the title compound were obtained in the form of a yellow solid, mp 66-67 ° C. Intermediate product 12. 4- (4-morpholinyl) benzenebutanol. Mixture 7.5 g of 4-aminobenzenebutanol, 6.5 g (5.32 ml) of 2-chloroethyl ether, 11.74 g of DEA and 15.0 g of finely ground potassium iodide were stirred in 500 ml of DMF at 100 ° C. under nitrogen for 65 hours. The mixture was cooled, the solvent was removed in vacuo at 55 ° C. and the residue was partitioned between 250 ml of EA and 100 ml of water. The aqueous layer was extracted with a further 100 ml of EA, the combined organic solutions were washed with 150 ml of brine, dried and evaporated onto 15 g of silica in a chromatography column. The impregnated material was applied to the FCC column and the ER-CX was eluted (2: 1). 6.13 g of the title compound were obtained in the form of a waxy cream solid with a melting point of 51-52 ° C. Intermediate 13.1,1-dimethyl-5- (4- {4-) 4-morpholinyl (phenyl] butoxy] pentanamine I. 2,2-Dimethyl-6- {4-4- (4-morpholinyl) phenylo} butoxy] caproic acid. Lithium diisopropylamide solution was prepared by adding 5.32 g of diisopropylamine in 20 ml of dry THF 34.3 ml of 1.53 m n-butyllithium in hexane at -40 ° C. under nitrogen atmosphere. The solution was stirred at 0 ° C. for 15 minutes, 2.32 g of isobutyric acid was added and the mixture was mixed with nitrogen. The mixture was stirred for 3 hours at room temperature, 6.0 g of intermediate 3 was added, the mixture F was stirred at room temperature for 20 hours under nitrogen atmosphere, then the solvent was evaporated under vacuum at 40 ° C. The viscous residue was triturated at room temperature. 250 ml water, the pH was adjusted to 6 by adding 2N hydrochloric acid and the mixture was extracted with 2 X 290 ml EA. The organic layer was dried and concentrated in vacuo, keeping 5.75 g of tithe compound as a light brown oil. Thin layer chromatography (ER) showed Rf% 9. II. phenylmethyl 1,1-dimethyl-5- {4- [4- (4-morpholinyl) phenyl] butoxy] pentylcarbamiriate 1.66 g of ethyl chloroformate in 5 ml of acetone was added dropwise to a solution of 5.5 g of the product from steps I and 2 , 13 ml of triethylarriin in 50 ml of acetone and 5 ml of water while stirring at 0 ° C. The mixture was stirred at 0 ° C for 40 minutes, and 1 g of sodium azide in 10 ml of water was added dropwise. The resulting suspension was stirred at room temperature for 45 minutes, diluted with 100 ml of water and extracted with 2 × 100 ml. The dried extract was heated at 75-80 ° C for 2 hours under nitrogen and evaporated in vacuo. at 40 ° C. The oily residue was dissolved in 10 ml of benzyl alcohol and the solution was stirred at 70-75 ° C for 60 hours under nitrogen atmosphere, after which excess alcohol was removed under vacuum at 95 ° C. The oil obtained was purified by FCC eluting with ER-CX (1: 2) to give 5.34 g of the title compound as a pale yellow oil. Thin layer chromatography (ER - CX 1: 2) showed an Rf of 0.23. 5 III. 1,1-dimethyl-5- [4- [4- / 4-morpholinyl / phenyl] -butoxy] pentanamine. A solution of 4.60 g of the product of stage II in 75 ml of asbolic ethanol was hydrogenated at room temperature under atmospheric pressure over 10 KTtyo PdO-C pre-reduced catalyst (1 g, 50 µ / * paste in water) in 25 ml of absolute ethanol. The catalyst was filtered off through Hyflo and the solvent was evaporated under vacuum at 40 ° C to give 3.0 g of the title compound as a colorless oil. Thin layer chromatography (T - ET - A 39: 10: 1) showed an Rf of 0.32. : / Intermediate 14. NN-dipropyl-4- [44 [6- (phenylmethyl) amino] hexyl] oxy] -1-butynyl) benzamide 20 10 mg of copper (I) iodide were added to a stirred solution of 2 g. Intermediate 7.1, 1.57 g of N- {6 - [(3-butynyl / oxy] hexyl] b-isenomethanainine and 70 mg of BTPC in Sd ml of diethylamine under nitrogen atmosphere and the mixture was stirred for 2s overnight in this atmosphere. The solution was evaporated in vacuo, the residue was dissolved in 50 ml of MC and the solution poured onto silica in a column chromatography. Purified on FCC eluting with ER. 1.2 g of the titanium compound was obtained in the form of an orange oil, 30 JU. Elemental analysis for CseltaNtOi calculated: C 77.9 H 9.2 N 6.1. Found: C 77.6 H 9.4 N 6.3M Intermediate 15. N- (4- [4 - [[6- [[2- [3 - [/ Aminocarbonyl / amino] -4- (phenylmethoxy / phenylJ-2-ketoethyl] / phenylmethyl / amino ] hexyl] oxy] butyl] phenyl] -butanesulfonamide The title compound was made as a white foam and (0.90 g), t.Lc. (EA - CX 3: 1) Rf 0.27] by traditional reaction sequence and using N- [5-bromoacetyl-2- (phenylmethoxy) phenyl] urea, 1-bromo-6 - [(3-butynyl] oxy] hexane, benzylamine and N- (4-iodophenyl) n-butanesulfonamide as starting materials 45 Intermediate 16. / E / -N- [5- [2- [f6-f {4V4-hydroxy-3-methoxyphenyl] -3-butenyl] oxy] hexyl] - (phenylmethyl) amino] -1-ketoethyl] -2- (phenylmethoxy) phenyl] methanesulfonamide. Solution 0.6 g of N- [5-bromoacetyl-2- (phenylmethoxy) -phenyl] methanesulfonamide, 0, 48 g of intermediate 4 and 0.39 g of DEA in 10 ml of THF were left for 48 hours. The precipitated DEA hydrobromide was filtered off and the filtrate was evaporated in vacuo to give an oil which was preabsorbed onto 5 g of silica in a chromatography column and purified on TCC eluting with CX-EA (3: 2). 0.38 g of the title compound was obtained in the form of a yellow oil. Thin layer chromatography (CX - EA 3: 2) showed R f 0.20. w Intermediate 17. N45- [2 - [[5- [4- [4- (3-methoxypropyl / phenyl] butoxy] perityl / phenylmethyl / amino] -1-ketoethyl] -2- (phenylmethoxy / phenyl] formamide The title compound was drawn up in the form of a colorless oil, tlc (EA - H 1: 1) Hf 0.45, in the traditional sequence of the reaction, starting from N- [5-bromoacetyl-2- (phenylmethoxy) phenyl] formamide, intermediate 2, benzylamine, 1,4-diiodobenzene, propargyl alcohol and dimethyl sulfate Intermediate 18. 4- [4- [and [6 - [[2- [3- [] [dimethylamine / sulfonyl] amino] -4- (phenylmethoxy) -phenyl] -2-ketoethyl] (phenylmethyl) amino] hexyl] oxy] -1-butynyl] -N, N-dipropylbenzamide 0.7 g N, -5- [bromoacetyl-2 - (phenylmethoxy) phenyl] -N, N-dimethylsulfonamide, 0.76 g of intermediate 14 and 0.23 g of DEA were stirred in 10 ml of DMF under nitrogen for 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in 100 ml of EA and washed with a solution of 75 ml of water. The aqueous phase was re-extracted with 2 X 50 ml EA and the combined extracts dried and evaporated in vacuo to give a yellow oil. Purified on TCC eluting with T-EA (7: 1). 0.47 g of the title compound is obtained in the form of a yellow oil. Thin layer chromatography (T - EA 5: 1) showed Rf 0.28. Intermediate 19. (E) -N4 [- 2-hydroxy-5- [1-hydroxy-2- [and [6 - [(443 , 5-bis (phenylmethoxy) phenyl] -3 -butenyl] oxy] hexyl] amino] ethyl] ethyl] phenyl] methanesulfonamide 2.13 g 3,5-bis (phenylmethoxy) -1- {4 [/ 6 -bromohexyl] oxy] -3-butenyl] benzene was added dropwise to a stirred solution of 1.5 g of intermediate 21 and 0.57 g of DEA in 25 ml of DMF at 70 ° C. under nitrogen atmosphere, and the solution was stirred at this point. Temperature for 6 hours, diluted with 100 ml of water, extracted with 2 X 100 ml of EA, washed with 100 ml of water, dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with EA - ME (9: 2) gave 0.79 g of title compound as brown oil. Thin layer chromatography (T - ET - A 39: 10: 1) showed Rf 0.22. Intermediate 20. N- [5- [l-hydroxy-2-i [{ 1,1-dimethyl-5- [4- [4-morpholinyl / phenyl] butoxy] -pentyl] amino] ethyl] -2- (phenylmethoxy) phenyl] methanesulfamide. A mixture of 0.74 g of N- [5 - (ketoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide and 0.70 g of intermediate 13 in 20 ml of benzene were stirred under reflux with a Dean-Stark trap for half an hour until no more water was evolving. The solvent was removed under vacuum at 40 ° C., the residual oil was dissolved in 25 ml of methanol and the solution was stirred at 0 ° C. under a nitrogen atmosphere. 0.75 g of sodium bromohydride was added in portions over half hours, the mixture was stirred for 15 minutes at 0 ° C., then left to stand at room temperature for 20 hours. The solution was acidified to pH 2 with 2N hydrochloric acid, most of the methanol was evaporated under vacuum at 40 ° C and the residual oil was partitioned between 75 ml EA and 8% sodium bicarbonate solution. The aqueous phase was extracted with a further 50 ml of EA, the combined organic solutions were dried and concentrated to give a product which was purified on TCC eluting with T - ET - A (39: 10: 1). 0.75 g of the title compound was obtained in form a pale brown, sticky resin. Thin layer chromatography (T - ET -? 39: 10: 1) showed a Rf of 0.42. Intermediate 21. N- [5- (2-Amino-1-hydroxyethyl) -2-hydroxyphenyl] methanesulfonamide. Intermediate 22. N- (4-iodobenzoyl) piperidine 10 10 0 g of 4-iodobenzoyl chloride was added portionwise to 3.53 g of piperidine in 40 ml of triethylamine at 0 ° C, and the suspension was stirred for 1 hour at room temperature under nitrogen, then the reaction mixture was poured into 200 ml of 2N hydrochloric acid and extracted. 3 X 100 mL EA. The combined extracts were washed with 100 mL of water, 100 mL of 8% aqueous sodium bicarbonate and 100 mL of water, dried and concentrated. The resulting 10.25 g of solid was purified by FCC eluting with ER - 20H (1: 2 with a gradual transition to 1: 1), 9.33 g of the title compound was obtained as a white solid, mp 126-127 ° C. Intermediate 23. N, N-Diethyl-4-iodobenzene acetamide 10.62 g of 4-iodobenzeneacetyl chloride was added portionwise to 3.0 g diethylamine in 40 ml triethylamine, washed with 5 ml MC at 0 ° C. under nitrogen and the suspension was stirred at room temperature for 2 hours. 150 mL of ER was added, the mixture was filtered and the filtrate was concentrated to give 7.94 g of a residue which was purified on FCC eluting with ER - H (2: 1). 4.72 g of the title compound are obtained in the form of a yellow oil. Thin layer chromatography (ER) showed Rf 0.31. Intermediate 24.1-Bromo-6 - [/ 2-propynyloxy] hexane. Mixture 5.6 g of propargyl alcohol, 73.2 40 g 1.6 -dibromohexane, 0.5 g of TAB and 25 ml of 50% strength aqueous sodium hydroxide were stirred for 20 hours at room temperature, diluted with 50 ml of water and extracted with 2 x 100 ml ER. The dried extracts were evaporated and the residue was purified on FCC, eluting with CX - ER (19: 1). 15.0 g of the title compound are obtained as a colorless oil. Thin layer chromatography (CX - ER 9: 1) showed Rf 0.4. Intermediate 25. 2- [4 - [(6-bromohexyl) oxy 50 butyl] -N, N-diethylbenzamide Mixture 20 mg Cul, 3.04 g of l-bromo-6 - [(3-butin / oxy] hexane, 3.95 g of N, N * diethyl-2-i-benzamide, 200 mg of BTPC, 2.60 g of N, N-dicyclohexylamine and 20 ml of acetonitrile are stirred for 4.5 hours under a nitrogen atmosphere at room temperature, diluted with 200 ml of ether. and filtration. The filtrate was evaporated in vacuo, the residue in 100 ml of ethanol was treated with activated charcoal and the solvent was evaporated in a vacuum. The residue, 5.32 g of oil in 190 ml of absolute ethanol, was hydrogenated over 1.25 g of PdO-C reduced (50% paste in water) in 20 ml of absolute ethanol, filtered through Hyflo and it was evaporated in a vacuum to oil. Purified on FCC eluting with T - EA - triethylamine (95: 5: 1) then a148 274 15 16 on FCC eluting with CX-EA (2: 1). 2.04 g of the title compound are obtained as a yellow oil. Thin layer chromatography (T — ET — A 40: 10: 1) showed Rf 0.14. In a similar manner, intermediates 26 - 29 were prepared. Intermediate 26. 4- [4 - [(5-bromopentyl / oxy]) - -butyl] -N, N-diethylbenzamide in the form of a pale (azo) oil [(5.81 g), tlc (ER) Rf 0.37] was obtained from 25 mg of Gul, 7.06 g of N, N-diethyl-4-iodobenzamide, 4.38 g of intermediate 4, 250 mg of BTPC and 4.0 g of dicyclohexylamine in 30 ml of acetonitrile for a reaction time of 2 hours and subsequent hydrogenation with 10% Pd-C (50% aqueous paste) as catalyst. Purification of the product was carried out by chromatography using Merck 7734 silica, eluting with H - ER (1: 1) and ER. Intermediate 27. N- [4- [4 - [(6-bromohexyl) oxy] butyl] benzoyl] piperidine in the form of a dark brown oil ((7.55 g), t. l, c. (ER - H 2: 1) Rf 0.25] was obtained from 9.30 g of intermediate 22, 6.46 g of 1-bromo-6 - [(3-butynyl) oxy] hexane, 5.90 g of N, N , dicyclohexylamine, 150 mg of BTPC and 30 mg of CuI in 90 ml of acetonitrile with a reaction time of 20 hours. 10% Pd-C was used as a hydrogenation catalyst and for FCC purification the eluents ER - H (2: 1) and Cf. Intermediate 28. 4- [4 - [(6-bromohexyl / oxy] butyl] -N, N -diethylbenzeneacetamide in the form of a dark brown oil ((3.51 g). tlc (ER - H 2: 1) Rf 0.18] was obtained from 4.65 g of intermediate 23, 3.22 g of l-bromo-6- [(3-butynyl) oxy] hexane, 2.94 g N, N-dicyclohexylamine, 75 mg BTPC and 15 mg CuI in 30 ml acetonitrile with the same reaction time, hydrogenation catalyst and FCC purification as in the intermediate 27. Intermediate 29. 3- [4 - [(6-bromohexyl / oxy] butyl] -N, N-diethylbenzamide in the form of a brown oil [/ 5.91 g /, Uc (H - ER 1: 1) Rf 0.175 ] was obtained from 8.49 g of N, N-diethyl-3-iodobenzamide, 6.99 g of 1-bromo-6 - [(3-butynyl) -oxy] hexane, 350 mg of BTPC, 250 mg of CuI and 6 45 g of dicyclohexylamine in 35 ml of acetonitrile was stirred for 2 days at room temperature, the solvent was then evaporated, and the residue was partitioned between 100 ml of water and 100 ml of EA. After washing, 5 g of activated carbon was added to the organic layer, dried and concentrated to an oil, to which was added 100 ml of ethanol. The precipitated brown fine precipitate was filtered off and the filtrate was hydrogenated with 10% Pd-C catalyst. ER-CX (1: 2) was used as the eluent for the FCC purification. Intermediate 30. 4- [3 - [[6-phenylmethyl-amino] hexyl] oxy] propyl] -N, N- Dipropylbenzamide Suspension 6.62 g of intermediate 7, 4.40 g of intermediate 24, 4.0 g of dicyclohexylamine, 250 mg of BTPC and 25 mg of CuI in 40 ml of acetonitrile were treated as for intermediate 25, it was then hydrogenated with a pre-reduced 10% Pd-C catalyst and H-ER (2: 1) eluent for FCC purification. To the resulting 5.1 g of orange oil was added 15 ml of benzylamine at a temperature of 140 ° C. under a nitrogen atmosphere. After 2 hours, the reaction mixture was poured into 200 ml of 2N hydrochloric acid and 100 ml of ice. The aqueous mixture was extracted with 3 x 100 ml of EA and the combined organic extracts washed with 2 x 100 ml of 2N sodium carbonate, water and brine, dried and concentrated to a dark oil which was purified on FCC eluting with T-ER-triethylamine (95: 5). : 1 with gradual * transition to 90: 10: 1). 2.4 g of the title compound were obtained in the form of a pale yellow oil. Thin layer chromatography of 10 T - ET - triethylamine (90: 10: 1) showed Rf 0.36. Intermediate 31. N- [6- [2- [4- / N, N-dimethylamino / phenyl] ethoxy] hexyl ] benzenemethanamine Mixture 73.84 g 1,6-dibromohexane, 10 g 4-15 - (N, N-dimethylamino) benzeneethanol, 200 ml 50 *% (w / v) sodium hydroxide solution and 3.4 g TAB were vigorously stirred at the temperature for 72 hours, diluted with 500 ml of water and extracted with 2 x 100 ml ER. The dried extracts were evaporated to give a yellow oil which was purified on FCC eluting with H progressively shifting to H-EA (9: 1) to afford 4- [2- [(6-bromohexyl / oxy] ethyl] N , N-dimethylbenzenamine as a yellow oil. While stirring, 15 g of benzenamine was added to 45 ml of benzylamine under nitrogen at 140 ° C. and stirring was continued for 2 hours. The benzylamine was removed under vacuum at 90 ° C, the solution was partitioned between 150 ml of sodium hydrogencarbonate and 2 X 100 ml of EA and the combined organic layers were dried and concentrated to give the product which was purified on FCC eluting with ER - H ( 1: 1) with gradual transition to ER. 11.1 g of the title compound were obtained in the form of a yellow oil. Thin layer chromatography (T - ET - A 95: 4: 1) showed Rf 0.62. Intermediate 32. (a) N, N-diethyl-4- [4 - {[6 - [[2-hydroxy- 2- [4-hydroxy-3 - (/ methylsulfonyl / amino] phenyl] ethyl] amino] hexyl] oxy] butyl] benzamide (salt) 1 g of intermediate 6 in 2 ml of DMF was added dropwise to solution 1, 2 g of intermediate 21 and 1.3 g of DEA in 20 ml of DMF at 75 ° C. The solution was heated at 75-80 ° C for 90 minutes and evaporated under reduced pressure. The residue was purified by column chromatography. liquid, eluting with T - ET - A (80: 20: 1) to give a colorless gum. These resins in 10 ml of CF were treated with 0.3 g of benzoic acid in 5 ml of CF and then the CF was evaporated. the residue was triturated with the ER (2 X 25 ml) to give 0.55 g of the title product as a white solid, mp 90-92 ° C. Elemental analysis for C29H48N * 0 "S" 07He02 55 calculated: C 62.8 H 7.9 N '6.1g / i found: C 63.3 H 7.55 N 5.91% Similarly prepared: (b) Propyl 4 - [{5 - {[2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl] amino] pentyl] oxy) -1-60-butynyl] benzoate as white solid (0.26 g) mp 88-90 ° C. Elemental analysis for C28H88N2O7S calculated: C 61.5 H 7.0 N 5.1% 65 Found: C 61.0 H 7.0 N5, flVe.17 148 274 18 This compound was obtained starting from 1.0 g of intermediate 21, 1.43 g of intermediate 5 and 1.0 g of DEA, after a reaction time of 2 hours but without the use of benzoic acid in the CF. (c) N- [2-hydroxy-5- {1-hydroxy-2 - [[6- [4- (4-nitrophenyl) butoxy] hexyl] amino] ethyl] phenyl] -methanesulfonamide in meringue form solid (1.15 g) mp 77-80 ° C. Elemental analysis C25H8N8O7S calculated: C 57.3 H 7.1 N 8.0% found: G 57.0 H 7.1 N 7.85% This requirement was obtained starting from 2.5 g of intermediate 21, 3.6 g of 11 [4 - [(6-bromohexyl) oxy] butyl] -4-nitrobenzene and 2.6 g of DEA, each reaction time of 2 hours without treatment with benzoic acid in CF. The following examples illustrate the process of the invention. Example 1 Preparation of N, N-diethyl-4- [4- [and [6n [and [2-hydroxy-2- [4-hydroxy-5 - [] methylsulfonyl N, N-diethyl-4- [4 - [[6-IN- (phenylmethyl) amdno] hexyl] oxy] butyl] benzamide / amino] -phenyl] ethyl] amino] hexyl] oxy] butyl] benzamide can be can be obtained in a known manner by treating 4- [4 - [(6-bromohexyl) oxy] butyl] -N, N-diethylbenzamide benzylamine. A solution of 5.50 g of the above N- (phenylmethyl) amino- N, N-diethylbenzamide in 15 ml of ethyl acetate was added to a stirred suspension of 5.25 g of Nj [5- (bromoacetyl) -2-phenylmethoxy) phenyl] methanesulfonamide in 10 ml of ethyl acetate. Then 15 ml of 1M sodium carbonate solution was added. After stirring for 17 hours, the organic phase was separated, washed with brine and evaporated to dryness. The residue in 35 ml of ethanol was cooled in an ice bath under a nitrogen atmosphere, 5.25 ml of ethanol were added, and 475 mg of sodium borohydride was added portionwise over 5 minutes. The reaction mixture was allowed to warm to room temperature and after 1.5 hours it was cooled in an ice bath and 12.5 ml of 5N hydrochloric acid was added over 10 minutes keeping the temperature below 10 ° C. After stirring for 5 minutes, 15 ml of 5N sodium hydroxide solution were added. The organic phase was washed with water, 0.4 M phosphoric acid, water, 1 M sodium carbonate solution and brine, dried and evaporated to give 8.67 g of N, N-diethyl-4- [4 - {] [6- H 2 -hydroxy-2- [3 - [(methylsulfonyl) amino] -4- (phenylmethoxy) phenyl] ethyl] (phenylmethyl) amino] hexyl] oxy] butyl] benzamide as a pale yellow oil. A solution of 6.0 g of the above phenylmethoxy-phenylmethylamino-N, N-diethylbenzamide in 60 ml of ethanol was hydrogenated over a catalyst constituting 10% PdC-O (1.2 g, 50% paste in water) adding further catalyst (1 , 2 g) after 17 hours. After a further 5 hours the catalyst was removed by filtration by "Hyflo". Evaporation of the filtrate under vacuum yielded 4.64 g of the title compound as a light brown foam. In the form of benzoate, the product had a melting point of 90 - 92 ° C. Elemental analysis for CsoH47N80eS calculated: C 62.36 H 8.20 N 7.27 S 5.55% Found: C 62.30 H 8.47 N 6.90 S 5.22%. Example II . (a) 4- [4 - [[5 - [[2-hydroxy-2- 5 -i [4-hydroxy-3 - [/ me Tylsulfonyl / amino] phenyl] ethyl] amino] pentyl] oxy] butyl Propylbenzoate A solution of 0.2 g of intermediate 32 (b) in 20 ml of ET was hydrogenated over 10% Pd-C (0.05 g), filtered through Hyflo and evaporated. The residue was triturated with 20 ml of ER to give 0.19 g of the titular compound as an off-white solid, mp 74-76 ° C. Elemental analysis for C28H42N2O7S calculated: C 61.1 H 7.7 N 5.1% Found: C 60.6 H 7.4 N 5.0%. Similarly, we have prepared: (b) N- [2-hydroxy-5- [1-hydroxy-2 - [[6- [ 4- (3,5-dihydroxyphenyl) butoxy] hexyl] amino] ethyl] phenyl] methanesIphonamide as a meringue solid (0.27 g), mp 73-74 ° C (decomposition). Elemental analysis for C2bHs8N2O7S1H2O the following was calculated: C 56.8 H 7.6 N 5.3% Found: C 56.3 H 7.6 N 5.2%. This compound was obtained starting from 0.5 g of intermediate 19 40 mg of initially reduced 10% Pd-C and 30 mg of Pt-C. (c) N- [4- [4- [i [6H [[2- [3-i [/ aminocarbonyl) -amino] -30 -4-hydroxyphenyl] ethylp] amino] hexyl] oxy] butyl] phenyl ] butanesulfonamide as a meringue foam (0.45 g). Thin layer chromatography (T - ET - A, 38: 10: 1) showed Rf 0.16. Elemental analysis for C29H4 "N40" S-HbO35 Calculated: C 58.4 H 8.1 N 9.4% Found: C 58.3 H 7.75 N 8.9%. This compound was obtained starting from 0.8 g of intermediate product 15, 200 mg of Pd-C, which was reduced by 10%, and 200 mg of Pt-C, 5%. 40 (d) N- [5- [2- {I6- [4- (4-aminophenyl] butoxy] hexyl] amino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide meringue solid (0, 3 g), m.p. 57-60 ° C. Elemental analysis for C25H9Ns05S * H2O45 Calculated: C 58.7 H 8.0 N 8.2% Found: C 58.3 H 7.5 N 8.0%. This compound was obtained starting from 0.5 g of intermediate 32 (c), 0.1 g of 10% Pd-C and 0.1 g of 5% Pt-C. 50 Example III. N- [2-hydroxy-5- J [1-hydroxy-2 - [[5- (4- [4- (3-methoxypropyl / phenyl] butoxy] pentyl] amino] ethyl] phenyl] formamide benzoate (salt) A solution of 0.85 g of intermediate 17 in 25 ml of absolute ET was hydrogenated to 0.5 g of PdO-C reduced by 10% and 0.25 g of PtO-C 5%. The mixture was filtered through Hyflo and removed. is a solvent to give an oil which was purified by liquid column chromatography eluting with T - ET - A (J39: 10: 1). 60 g of the free base of the title compound were obtained as a viscous colorless oil which was dissolved in 5 ml of ME, 50 mg of benzoic acid were added and the solvent was evaporated. A sticky oil was obtained which, when rubbed! with ER 65 0.16 g of the title compound was obtained in the form of 148 274 19 20 white powder with a melting point of 88-91 ° C. Elemental analysis for CaHuNiOs • C7HeO • 0.5 HiO calculated: C 68.04 H 7.99 N 4 . 53 "* Found: C 68.21 H 7.75 N 4.54%. Example IV. N- [2-hydroxy-5- [1-hydroxy--2-H6- [4- / 4-hydroxy-3-methoxyphenyl / butoxy] hexyl] amino] ethyl] phenyl] methanesulfonamide 0.36 g of product solution intermediate in 20 ml of absolute ethanol was hydrogenated over 40 mg of pre-reduced 1 (f / t Pd-C and 40 mg of 5% of Pt-C in 5 ml of absolute ET. The mixture was filtered through Hyflo and evaporated to give a brown oil. Purification by column liquid chromatography eluting with T - ET - A (39: 10: 1) yielded a brown oil which was triturated with the ER to give 40 mg of the title compound in the form of a brown foam. Thin layer chromatography (T - ET - A, 39: 10: 1) showed Rf 0.23. * O Elemental analysis for CUH40N2O7S • 0.5 HtO calculated: C 58.5 H 7.7 N 5.25 »/ t found: C 58.4 H 7.85 N 4.9 "/". Example 5 N - [[4- [4H] [6- [ia-hydroxy-2- [4-hydroxy-3 - [(methylsulfonyl] amino] - benzoate 25-phenyl] ethyl] amino] hexyl] oxy] butyl] phenyl] methyl] pentanamide (salt). Solution 0.9 g Ni [5- (bromoacetyl) -2-) phenylmethoxy) -phenyl] methanesulfonamide, 1.0 g of intermediate 11 and 0.65 g of DEA in 15 ml of THF left at room temperature for 20 hours, filtered and evaporated. The residue was purified by liquid column chromatography, eluting with the ER. A yellow oil was obtained. The oil in 40 ml of Et1 was hydrogenated over 0.3 g of L 52 F * -C, filtered and evaporated. The residue was purified by liquid column chromatography eluting with T - ET-A (80: 20: 1) to give a colorless gum. A solution of 0.2 g of this resin in ft ml of CP was added to 0.7 g of benzoic acid and evaporated. The residue was triturated with 15 ml of ER to give 0.2 g of the title compound as a white solid, mp 88-89 ° C. Elemental analysis for CsiHuNsOe • C7H8O1 calculated: C 63.1 H 7.8 N 5 , 8% found: C 63.0 H 7.7 N 5.8M. Example VI. (E) 4- [4 - [[6-II2- [3 - [[/ dimethylainine / sulfonyl] amino] -4-hydroxyphenyl] -2-hydroxyethyl] amino] hexyl] oxy] butyl (E) ] -N, N-dipropylbenzamide (salt) (1: 1) A solution of 0.45 g of intermediate 18 in 30 ml of absolute ET was hydrogenated over a mixture of 100 mg of 5 * / «pre-reduced PtO-C and 100 mg of lWt PdO-C in 10 ml ET. The mixture was filtered over Hyflo and evaporated in vacuo to give 0.27 g of a yellow oil. Purification by column liquid chromatography eluting with T - ET - A (39: 19: 1) gave 200 mg of a yellow oil which was dissolved in 2 ml of methanol and treated with 40 mg of fumaric acid. The solution was evaporated under vacuum and the residue was triturated with the ER to give 0.2 g of the title compound as a cream foam. Thin layer chromatography (T - ET-A, 39: 10: 1) showed Rf 0.24. es Elemental analysis for CmHmN40cS • C4N2O r 0.2 H2O Calculated: C 58.9 H 7 * 8 N 7.4% Found: C 58.6 H 8.0 N 6.9% / t. Example VII. N- [2-hydroxy-5- [1-hydroxy-2- - [[1,1-dimethyl-5- [4- [4- / 4-morpholinyl / phenyl] butoxy] pentyl] amino] ethyl] phenyl] methanesulfonamide. A solution of 0.6 g of intermediate 20 in 25 ml of absolute ethanol was hydrogenated under atmospheric pressure and room temperature over 0.5 g (50% paste in H 2 O) of pre-reduced 10% PdO-C. The catalyst was filtered off over Hyflo. Purified by liquid column chromatography, eluting with T - ET-A (39: 10: 1). 128 mg of the title compound was obtained in the form of a pale powder, mp 165-167 ° C. Elemental analysis for CtoH470eS calculated: C 62.36 H 8.20 N 7.2 W # found: C 62.22 H 8.37 N 6.99Ve. Example VIII. N, N-dipropyl-4- (3- -I [6 - [(24-hydroxy-2- (4-byroxy-3 - [(methylsulfonyl] -aminolfenyl] ethyl] amino] hexyl] oxy] propyl] - benzoate) -benzamide (salt). A solution of 1.93 g of N2- (bromoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide, 2.10 g of intermediate 30 and 0.68 g of DNA in 45 ml of dichloromethane were stirred in under nitrogen atmosphere for 24 hours, the mixture was diluted with 150 ml of water, extracted with 200 ml of ether and the organic phase washed with 50 ml of brine, dried and evaporated in vacuo. A solution of 3.57 g of the obtained yellow oil in 170 ml of absolute ethanol was hydrogenated on the catalyst mixture, 1.0 g of the reduced IOP / 4 PdO-C and 1.2 g of 5% PtO-C in 20 ml of absolute ethanol was filtered over Hyflo and evaporated under vacuum to give an oil. Column liquid chromatography with T - ET - A (40: 20: 1) elution yielded an oil which was triturated with E to give the free base of the title compound as a white foam (1.40 g). Thin layer chromatography (T- ET - • A, 40: 10: 1) away the result of Rf 0.16. Part of the product (0.60 g) was dissolved in 10 ml of methanol and treated with 0.14 g of benzoic acid to obtain 0.54 g of the title compound in the form of a white solid, mp 100.5 - 101.5 ° C. Elemental analysis CnH4tNtOtS * C7H602'H * O the following was calculated: C 62.3 H 7.8 N 5.7, Vt found: C 62.2 H 78 N 5 / m. Example IX. N- [2-hydroxy-5- [1-hydroxy-2H [[6- H [2- {4- (dimethylamino / phenyl] ethoxy] hexyl] amino] ethyl] phenyl] methanesulfonamide Starting from 4 g N- [ 5-bromoacetyl (-2-) phenylmethoxy-phenyl] methanesulfonamide, 3.54 g of intermediate 31 and 2.1 g of DEA and following the procedure of Example VIII, except that 1.5 g was used as a hydrogenation catalyst. 10% / t Pd-C and 1.5 g 5PA | Pt-C was used as the eluent for the chromatography T-ET-A (80: 20: 1) and was not treated with benzoic acid. 450 g of the titanium product was obtained in the form of a light brown solid with a melting point of 45-50 ° C. Elemental analysis for CsHttNtOsS * 0.7H2O calculated: C 59.31 H 8.04 N 8.29 S 6.33M found: C 59.27 H 8.05 N 8.05 P / #. 148 274 21 Claims 22 1. Process for the preparation of new amino phenol derivatives of general formula I, in which X is a C1-7 alkylene chain, Y is a chain Ci_6alkylene, the sum of carbon atoms in both X and Y chains is 5, 6 or 7, Rf1 and R2, each independently represent a hydrogen atom or a methyl group, Q is the group HCO-, NH2CO-, / CH8 / 2- NSO2- or CH8SO2-, and Ar is a phenyl group substituted with groups such as amino, dimethylamino, morpholino, group - / CH2 / qNHCOR6 where R6 is C1-4alkyl and q is zero or 1, group -NHSO2R7 in which R7 is C1-4alkyl, a group -COR8 in which R8 is a C1-4 alkoxy group, or a -NRW group wherein R8 and R4 are each C1-4alkyl, or a group - (CH2r) -R10 in which r is equal to 3 and R10 is C1-4alkoxy or Ar is 3,5-dihydroxyphenyl or 3-methoxy-4-hydroxyphenyl group, and their physiologically acceptable salts and solvates, characterized in that the compound is reduced by Formula 2, wherein R15 is a hydrogen atom or a protected group capable of being converted to a hydrogen atom under the reducing conditions used, such as an arylmethyl group such as benzyl, benzhydryl or alpha-methylbenzyl, X1 is -CH / OH / - or a group convertible to a group -CH (OH) - under the reaction conditions employed, such as the group C = O, X2 represents the group -CH2NR16 in which R18 is a hydrogen atom or a group capable of conversion to a hydrogen atom under catalytic reduction conditions, such as the above-defined arylmethyl group, imino group or -CONH- group, X8 represents a -COX- group or a -CR ^^ - group in which Ra, Rs and X are as defined above, with the proviso that at least one of X1, X2 and X8 is a reducible group and Q, Y and Ar are as defined above, wherein both Y and Ar may contain reducible groups, then optionally the residual protecting groups are removed and the resulting compound of formula (I) or a salt thereof is optionally converted to its physiologically acceptable salt or solvate. 2. The method according to claim 2. The process of claim 1, wherein Ar is a phenyl group having a single -CON / CH2CH8 / 2 substituent, and Q, R1B, X1, X2, X8 and Y are as defined in claim 1.QNH pi HO ^ QhCHCH2NH CXCH2PCH2YAr OH R2 Formula 1 QNHx R, 5 ° / jy X1- X2- * - CH £ CH2Y-Ar Formula 2 QNH R, 5 ° A = 7 CHCH2NR16 CXCH2QCHaYAr ÓH fc Formula 3 PL

Claims (1)

Claims 22 1. A method for the preparation of new amino phenol derivatives of the general formula I, in which X represents a C1-7 alkylene chain, Y represents a C1-6 alkylene chain, the sum of carbon atoms in both X and Y chains being 5. 6 or 7, Rf1 and R2, each independently, represent a hydrogen atom or a methyl group, Q is a group HCO-, NH2CO-, / CH8 / 2- NSO2- or CH8SO2-, and Ar is a phenyl group substituted with groups such as an amino group , dimethylamino, morpholino, - (CH2) qNHCOR6 where R6 is C1-4alkyl and q is equal to zero or 1, -NHSO2R7 where R7 is C1-4alkyl, -COR8 where R8 is C1-4alkoxy or the group -NRW where each of R8 and R4 is C1-4alkyl or a group - (CH2r) -R10 where r is equal to 3 and R10 is C1-4 alkoxy or Ar is 3,5-dihydroxyphenyl or 3 -methoxy-4-hydroxyphenyl, and their physiologically acceptable salts and solvates, characterized in that the compound of the general formula is reduced Is a hydrogen atom or a protected group capable of being converted to a hydrogen atom under the reduction conditions used, such as an arylmethyl group such as benzyl, benzhydryl or alpha-methylbenzyl, X1 is -CH / OH / - or 5 a group convertible to a group -CH (OH) - under the reaction conditions used, such as the group C = O, X2 represents a group -CH2NR16 in which R18 is a hydrogen atom or a group capable of conversion to a hydrogen atom under the conditions catalytic reduction, such as the above-defined arylmethyl group, imino group or -CONH- group, X8 represents the -COX- group or the -CR ^^ - group, in which Ra, Rs and X are as defined above, wherein at least one of X1, X2 and X8 is a reducible group and Q, Y and Ar are as defined above, whereby both Y and Ar may contain reducible groups and optionally residual protecting groups are removed and optionally converting the obtained compound of formula I or its salt into its physiological value ¬ologically acceptable salt or solvate. 2. The method according to claim 2. The process of claim 1, wherein Ar is a phenyl group having a single -CON / CH2CH8 / 2 substituent, and Q, R1B, X1, X2, X8 and Y are as defined in claim 1. QNH pi HO ^ QhCHCH2NH CXCH2PCH2YAr OH R2 Formula 1 QNHx R, 5 ° / jy X1- X2- * - CH £ CH2Y-Ar Formula 2 QNH R, 5 ° A = 7 CHCH2NR16 CXCH2QCHaYAr ÓH fc Formula 3 PL