PL144516B1 - Method of obtaining novel aromatic compounds - Google Patents

Description

The subject of the invention is a method for the preparation of new aromatic compounds with antihistamine and antiallergic properties. These compounds are suitable for use in medicine in the form of pharmaceutical compositions containing them. In U.S. Patent No. No. 2,530,451 discloses a group of 9- / dialkylaminoalkyl / phenothiazines with antihistaminic activity9, the most important of which is the compound called promethazine. ^ 10- (2-dimethylaminopropyl / pheno «thiazine_7 # It has been widely accepted in clinical practice as an antihistamine tranquilizing agent. Currently used compounds with antihistamine activity, including compounds with the usual names diphenylinehydramine, phemyramines, * pyrilamine, promethamine, promethamine, a common potential disadvantage, namely inducing sedation and drowsiness in some patients, Promethazine has the additional disadvantage that it is potent anti-cholinergic. A new group of compounds has now been discovered with an in vivo antiallergic effect that is blocking the anaphylactoid effect. Some are also good. antihistamine activity and appear to have no side effects on the peripheral nervous system and have much less anticholinergic activity than promethazine. Thus, according to the invention, the compounds of the general formula I are produced, in which R, is divalent saturated l or an unsaturated group of an aliphatic hydrocarbon with 1-7 carbon atoms or a single bond, R2 and R3, the same or different, means each hydrogen atom, a C1-C6 alkyl radical or together with the nitrogen atom form a pyrrolidine ring, R. is a hydrogen atom, halogen or a C1-6 alkyl group optionally substituted with 1-3 halogen atoms and A is a C1-6 alkylene group, optionally in the form of a salt, a (C- CC) alkyl ester of a non-susceptible amide or a N- (C1-C ^) alkylamide or a hydrate or C ^. of the alkanolate. Preferred compounds of formula 1 are compounds of formula 2 in which R 1, R 2, R f R and A are as defined above, or their derivatives as defined above. R- can be a saturated 2 14 * 516 or an unsaturated straight-chain or branched-chain hydrocarbon group or a single bond * Correspondingly, R- is a 1-3 carbon hydrocarbon group or a single bond * Correspondingly, R- contains at most one single bond * Favorable. Rj is a group of formula / GH ^ n * w * t (* rym n is an integer 0-3 f group CH »CH. Group of formula -CH / CH ^ / / CHy / m- where m is 0 or 1 or the group -C / CH2 / g- Most preferably the group -H-JCoJi is the group -CHgCOgH. Preferably, Rp and R3 sft are the same or different and each is methyl or ethyl9 or together with the nitrogen atom to which they are attached form the pyrrolidine ring. HR9R3 is suitably most preferably a dimethylamino or diethylamino group, in particular a dimethylamino group. Preferably R * is trifluoromethyl, methyl, ethyl, chlorine or fluorine, especially hydrogen. When R is other than hydrogen, it is linked in the 7- or 8-position of the phenotlazine ring system, in particular in the 7-position. Preferably A is ethyl or n or isopropylene. The amides of the compounds of formula I are amides formed in known manner with carboxylic acids. Particularly suitable are amides formed from ammonia, primary amides or amino acid amino acid such as glycine. The method of the invention also comprises the preparation of hydrates of the compounds of the formula 11 and the C1-alkanolates. The esters and amides of the compounds of formula I, while having some antihyl sternin activity, may also be useful intermediates in the preparation of the carboxylic acid compounds of formula 1. Suitable esters include compounds with known ester groups known to be useful in protecting carboxylic acid groups. such as C 1 -alkyl esters in which the alkyl group is straight or branched chain and is optionally substituted with a halogen atom. The salts of the compounds of formula I may be either acid addition salts or salts formed by the carboxyl group. Acid addition salts are preferred, however, the salts formed by the acid carboxyl group may be particularly suitable for the preparation of the corresponding carboxylic acid compounds. Pharmaceutically acceptable salts are preferred. The salts of the compounds of formula I for use in medicine should be both pharmacologically and pharmaceutically acceptable, but for the preparation of the free active compound or its pharmaceutically acceptable salts, pharmaceutically unacceptable salts may conveniently be used, which also fall within the scope of the invention. invention. Such pharmacologically and pharmaceutically acceptable acid addition salts include, but are not limited to, salts made with the following acids, hydrochloric, sulfuric, nitric, phosphoric, malelic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic. , melon, isotlon, amber. 2-naphthalenesulfonic acid and benzene sulfonic acid. The pharmaceutically acceptable salts can also be prepared as alkali metal or alkaline earth metal salts, such as the sodium, potassium, or calcium salts of an acid carboxyl group. While the compounds of formula I contain a double bond in a side chain terminated with a carboxyl group, they exist in the form of cis or trans isomers (with respect to the aromatic ring). The method of the invention comprises the preparation of both isomers as well as of an isomeric mixture of these compounds. When the R 1 COpH moiety contains a double bond, isomers in which the carboxyl group is trans to the aromatic ring are preferred. Preferred compounds of Formula I include: 3- (2-carboxyvinyl) -10- / 2-dimethylaminopropyl / phenothiazine / example I / t 4- / or 1 - / - / 2-carboxyethyl / -10- / 2-dimethylaminopropyl / phenotlazine / example II /, acid ≤ ~ 7-chloro-1 Q / 2-4-dimethylaminopropyl (phenotlazisyl-2-7 acetic acid (example III), α-10-2 (dimethylaminoethyl) -7-methylphenothiazinyl-2_ (acetic acid) / example IY), 2-10- (2-dimethylaminoethyl) -7-fluorophenothiazyl acid -2-acetic acid (example?), 2-6 ~ 10- / (2-dimethylaminopropyl) phenothiazinyl-2? -2-methylproplonic acid (example TI), 2-6 ~ 10- (3-dimethylaminopropyl) phenothiazinyl-2a7 acid -2-methylpropionic (example YII / or their derivatives as defined above) H4 516 3 Pharmacokinetic studies comparing the relative separation in the brain and platelets of the two compounds according to the invention and promethazine indicated see that, unlike promethazine, the active compounds do not readily penetrate into the brain of rodents. According to the invention, compounds of growth 1 are produced in this way, the compound of the general formula 3 * is alkylated in which Rj and L have the meaning given above and the group COR - represents an ester or amide group, the resulting compound of formula I is then optionally converted to another compound of formula I in a known manner, for example by reduction of one or more double bonds or by deesterification of the ester group or hydrolysis of the amide * The alkylation of compounds of formula III is carried out under conditions well known to those skilled in the art. An alkylating agent of formula LANRpR, wherein A, R2 and R3 are as defined above, and L is a leaving group such as a halogen atom or a sulfonate group, e.g. tosyl or mesylate, is reacted with a compound of formula III in the presence of a base, with little high temperature, e.g. * 0-150 ° C, in an inert solvent * Conveniently a strong base is used, e.g. an alkoxide such as tertiary butoxide, a hydride such as sodium hydride or sodium amide. Preferably a temperature of 20-90 ° C is used, and a suitable solvent is a hydrocarbon such as toluene, an ether such as tetrahydrofuran, or a dipolar aprotic solvent such as dimethylformamide or dimethylsulfoxide. The compounds of formula III may be prepared as shown. in the diagram where all symbols have the meaning given above * Nitration is carried out with a nitrating agent, e.g. a mixture of HNCK / H 2 SO, at a temperature of 0-100 ° C, preferably 60 ° C * To the obtained nitro compound is added thiol with Formula 4, wherein R is as defined above * and base, e.g. * sodium carbonate, in a polar solvent such as an alcohol, e.g. methanol or ethanol, and the reactions are carried out at an elevated temperature, e.g. 50-10 ° C, preferably at reflux temperature * The product obtained is subjected to a ring closure reaction, using 2 moles of P / OEt / ^ 1 for each mole of this compound to be reacted, carrying out reactions in a high-boiling hydrocarbon well, e.g. -n-propy lobenzene, at elevated temperatures, e.g. 125 ~ 200 ° C., preferably at reflux temperature. Reduction of one or two double bonds, i.e. reduction of the side chain double bond with the carboxyl group, can conveniently be carried out by hydrogenation in the presence of a metal catalyst of a transition group, e.g. * platinum on charcoal * The preparation of esters or amides from the corresponding carboxylic acid and vice versa can likewise be carried out by methods known to the person skilled in the art. The production of these intermediates, which are new, is an important aspect of the method according to the invention * Manufactured compounds According to the invention, having antiallergic activity may be used in some indications as clinically used anti-asthmatic compounds to help regulate bronchial constriction or bronchospasm characteristic of allergic and exercise-induced asthma, as well as symptoms of bronchoconstriction and bronchospasm. caused by acute or chronic bronchitis * These compounds are believed to inhibit the release of autacoids (i.e., histamine, serotonin and the like) from fatt cells and directly inhibit antigen-induced histamine production * Thus, these compounds can be classified as mast cell stabilizers antihistamine * The antihistamine compounds of the invention can be used for certain indications as clinically used antihistamines for the relief of nasal respiratory difficulties caused by nasal rhinitis, vasomotor dysfunction, and symptomatic management of allergic conditions including nasal allergy, persistent rhinitis, urticaria, nervous swelling, allergic conjunctivitis, food allergy, drug and serum reactions, insect bites, and desensitisation reactions. These compounds may also be considered because of their anticorrhoeic effect in skin diseases caused by allergy, sclerosis, aaogenital itching and pruritus of non-specific origin, such as eczema 1 with specific causes, such as chicken pox, photosensitivity and dermatitis . The compounds prepared according to the invention therefore find application in the symptomatic treatment of allergic conditions by administering an effective amount of a compound of formula 1. The use of the compounds according to the invention also ensures that the endogenous release of histhorn is not prevented by administering a cured amount of a compound of the formula 1. Formula 1. It has been found that some of the compounds according to the invention are completely devoid of sedative effect, and have little or no anticholinergic effect. * The amount of active compound required for use under the above conditions varies depending on the type of agent used of the compound, route of administration and condition of the mammal to be treated, ultimately depending on the physician *. A suitable oral dose of active compound for mammals is 0.003-1.0 mg per kilogram body weight per day, preferably 0.04 * 0.24 mg / kg. The desired daily dose is preferably presented as one to six partial doses administered as needed throughout the day at appropriate intervals. When three partial doses of the compounds of formula I are used, each of them preferably contains 0.014-0.08 mg / kg of body weight, e.g. a typical human dose of such a compound is 1-20 mg, for example 4-8 mg. A. In vitro antihistamine effect. From the intact mole of guinea pigs / Hartley, males 250-400 g /, the longitudinal muscle is isolated and placed in a bath where experiments are carried out on individual parts of the body. The month for the test was held under a tension of 300 mg. After one hour of equilibrium, cumulative concentration dependence curves are obtained - response to histamine / Van Rossum, J.M.Arch.Int.Pharmacodyn.Ther. 143, 299-330, 1963 /. After washing, the tissues are incubated for one hour with the test compound and then a second histamine-response curve is plotted against the action of histamine. Right shifts of the antagonist-response curve obtained for the histamine antagonists are used to construct the SchiId / Arunlaxban plot, 0, and Schild, H.O., Br.J. Pharmacol. 14, 48-58, 1959 / * Regression Log / dr - 1 / depending on Log / B /, where dr is a response with equal activity in the presence and absence of an antagonist and / B / is the molar concentration of the antagonist, allows to estimate pAp »this is the value of the negative log concentration of the antagonist that shifts the control histamine concentration curve - answer 2 x to the right. Compound I Promethazlne 3- / 2-carboxyethyl / -10- / 2-dlmethylamino-propyl / phenothiazine 4- / or 1 / - (2-carboxyethyl) -10- (2-dimethylamylamino-propyl) -phenothiazine acid, N "7-chloro-10- (2-dimethylaminopropyl) - I 2-phenothiazinyl-acetic acid I 1" ° 10 - (2-dimethylaainoethyl) - N -7-methyl-2-phenothiazinyl-7-acetic acid. £ ~ 10- (2-dimethylaminoethyl) -7-methyl- and 2-phenothiazinyl-7 acetic acid and £ ~ 10- (2-dimethylaminoethyl) -7-fluoro - 1 2-phenotlazinyl-7-acetic 1 2- 10- (2-dimethylamino-propyl) -2-phenothiazinyl- ethyl-2-methylproplonate 1-2-1-10- (2-dimethylamino-propyl / -2-Iphenothiazinyl-7-2 -me Tylopropionic pA2 8.9X 5f2 7.2 8.8 9.1 8.9 8.6 8.5 8.8 B. Barlow, Introduction to Chemical Pharmacology. 2nd, ed, p 363, Wlley, Mew York. 1964 144 516 5 B. In vivo antihistamine activity. Guinea pigs (Hartely, male, 300-3508) are starved for 20 hours and then administered orally or intraperitoneally with test compound * One hour after test compound administration, each guinea pig is placed in a transparent plastic chamber saturated and continuously gassed by aerosol spray of 0.25% histamine. The behavior of guinea pigs for signs of amaphylaxis / e.g. coughing, sneezing, heavy abdominal movements, cyanosis or histamine induced loss of balance. Under the test conditions, the control animals show histamine-induced symptoms after an average of 35 seconds. The BDcq value for protection against histamine is calculated by probit analysis. In this trial, the EDcq value indicates that at this particular dose, 50% of the animals were completely protected during the trial / 1 hour post-treatment / to the action of histamine. Total immunity is defined as the absence of histamine-induced symptoms within 6 minutes in the aerosol chamber / approximately 10 and longer than the onset of histamine symptoms in control animals / * Anaphylactoid reaction studies ... Non-starved Wistar rats were given subjects the compound (intraperitoneally / or orally) 2 hours prior to the administration of formulation 43/80, ie any agent which induces an anaphylactoid reaction. One hour before the administration of this formulation, 5 mg / kg of prepanolol was administered intraperitoneally. Preparation 48 / BO was administered intravenously at 2 mg / kg and the animals were observed for signs of respiratory difficulties. The data was analyzed by the Probit method. The answer was quantified with the dose of the test compound which would prevent the animals from dying at the given time point of $ 50. The above experimental formula did not give positive results with selective antihistamine agents. Rats are also unresponsive to histamine (IV administration) / symptoms of anaphylaxis * Blocking agents of 48/80 are usually classified as inhibitors of anaphylactic mediators or inhibitors of the release of anaphylactic mediators. Although compounds of Formula 1 may be administered alone as harsh chemicals, it is preferable to give them in the form of pharmaceutical preparations. Thus, the compounds of the present invention are formulated into pharmaceutical compositions for both human and veterinary treatment, containing a compound of formula I together with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients. For example, preparations may be made containing the active compound and a sympathomimetic agent such as a pseudo-ephedrine decongestant, an antitussive agent such as codeine, an analgesic, an anti-inflammatory, an antipyretic or an expectorant. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the formulation. • Formulations are formulated in a form suitable for oral, rectal, topical, nasal, ophthalmic or parenteral administration (including subcutaneous, intramuscular and intravenous administration). These preparations may be made into unit dose forms by any of the methods well known in the art of pharmacy. All these methods involve the stage of deposition of the active compound with the carrier, which is one or more accessory ingredients. Typically, formulations are prepared by bringing the active compound into a homogeneous and accurate association with a liquid carrier or a finely divided solid carrier, test both with both, and, if necessary, shaping the product into the desired formulation form. Formulations containing the compounds according to the invention are suitable for oral administration. may be formulated as discrete units such as capsules, wafers, tablets or lozenges, each containing a predetermined amount of active compound (compound of formula I); powder or granules; or a suspension in an aqueous or non-aqueous liquid, such as a syrup, elixir, emulsion, or drink. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. The compressed tablets may be made by compressing in a suitable machine, the active compound in a free flowing form such as a powder or granules, which is optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or dispersant. Molded tablets consist of a mixture of the powdered active compound with any suitable carrier, formed by molding in a suitable machine.144 516 Mina syrup is prepared by adding the active compound to a concentrated aqueous solution of sugar, e.g. sucrose, to which any excipient may also be added. Such excipients may be flavors, a sugar cyclization retarder, or a solubiliser for any other ingredient, such as a polyhydric alcohol such as glycerin or sorbitol, and suitable preservatives. Rectal formulations are formulated as suppositories. a commonly used carrier such as cocoa butter or hydrogenated fats or hydrogenated fatty carboxylic acids. Preparations suitable for parenteral administration are suitably sterile aqueous preparations of the active compound, preferably isotonic with the blood of the recipient. Nasal spray preparations are purified aqueous solutions of the active compound, preservatives and isotonic agents. The pH of such preparations is adjusted to be isotonic with the nasal mucosa. Ophthalmic preparations are similar to those of nasal sprays, except that the pH value is 1 and the isotonic factors are adjusted to the compatibility with the eye. Topical formulations are the active compound dissolved or suspended in one or more mediums, such as mineral oil, kerosene, polyols, or other bases used in the preparation of topical pharmaceutical formulations * It may be desirable to add other excipients as previously mentioned * Apart from the previously mentioned sklanlkas. , preparations containing compounds according to the invention may further contain one or more excipients such as diluents, buffering agents, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants / antioxidants / antioxidants. including / and the like. The compounds of formula I prepared according to the invention were used in medicine for the first time. The invention is illustrated by the following examples. All temperatures are given in ° C. Example I. Preparation of 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine Hydrochloride solution (E) -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine / 1 g / in methanol / 20 ml / containing palladium on charcoal as a catalyst / 100 mg / is stirred in an atmosphere of hydrogen until the setting is complete (9 hours). The catalyst is filtered off and the solvent is evaporated to leave the hydrochloride of the saturated carboxylic acid. It is freed from fine impurities by esterification, then the ester is chromatographed on a silica column, eluting with a chloroform-methanol (50 t1) mixture and hydrolyzing it crude ester * The 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) -phenothiazine thus obtained is crystallized from an ethanol-ether mixture in the form of a cream-colored solid, m.p. 172-173 °. Example II. Preparation of 4- / or 1 / - / 2-carbokeyethyl / -10- / 2-dimethylaminopropyl / phenothiazine Solution / B / -4 / or 1 / -2 / -methoxycarbonylvinyl / -10- / 2-dimethylaminopropyl / phenothiazine / 500 mg / in ethyl acetate / 20 ml / is heated under a hydrogen atmosphere in the presence of a Raney nickel catalyst until the hydrogen is no longer absorbed * The filtered solution is evaporated to give 4- / or 1 / -2-methoxycarbonylethyl / -10- / 2 -durethylaminopropyl / phenothiazine, which is hydrolyzed in an ethanolic-aqueous sodium hydroxide solution * The 4 / or 1 / -2-carboxyethyl / -10- / 2-dimethylaminopropyl / phenathiosin thus obtained crystallizes from isopropanol in the form of colorless needles with a melting point of 155- 157 °. Example III. Preparation of 4'-7-chloro-10- (2-dimethylaminopropyl) phenothiazinyl-2-7 acetic acid. A (Preparation of 4'-bromo-3 "-nitrophenylacetic acid (compound 3a). HKO (20 ml) and HpSO concentrations are mixed * (20 ml) and 4 * -bromophenylacetic acid (21.5 g) is added to the stirred solution in portions over a period of more than 20 minutes, while the reaction mixture is cooled with water, so as to maintain the temperature of the mixture within 50-55 ° C. Nine is heated for 10 minutes at 85 ° C, then it is poured over ice and diluted with HgO. The resulting yellow body is constantly filtered off, washed with HpO, dissolved in a small excess of 2H NaOH and then lost again by the addition of excess concentrated HCl. The precipitate is dried and recrystallized three times from benzene to give compound 3a (1092 g), mp 100-113 °. The results of the analysis are consistent with the indicated structure of a single isomer. 144 516 7 b) Preparation of ethyl 4 * -bromo-3 * -nitrophyl nitrophylacetate (compound 3t). Compound 3a is suspended in ethanol solution (400 ml), triethyl orthoformate (25 al / 1) concentrated H2SO. (2 Al) and heated for 3 hours under reflux. The solvent is evaporated and the residue is dissolved in ether and washed successively with Hp0, 5 * HaOH and saturated solution of Soot * The ether is dried and evaporated to give compound 3b / 35.1 g / v of the mobile yellow orange oil whose spectrum * nmr matches that of the indicated structure. c) Preparation of 4 # * (ethyl 4-chlorophenyl) -3-n-ethylenyl ethane (compound 3c) * mixtures of compound 3b / 896 g / 9 4-chlorothiophsnol / 595 g / and HagCO * / 693 g / in ethanol / 75 ml / mixed for 5.5 hours under a nitrogen atmosphere under reflux conditions, 1 poured into ice-cooled 5% B&OH / 900 ml / 1, extracted with esters / 5 with 100 ml /. The ether extract is washed with 5 * HaOH 1 then dried (MgSO./ 1) evaporated to give compound 3c / 1093 g / as a yellow oil which solidifies / mp 71-82 ° / # whose nmr is as indicated structure. The product is not purified further. * D (Preparation of (7-chlorophenothiazinyl) ethyl acetate (compound 3d). Compound 3c (24.3 g) and triethyl phosphite are heated together for 4 hours under a nitrogen atmosphere under reflux in a deoxygenated condenser. n-propylbenzenes / 200 ml / * Volatiles are removed at 80 ° with a water pump * The remaining dark oil is obtained by flash column chromatography on silica eluted with a mixture of * hexane / ethyl acetate / 6: 1 / * Obtained 691 g of a yellow solid which is recrystallized from ethanol / ethyl acetate (1s1). The product, compound 3d, is a colorless solid (melting point 193-194 °), the nmr spectrum of which corresponds to the proposed structure * Ta The cyclization / rearrangement reaction has been described by Cadogan et al *, J * Chem * Soc * / 1970/2437 * e (Preparation of 4-chloro-10- (2-dimethylaminopropyl) ethyl phenothiazinyl-2-acetate (Compound 3e). Compound 3d. / 4.1 g / 1 Hl-pre-butoxide potassium / 1.52 g / the mixture is stirred for 10 minutes under nitrogen in dry deoxygenated toluene (30 ml). 2-chloro-1-dimethylaminopropane (1.77 g) is added and the reaction mixture is heated for 1 hour at 80 °. A further 1.5 g of potassium 111-butoxides and 1.7 g of 2-chloro-1-dimethylaminopropane are added and stirring is continued and heating for 2 hours. The reaction mixture is diluted with toluene (50 ml), washed with HpO and saturated KeCl * solution is then extracted with dilute HCl, the extract washed once. with toluene, alkalinize (litmus, NH-OH concentrations) and extracted with CHCl. After evaporation of CHCl, 5.85 g of an oil containing various components are obtained (silvered background), EtOH / EtAc 6: 1). This oil fractions Flash column chromatography eluting with EtOAc / BtOH / 12: 1, 8: 1, 5: 1 successively). The title compound 3o is in the form of an oil. An acid maleate salt of 3o is formed, which melts at a temperature after crystallization from ethyl acetate. 158-160 ° / with decomposition / * Its nmr spectrum and CHK elemental analysis results are consistent with the indicated structure. f) Preparation of the " 7-chloro-10- (2-dimethylcaminopropyl / phenothiazinyl-2-7oic acid). A solution of compound 3c / 0.4 g / in concentrated HCl / 10 ml / and HgO / 10 ml / is heated during Steaming for 16 hours * After evaporation of the solvent, a glassy residue remains, which dissolves in propanol-2 and becomes discolored (charcoal). After cooling the solution, the hydrochloride salt is obtained as an almost colorless solid with a melting point of 140 ° (decomposition) The melting point (decomposition) is difficult to reproduce, as it depends largely on the rate of heating * The obtained compound, hydrochloride hydrate, gives the results of elemental analysis CHH nmr and mass spectrometry * are appropriate for the given formula 1 structure * Example IV * Preparation R "10- (2-dimethylaminoethyl) -7-methylphenothiazinyl--2-acetic acid. a / Preparation of ethyl 4f- (4-methylphenylthio) -3i-nitrophenylacetate (compound 4a) The procedure is as in example IIIc except that 4-methylthiophenol is used instead of 4-chlorotlphenol * The crude product compound 4a is yellow solid with a melting point of 78-32 °, the nmr spectrum of which is consistent with the proposed structure * It is used in the next step without further purification. 8 144 516 b / Preparation of / 7-methylphenothiazinyl-2 / ethyl acetate / compound 4b / # Compound this is synthesized from compound 4 & by the method described in example III. This is also the method of chromatography on column 1 recrystallization * The product, compound 4b, is a crystalline solid with a melting point of 189-192 ° f, the nmr spectrum of which corresponds to the indicated structure * c / Preparation of ε ~ 10- / 2-dimethylaminoethyl / Ethyl acetate -7-non-ethylphenothiazinyl-27 (Compound 4c). This compound is prepared as in example Illd using 2-dimethylaminoethyl chloride * The free base is purified by flash column chromatography eluting with EtOH / EtOAc / 1: 10 / «Convert Oil turns into acid maleate salt and crystallizes from EtOAc. The acid maleate of compound 4c, m.p. 146-148 °, is obtained, the nmr spectrum and elemental analysis are consistent with the indicated structure * d (Acid production. 10- (2-dimethylaminoethyl) - 7-methylphenothiazinyl-2-acetic acid * Compound 4c / 0.50 g / is dissolved in 3t5 N HCl / 14 ml / and heated for 10 hours on a steam bath * After evaporation to dryness, the residue is taken up in 2-propanol and discolored /in wood charcoal / and then evaporated again * The residue is triturated with ether until a solid is formed, which is partially purified by dissolving in methanol and adding ethyl acetate and ether * A yellow powder is obtained, the HPIC chromatogram of which shows the presence of significant impurities * Therefore, it is purified by a semi-preparative HPIC method on a Spherlsorb GP column * Co 10 mm with 50 cm with a Brownlec C ^ g protective column, eluting with a mixture of 40 $ MeOH + 0.1% triethylamine and finally 100 $ MeOH + 0.1 $ triethylamine * The title compound is obtained in the form of an indifferent solid with a melting point of 127 * 132 ° (decomposed), the spectrum of which nmr 1 elemental analysis CHN and the mass spectrum are satisfactory, although it still contains at least one unidentified compound ¬ cleaning (background, nmr and mass spectrum) * Example V * Preparation of α-10- (2-dimethylaminoethyl) -7-fluorophenothiazinyl-2 7-acetic acid * a / Preparation of 4f- (4-fluorophenylthio) -3, -nitrile Ethyl-ohenylacetate / Compound 5a / «Proceed as in example IIIc, using 4-fluorothiophenol * The crude product, compound 5a, is a yellow solid with a melting point of 41-18 °, the nmr spectrum of which corresponds to the structure indicated, and which is used without further purification * b / Preparation of (7-fluorophenothiazinyl-2) ethyl acetate / compound 5b / * This compound is synthesized from compound 5a as described in the example lila * Recrystallized product, compound 5b, mp 167-169 ° • has a nmr spectrum consistent with the indicated structure * c (Preparation of β "10- (2-dimethylaminoethyl) -7-fluorophenothiazinyl-2) ethyl yacetate (compound 5c) * This compound is obtained in the form of an oil, synthesizing from compound 5b by the method described in the example Illd and purification by flash column chromatography on a silica column eluted with ether * Its nmr spectrum and mass spectrum are consistent with the indicated structure * d) Preparation of α "10- (2-diaminoethyl) -7-fluorophenothiazinyl-2-7-acetic acid * Zwi The row 5c (0.6 g) is suspended in a mixture of dioxane (3 ml) and 1N NaOH (6 ml) and the mixture is heated under reflux for 24 hours, then evaporated, acidified with 1N HCl (8 ml) and evaporates to dryness * The residue is boiled in propanol-2/30 ml / * After filtration and evaporation of the solvent, the hydrochloride of compound N is obtained as a gummy mass that does not want to crystallize * It is purified by HPIC chromatography using a 10 mm x 50 cm column Spherlsorb CP * C ".q / reverse phase" and Brownlec C ^ q protective column eluting with 50% MeOH and 0.1% triethylamine * A neutral solid is obtained, which after recrystallization from ethyl acetate has a melting point of 141- • Its elemental CHN analysis, nmr spectrum and mass spectrum conform to the structure indicated. 144,516 9 Example TI. Preparation of 2- (2-dimethylaminopropyl) phenothiazinyl-2 (-2-methylpropyl) acid • Preparation of 2- (4-bromophenyl) -2-mefcylopropionic acid (compound 6a) * Preparation of the title compound ethyl ester as described in J * Aa * Chem * 3oc * 93 • 6877-87 / 1971 /. This ester / 54 * 1 g / is heated for 5 hours under reflux in a solution of ethanol / 50 ml / and NaOH ~ 40 gf in H 2 O / 400 ml / 7 * mixture, the reaction is cooled to room temperature , washed with pentane and acidified with concentrated HCl (100 ml). Compound 6a is recovered in the form of a white powder, mp 121-124 ° *, the nmr spectrum of which corresponds to the indicated structure. b) Preparation of 2- (4-bromo-3-nitrophenyl) -2-methylpropionic acid (compound 6b). This compound is prepared from compound 6a by the method described in Example Illd. Compound 6b is obtained as a solid * with a melting point of 167-171 ° * Its nmr spectrum is consistent with the indicated structure * c / Preparation of ethyl 2- / 4-bromo-3-nitrophenyl / -2-methylpropionate / compound 6c / Compound 6c obtained from compound 5b the method described in example IHb. The obtained compound 6c is a solid * melting at a temperature slightly above room temperature * Its nmr spectrum matches the structure indicated and it is used without further purification * d (Preparation of 2-methyl- (3-nitro-4-phenylthiophenyl) - ethyl propionate (compound 6d) * The synthesis of this compound is carried out using thiophenol and the compound 6c * product * compound 6d * is obtained in quantitative yield as a viscous yellow oil * which does not solidify * Its chromatography is essentially homogeneous * and the spectrum is nmr according to the indicated structure * yes * it is used without further purification * e / Preparation of 2-methyl-2- / phenothiazinyl-2 / ethyl propionate / compound 6e / # This compound is prepared from compound 6d, cyclization method described in the example Illd and is purified to visible homogeneity and column chromatography * The product does not crystallize * but its nmr matches the indicated structure * and it is purified without further purification * f) Preparation of 2- "10- / 2-dimethyl Ethyl oaminopropyl (phenothiazinyl-2w7-2-methylpropionate) compound 6f * This compound is synthesized from compound 6e (possibly in the form of an acid) by an alkylation reaction according to the example of Ule * The free base compound is in the form of an oil * from which A crystal salt is prepared and crystallized from a mixture of ethyl acetate / hexane hydrate of 6f maleate acid, m.p. 107-110 °. Its elemental analysis CHH * spectrum 1 mass spectral analysis are consistent with the indicated structure * g / Preparation of 2- ^ αv10- / 2-dimethylaminopropylO / phenotlazinyl-2 ^ 7- 2-methylpropionic acid. This compound is synthesized by alkaline hydrolysis / NaOH (compound 6f method described in Example Yd) The crude hydrochloride salt * obtained after acidification * by evaporation and refluxing in 2-propanol is solidified by trituration with ether and then recrystallized from a mixture of methanol / ethyl acetate * to give the hydrochloride of the compound with a melting point 192-196 ° (with decomposition), whose elemental analysis of CHH, the nmr spectrum and the results of the mass spectral analysis are in accordance with the indicated structure. Example Tli. Preparation of 2-. aethyl proplon. a) Preparation of ethyl 2- ^ 10- (3-dimethylaminopropyl) phenothiazilyl-2 ^ -2-methylpropionate (compound 7a). Compound 6e (2 * 9 g) is dissolved in dry dimethylfornamide / 30 ml / * and then KOBut is added / 1.15 g / and LU / 0 * 20 g / The total is heated under nitrogen to 80 ° C 1 adds 3-dimethylaminopropyl chloride / 1 * 2 g * freshly released from the hydrochloride salt / * After heating for 30 minutes at 80 ° C, a further 0 * 24 g KOBut and 0 * 7 g 3-dimethylaminopropyl chloride * are added and after 30 minutes the last 0 * 34 g KOBut * additions After a further 30 minutes the reaction mixture is poured into water and extracted with CHgClg. Evaporation of CHoClp gives 4 * 3 g of a viscous oil * which is flash chromatographed on silica * eluting with a mixture of CH 2 Cl 2 MeOH * 96: 4 * 2 * 8 g of compound 7a are obtained as an oil * which is clearly homogeneous * which it is found on the basis of thin layer chromatography that tic * and the nmr spectrum of which corresponds to the indicated structure * 10 144 516 b / preparation of kv / asu 2- (ToV3-dimethylaminopropyl) phenothiazinyl-2-methylpropionic compound. This compound is prepared by base hydrolysis (on OH) of compound 7a by the method described in Example Vd. The hydrochloride salt crystallizes from an aqueous HCl solution as a hydrochloride hydrate, which has a melting point of 126 ° (decomposition), the melting point is not reproducible, because it depends to a large extent on the heating rate. Elemental analysis CBN nmr spectrum and mass spectral analysis are consistent with the indicated structure and formula • Claims 1. A method for the preparation of new aromatic compounds of general formula 1, in which R- is a divalent saturated or unsaturated group of an aliphatic hydrocarbon with 1-7 carbon atoms or a single bond: Rp and Rot the same or different, mean each hydrogen atom, a C-C-alkyl radical or together with the nitrogen atom form a pyrrolidine ring: R. is a hydrogen atom, a halogen atom or a C 1-6 -alkyl group optionally substituted with 1-3 halogen atoms and A is a C group - 4-alkylene, optionally in the form of a salt, / C 1 -C / alkyl esters, unsubstituted amides or N- / C-C / alkyl amides or hydrates or 0-m alkanolates, known as In other words, the compound of formula III, in which R1 and R are as defined above, and the group CORg is an ester or amide group, is alkylated with a compound of formula LA-NRpR4, in which A, R2 and Ro have the above-mentioned and L is a leaving group and the resulting compound of formula I is optionally converted by reduction of one or more double bonds or ester deesterification or amide hydrolysis. 2. The method according to claim 2. The process of claim 1, wherein for the preparation of the compound of formula (I) wherein R- is the group (CH2) where n is an integer of 0-3 or R- is the group CH = CH or CH / CBU / (CH2) mt where m is 0 or 1, or the group -C / CH2 / g and the other symbols have the meaning as defined in claim 1, a compound of formula III in which the substituents are as defined above is alkylated, in the presence of a base, at a temperature of 0-150 ° C in an inert solvent *. A compound according to claim 1, characterized in that for the preparation of a compound of formula 1, wherein NR5 R-z represents dimethylamino or diethylamino, and the other symbols have the meaning given in claim 1. 1, the compound of formula III in which the substituents are as defined above is alkylated, in the presence of a base, at a temperature of 0-150 ° C in an inert solvent. 4 * Method according to claim For the preparation of a compound of formula 1, wherein R- is methyl, chlorine or fluorine, and the other symbols have the meanings given in claim 1, 1, a compound of formula III is alkylated in which the substituents are as defined above, in the presence of a base having a temperature of 0-150 ° C, in an inert solvent. 5. The method according to p. A compound according to claim 1, characterized in that for the preparation of a compound of formula I, wherein A represents an ethylene or n-iso-propylene group, and the other symbols have the meaning given in claim 1. 1, the compound of formula III in which the substituents are as defined above is alkylated, in the presence of a base, at a temperature of 0-150 ° C in an inert solvent. 6. The method according to p. 2. A process as claimed in claim 1, characterized in that in the preparation of 2- (2-dimethylamethylpropyl) phenotlazinyl-2 (-2-methylpropionic acid) 2- (2-phenothiazinyl) -2-methyl propionic acid is alkylated at a temperature of 0-150 ° C, in the presence of alkali, in an inert solvent. 144 516 K2 "3 MODEL 2 R1C02H R ^ OjH MOI lGl-RiCOR6 H MODEL 3 HS R, MODEL 4144 516 O + 'coo 0 LU O 5 LU XOZX Printing Workshop UP PRL. Mintage 100 copies Price PLN 220 PL

Claims (6)

Claims 1. A method for the preparation of new aromatic compounds of general formula I, in which R- is a divalent saturated or unsaturated group of an aliphatic hydrocarbon with 1-7 carbon atoms or a single bond: Rp and Rot, the same or different, denote each hydrogen atom, the radical C -C -alkyl or together with the nitrogen atom form a pyrrolidine ring: R. is hydrogen, halogen or C 1-6 alkyl optionally substituted with 1-3 halogen atoms and A is C-4 -alkylene, optionally in the form salts, esters of / C 1 -C / alkyl, unsubstituted amides or N- / C-C / alkyl amides or hydrates or 0-m alkanolates, characterized in that a compound of general formula 3, wherein R 1 and R are as defined above, and the group CORg is an ester or amide group, is alkylated with a compound of formula LA-NRPR5, in which A, R2 and Ro are as defined above and L is a leaving group, and the resulting compound of formula 1 is optionally subjected to a conversion reaction of pr by reduction of one or more double bonds or ester deesterification or amide hydrolysis. 2. The method according to claim 2. The process of claim 1, wherein for the preparation of the compound of formula (I) wherein R- is the group (CH2) where n is an integer of 0-3 or R- is the group CH = CH or CH / CBU / (CH2) mt where m is 0 or 1, or the group -C / CH2 / g and the other symbols have the meaning as defined in claim 1, a compound of formula III is alkylated in which the substituents are as defined above, in the presence of a base, at 0-150 ° C, in an inert solvent * 3. The method according to p. A compound according to claim 1, characterized in that for the preparation of a compound of formula 1, wherein NR5 R-z represents dimethylamino or diethylamino, and the other symbols have the meaning given in claim 1. 1, the compound of formula III in which the substituents are as defined above is alkylated, in the presence of a base, at a temperature of 0-150 ° C in an inert solvent. 4. * Method according to p. For the preparation of a compound of formula 1, wherein R- is methyl, chlorine or fluorine, and the other symbols have the meanings given in claim 1, 1, a compound of formula III is alkylated in which the substituents are as defined above, in the presence of a base having a temperature of 0-150 ° C, in an inert solvent. 5. The method according to p. A compound according to claim 1, characterized in that for the preparation of a compound of formula I, wherein A represents an ethylene or n-iso-propylene group, and the other symbols have the meaning given in claim 1. 1, the compound of formula III in which the substituents are as defined above is alkylated, in the presence of a base, at a temperature of 0-150 ° C in an inert solvent. 6. The method according to p. 2. A process as claimed in claim 1, characterized in that in the preparation of 2- (2-dimethylamethylpropyl) phenotlazinyl-2 (-2-methylpropionic acid) 2- (2-phenothiazinyl) -2-methyl propionic acid is alkylated at a temperature of 0-150 ° C, in the presence of alkali, in an inert solvent. 144 516 K2 "3 MODEL 2 R1C02H R ^ OjH MOI lGl-RiCOR6 H MODEL 3 HS R, MODEL 4144 516 O + 'coo 0 LU O 5 LU XOZX Printing workshop UP PRL. Mintage 100 copies. Price PLN 220 PL